{"text": "In the published version of this article , the Y-aThe authors apologize for the error in the published article."}
{"text": "Retraction note:Malaysian Journal ofMedical Sciences has been requested by the administrator of the youthin mind in the UK who is in charge of the SDQ questionnaire becausea translation of the Malay Parent-version Questionnaire into the Malay Children-versionwas done and published without the necessary authorisation via the author of themanuscript, Dr Idayu Badilla Idris and co-authors.The retraction of the manuscript titled above from the Editor-in-ChiefMalaysian Journal of Medical Sciences"}
{"text": "We theoretically investigate the optical bistability in the metal nanoparticles-graphene nanodisks-quantum dots hybrid plasmonic system in the infrared regime of the electromagnetic radiation. The quantum dot is considered to be a three-level atomic-like system of  The terahertz (THz) spectral range of the electromagnetic radiation, of the wavelength range between 1 mm to 30 \u03bcm has attracted much attention due to its wide potential applications, including sensing , spectroThe unique electronic structure of graphene resulting from the linear dispersion relation near the Dirac points provides an ultrawideband tunability as a result of Pauli blocking ; graphenl nature . Similarl nature . Moreoveplasmons .Recently, giant and controllable self-Kerr nonlinearity has been demonstrated in the metal nanoparticles-graphene nanodisks-quantum dots (MNP-GND-QD) hybrid system at the optical region of the electromagnetic radiation . ConsequIn the present work, we theoretically investigate the THz optical bistability in the MNP-GND-QD hybrid system situated in a unidirectional ring optical cavity. The QD is modeled as a three-level atomic system interacting with probe and control fields. Due to the unique properties of graphene plasmons including tunability via doping levels and long propagation distances, GND is utilized as a resonator of the system. The MNP is used to support the plasmons of GND and provide more options for optical control. Under the boundary conditions of the unidirectional optical ring cavity, we solve the time evolution of the density matrix elements, that describe the dynamics of the confined nonlinear plasmonic system, with the propagation equation of the probe field circulating inside the cavity. The effect of the parameters of both the system setup and the interacting fields are investigated in order to achieve the ultralow threshold of the controllable optical bistability demonstrated by our proposed plasmonic system at the THz regime of the electromagnetic spectrum.We consider the MNP-GND-QD hybrid system embedded in a fused silica substrate as shown in given as : (1)HRWA\u0394p\u03c311+\u03942\u03c3\u2212\u210f\u03a9p\u2202Ep\u2202tL in the steady-state limit [By solving the propagation equation of the probe field with the boundary conditions of a perfect tuned cavity of length te limit :(6a)Ep is derived by using the dipole-dipole interaction Hamiltonian that is sensitive to the distances between the components of the system, we discuss in n in Ref  is obtaiThe impact of the MNP size on the optical bistability behavior is examined in To conclude, compared to the relevant studies of the optical bistability behavior in the THz for simpler systems such as graphene-coated cylindrical core-shell nanoparticles , graphenWe have studied the optical bistability behavior in the MNP-GND-QD hybrid plasmonic system at the THz frequencies. We have found that the width of the hysteresis loop and the thresholds of the optical bistability can be controlled by the system setup in addition to the detuning and strength of both the probe and control fields. The optical bistability of our proposed system shows a high sensitivity to the detuning of the probe field and the center-to-center distances between the components of the system. Moreover, our plasmonic system has demonstrated ultralow optical bistability thresholds, implying that the proposed MNP-GND-QD hybrid plasmonic system can be employed to construct efficient controllable optical bistable devices that are also used as all-optical switches and optical transistors as well as medical biosensors. We hope that our study will stimulate future experimental investigations of the optical bistability in the MNP-GND-QD hybrid system which contributes a better understanding of this novel system and its nonlinear potential applications."}
{"text": "S-left-semimodule monad S. We show that the composition of almost the monad of convex subsets previously introduced by Jacobs: the only difference consists in the absence in Jacobs\u2019s monad of the empty convex set. We provide a handy characterisation of the canonical weak lifting of We describe the canonical weak distributive law"}
{"text": "In the age of the coronavirus epidemic, the implementation of urgent surveillance measures is sorely needed due to the lack of treatment for coronaviruses and the risk of transmission during the incubation period.The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is a current topic of investigation and the extent of transmission from individuals who are asymptomatic or within the incubation period remains to be understood . The impA recent single center report from Italy provided the first epidemiological data on the skin's involvement in 88 hospitalized patients with COVID-19 . EighteeShortly thereafter, in a Chinese series of seven critical COVID-19 patients, acral ischemia presenting as cyanosis of fingers and toes with blisters and gangrene was reported in all subjects and correlated to an hypercoagulative state secondary to viral infection .Presently, an unusual occurrence of acral ischemic lesions is being reported in Italy in a growing number of apparently healthy children, adolescents, and young adults. Whether these lesions could be due to virally induced microvascular thrombosis and endothelial damage remains speculative and is supported by positive viral swabs in two cases and by a suspicious family history in the remaining reports .In our routine clinical practice during the COVID-19 outbreak, we are observing a growing number of post viral cutaneous eruptions in apparently healthy individuals in the second or third decade of life that we feel is remarkable compared to the usual local epidemiology of this season. We observed multiple rounded erythematous-violaceous lesions appearing on the dorsal and palmar aspect of the fingers  of adoleIn the current outbreak, and considering the predicted high rate of asymptomatic cases, we wondered if these cases should be tested for the presence of novel SARS-CoV-2, as the serology to commonly associated viral agents is negative. However, due to a current shortage of diagnostic tests related to an ongoing emergency we could not perform a diagnosis of SARS-CoV-2 infection.It is remarkable to notice that these virally induced immune-mediated skin eruptions apparently occur in patients that have negligible symptoms of a systemic viral disease. These observations hint at the possible role of specific genetic factors that, while a predisposition to the development of skin eruptions, may protect from severely symptomatic presentations of coronavirus infection.In our current cases of atypical skin eruptions, in which a relationship with conventional viral agents has been ruled out by laboratory testing and clinical history, molecular testing with PCR could be performed on pharynx swabs to support the hypothesis of a possible association with the novel coronavirus. Forthcoming rapid and specific serum assays are expected to aid in the identification of asymptomatic carriers, which is key to controlling the spread of disease. In conclusion, highlighting a relationship between SARS-CoV-2 and virus-induced skin conditions may help identify asymptomatic carriers that are a critical source of inter-human transmission.MA conceived the idea. AS designed and drafted the manuscript. All authors contributed to the writing of the final version of the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The Emerging Role of the c-MET-HGF Axis in Non-small Lung Cancer Tumor Immunology and Immunotherapy. The correct title is The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy.In the published article the title was incorrectly given as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Psychological sense of community plays an important role in the wellbeing of older adults, especially in cultures that revolve around community involvement and support. In 2017, Hurricane Maria devastated Puerto Rico, deeply altering community structure and social life. This study draws on the Ecological Theory of Aging to test the proposition that older adults\u2019 sense of community is associated with self-assessed quality of life two years later. We conducted face-to-face interviews with a non-probability sample of 154 community-dwelling adults aged 60+ in Puerto Rico. We measured sense of community with the Brief Sense of Community Scale (BSCS)  and quality of life (QOL) with the EUROHIS-QOL 8-item index . We used multiple linear regression to test the association of sense of community and quality of life while controlling for relevant covariates. Higher levels of sense of community were associated with better quality of life , while increased mental health symptoms  and poor self-rated health  were associated with lower quality of life. Findings indicate that sense of community is an important contributor to older adult\u2019s quality of life in Puerto Rico, perhaps in part due to cultural and age-related factors. Moreover, sense of community may serve as a protective factor against adverse outcomes after large scale natural disasters. Researchers should continue to examine this association while advocating for and developing policies and programs that promote older adults' sense of community in post-disaster contexts."}
{"text": "We also summarized recent advance of PEGylated lipid-based siRNA delivery systems and included some successful research works in this field.RNA interference (RNAi) technology has become a powerful tool in application of unraveling the mechanism of disease and may hold the potential to be developed for clinical uses. Small interfering RNA (siRNA) can bind to target mRNA with high specificity and efficacy and thus inhibit the expression of related protein for the purpose of treatment of diseases. The major challenge for RNAi application is how to improve its stability and bioactivity and therefore deliver therapeutic agents to the target sites with high efficiency and accuracy. PEGylated lipid-based delivery system has been widely used for development of various medicines due to its long circulating half-life time, low toxicity, biocompatibility, and easiness to be scaled up. The PEGylated lipid-based delivery system may also provide platform for targeting delivery of nucleic acids, and some of the research works have moved to the phases for clinical trials. In this review, we introduced the mechanism, major challenges, and strategies to overcome technical barriers of PEGylated lipid-based delivery systems for advanced target delivery of siRNA  Since antisense oligonucleotides (ASOs) have proven to be efficient drugs for treatment of certain diseases by complementary base pairing to target mRNA to inhibit protein expression or splicing pre-mRNA to mature mRNA , till noin vivo. In previous work, the PEGylation on the surface of liposome for siRNA was well introduced to illustrate the effects in different kinds of liposomes  into short RNA duplexes as shown in of siRNA .in vivo circulation. It is reported that naked siRNA is subject to degradation and the half-life is no more than 5\u00a0min in plasma  formed nanoparticles, which contain a highly condensed DNA core of polycation and then encapsulated DNA/polycation cores with lipids around its surface. This formulation process is shown in Lipid\u2013calcium\u2013phosphate and siRNA complex , which could show higher tumor accumulation and gene silencing efficiency. With the development of this field, the strategy of PEG cleavable could be widely used in the designing of gene delivery system to improve the ability of targeting and endosomal releasing of siRNA  were first developed in 2001 . The strLipid nanoparticles (LNPs) which contain siRNA and ionizable cationic lipids have proven to be effective in delivering gene materials to target sites. Some of them were proven to be effective in clinical trials . The ionLipid-based nanoparticles have the potentials to be further used in clinical treatment. siRNA delivery and variety of lipid-based nanoparticles are developed in recent years. It is reported that mono-disperse precise carriers assemble by using the forming materials which conjugated two oleic acids to cationizable oligominnoamide, and the targeting anchor atherosclerotic plaque-specific peptides can couple to the end of the synthesized T-sharp configuration lipo-oligomers to recognize the targeting cell. Several apoptotic peptides are selected to conjugate to the siRNA by disulfide linkage to enhance apoptosis of the diseased cells . Lipid-bin vivo transfection , 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and cholesterol forming anionic liposomes could coat these positively charged siRNA/polycation complex core to assembly lipid membrane on the surface. This method could reduce the surface charges to avoid toxicity .via H-bonding and \u03c0-\u03c0 stacking with relative low toxicity, were applied to encapsulate 3\u2032,3\u2033-bis-peptide-siRNA (pp-siRNA) to form nanoparticle. DSPE-PEG-cyclic Arg-Gly-Asp (cRGD) was post-inserted to this nanoparticle to improve the ability of recognize target cells express integrin \u03b1v\u03b23 to accumulate in tumor tissue with high specificity. The result shows that this nano carrier could also help siRNA to escape from lysosome to avoid siRNA degradation  liposome need series of processing with limited loading efficiency . The devradation . By the herapies .Cationic lipids were most used in the formulation of lipid-based nanoparticles in the delivery of siRNA. Most of the nanoparticles are comprised of cationic lipids, neutral lipids, and gene materials in oligonucleotides delivery due to the electrostatic interaction of cationic lipids and oligonucleotides can provide feasibility to encapsulate these nucleic acids. Cationic lipids help the lipid-based nanoparticles loaded with siRNA to be absorbed on the surface of target cells based on the positive charges and to escape from endosomes after being trapped . Howeverin vivo, as mentioned above, most of these lipid-based nanoparticles were administrated systematically, so how to keep these nanoparticles stable to avoid releasing siRNA before reaching the target place and help these nanoparticles to release in the target site are the key factors. The common strategies are the modification of PEG on the surface of nanoparticles and optimization of the sizes and distribution of these nanoparticles to help with long half-life in vivo. For disease cell reorganization, the targeting molecules were selected and modified on the surface of lipid-based nanoparticles to enhance the attachment of the targeting cells.After formulating siRNAs with lipid forming nanoparticles, which should be stable enough before application in vivo. However, the increased proportion of PEG on the surface of the lipid-based nanoparticles may reduce the mechanical stability and induce the dissociation. PEG can form a mushroom conformation or a brush-like conformation with different degree of polymerization (N), monomer size (a), and distance of two grafting sites, which can be described as the radius of the random coil -derived peptide, can also be used in the design of lipid-based nano-vesicles to help with endosome escaping processing . Most ofFor endosome escaping, the degradation should be taken into consideration. It not only affects the releasing of siRNA but also is related to biocompatibility. It is reported that designing of precise enzymatic cleavable smart lipid-based nanoparticles may provide new solution for enhanced target delivery of siRNA with relative low toxicity induced by materials. To reduce the toxicity of amphiphilic molecules accumulated to lysosomes and other intracellular organelles, the carriers forming materials can be synthesized as cationic lipo-oligomers containing amino acids with precise enzymatic cleavage sites which can be degraded to low toxicity fragments by endolysosomal enzymes to facilitate the excretion. This research work provided possibility for incorporating new motifs in rational design lipo-oligomers to achieve safe and efficient siRNA delivery .The toxicity of the lipid-based nanoparticles for delivery of siRNA is critical to turn research work to clinical applications. The toxicity of the lipid-based nanoparticles for siRNA delivery is mainly caused by usage of cationic lipids and also the immune response from siRNA . siRNA cAs discussed above, these factors may affect the targeting delivery efficiency of siRNA after administration. The desired requirements for delivery of siRNA by lipid-based nanoparticle are summarized in From the webpage of Food and Drug Administration (FDA), more than 30 RNA-based therapies are in clinical trials. Although the development of siRNA drugs experienced a hard time, the approved lipid-based RNA drug patisiran is very inspiring . The DliLipid-based nanoparticles are widely used in targeting delivery of nucleic acids and function as a promising platform in the generation of more siRNA drugs. In the last decade, more efforts have been put to the discovery of the mechanisms, delivery pathways, biological barriers and solutions, and methods for evaluating the behavior and performance of the lipid-based nanoparticles. Although great progress has built in lipid-based siRNA delivery system, we still need to put much more effort in turning these research work to practical applications. It is important to learn more about the relationship between \u201cstructure\u2014activity\u201d of the lipids to balance the silencing efficiency and biocompatibility and to know more information for potential toxicity and immunity induced by these materials. To realize the clinical applications of siRNA, more efforts should focus on the design of these lipid-based nanoparticles with safe delivery after administration and the ability to get access to various disease cells with high efficiency and specificity. For further applications, we still need to think about how to develop lipid-based siRNA nanoparticles easily. All of these works will be helpful for advancing the siRNA lipid-based nanoparticles to be more suitable.WY conducted the review and XG wrote the draft while BZ and LC revised the manuscript and helped with the figures. All authors contributed to substantial enhancement of the manuscript.This work was financially supported by the National Science Foundation of China .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Session types describe patterns of interaction on communicating channels. Traditional session types include a form of choice whereby servers offer a collection of options, of which each client picks exactly one. This sort of choice constitutes a particular case of separated choice: offering on one side, selecting on the other. We introduce mixed choices in the context of session types and argue that they increase the flexibility of program development at the same time that they reduce the number of synchronisation primitives to exactly one. We present a type system incorporating subtyping and prove preservation and absence of runtime errors for well-typed processes. We further show that classical  sessions can be faithfully and tightly embedded in mixed choices. Finally, we discuss algorithmic type checking and a runtime system built on top of a conventional (choice-less) message-passing architecture."}
{"text": "The majority of self-perceptions of aging (SPA) research uses either a combination of the Age-related Cognition (AgeCog) scales of Ongoing Development and Physical Loss, or the Attitudes Towards Own Aging (ATOA) subscale to assess views on aging. Although these scales are used interchangeably, the valence (positive/negative) and the specificity of the view on aging  being assessed are not consistent. This study investigates how different measures of SPA relate to one another and whether they differentially predict various types of health outcomes . Data from the 2008 and 2014 waves of the German Aging Survey , a population-based representative survey of adults aged 40 to 95, was used to examine the relationship between the AgeCog scales and the ATOA subscale, as well as the differences in the types of health outcomes each predicts. The correlations between the AgeCog scales and the ATOA were higher than the correlation between the AgeCog scales (p < .001). The AgeCog scale of Ongoing Development significantly predicted psychological health outcomes across a six-year period, while the AgeCog scale of Physical Loss and the ATOA subscale predicted both physiological and psychological health outcomes. Evidence supports using the AgeCog scale of Ongoing Development to predict domain-relevant, psychological health outcomes. However, the multidimensionality of SPA is best measured by the ATOA subscale or a combination of the two AgeCog scales. Both forms of measurement were found to maximize the amount of explained variance for psychological and physiological indicators of well-being and ill-being."}
{"text": "Antibiotics Editorial Office has taken the decision to retract the paper with the consent of the authors. The authors assert that the findings, that vanillic acid exerted a significant antibacterial activity against carbapenem-resistant Enterobacter cloacae (CREC), are nevertheless reliable [The authors have been made aware that two figures were published in two papers: Figure 5A in paper  is duplireliable .Antibiotics Editorial Office and authors apologize to the readers of Antibiotics for any inconvenience caused.The Editor-in-Chief has checked the case and communicated with the authors. The decision to retract has been taken in agreement with the authors of the paper . The AntTo ensure the addition of only high-quality scientific works to the field of scholarly publication, this paper  is retra"}
{"text": "Transparency Statement is required to ensure full transparency of the previous review process and to prevent any perception of a conflict of interest.Due to the addition of the published article to the Research Topic \u201cFeed-forward and Feed-back Processing in the Cerebral Cortex: Connectivity and Function,\u201d the inclusion of the following This manuscript was published prior to the launch of the Research Topic\u201d Feed-forward and Feed-back Processing in the Cerebral Cortex: Connectivity and Function \u201cfor which the handling Editor and the author are co-Editors. The handling Editor and the author confirm the absence of any collaboration during its review process.\u201d\u201c"}
{"text": "Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in, the title should be Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in First-Episode Schizophrenia Patients.There is an error in the article title. Instead of The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Older adults with comorbid dementia and cancer is an increasing phenomenon with the aging population worldwide. Caregivers of these older adults might have a totally different and unique end-of-life caregiving experience. This is because all physical and behavioral signs and symptoms of dementia and cancer may interact with each other and complicate the caregiving experience. The aims of this study was to understand and examine the end-of-life caregiving experiences for older adults with comorbid dementia and terminal cancer from the perspective of family caregivers. Twenty-one caregivers were invited to participate in a semi-structured interview that examined the end-of-life caregiving experiences, its impact and how they coped with the challenges they faced. The interviews were transcribed and analyzed using interpretative phenomenological analysis. The essential meaning of the phenomenon is understood as \u201cgrieving thrice, suffering dually and becoming one\u201d, characterized by how caregivers understood the meaning of togetherness after going through the time of recurring losses from dementia through cancer to death and experiencing ambiguous sufferings dually with their loved one. Ambiguous sufferings were not \u201cthere\u201d before the diagnosis of cancer but emerge in the context of comorbid dementia and cancer and in the connection with the caregivers making interpretation and appraisal of their internal and external resources. These important findings fill in the knowledge gap in the literature related to end-of-life caregiving experience for older adults with comorbid dementia and cancer; and may guide the development of appropriate interventions to support the older adults and their caregivers in a holistic approach."}
{"text": "Background: The telehealth approach offers enhanced service delivery for older patients living in rural areas. Purpose: We conducted a pilot study to evaluate the feasibility of using the Zenbo robot to improve the quality of care of elderly individuals with dementia. Methodology: In this study, we developed a digital solution on service robots and smart devices, which can leverage the capacity of the user-friendly interactive interface and digital dialog system. A group of eleven volunteered older adults was selected for this study. To assess the likability and acceptance of the Zenbo, we conducted a one-on-one (robot vs human) pilot study in our long-term care stations. Each participant engaged in conversational interactions for five consecutive days and completed a survey of 12 questions about the experiences they had with the Zenbo, at the beginning and the end of the study respectively. Results: Subjects with lower GDS-15 scores have more positive attitudes toward the robot before the intervention. 27% of older adults had an increase in positive attitudes toward the interaction with the Zenbo robot. With the aid of teleoperated mobile robotic systems at home, the innovative service model can be achieved through telecommunication between primary health professionals or caregivers at remote locations and psychiatrists at the medical center to make the seamless care environment real. Conclusion: The IoT technologies can be used to assist physicians in switching from a hospital-centered model of care to a home-based service for older people with dementia. It merits more future clinical trials and usability tests."}
{"text": "Brazil lacks an Occupational Therapy methodology of action, justifying the cross-cultural adaptation of TAP. Objectives were to adapt TAP reference materials to the Brazilian culture and evaluation of the applicability of the Portuguese version by perceptions of Occupational Therapists (OT) and family caregivers. The methodology used translation, back translation, evaluation of semantic, idiomatic, conceptual and cultural equivalences and pre-test of materials for production in Portuguese. The OT applied the translated version and evaluated its applicability. Caregivers evaluated the social impact of the adapted program. The cross-cultural adaptation process adapted the entire materials program to Portuguese culture. The OT perception is a need to include one session to guide caregivers and to modify the cognitive assessment used. The caregivers pointed out that TAP helps them in understanding and caring for the elderly with dementia. The TAP-BR has been adapted to the Brazilian culture. Part of a symposium sponsored by the Behavioral Interventions for Older Adults Interest Group."}
{"text": "The complete information in the Funding section should have been given as follows (the added information is highlighted in bold):FundingCo-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH - CREATE - INNOVATE (project code: ?1EDK-05479)The present study was funded by the post-graduate programs \u2018Toxicology\u2019 and \u2018Biotechnology-Quality Assessment in Nutrition and the Environment\u2019 in the Department of Biochemistry and Biotechnology at the University of Thessaly. The authors apologize to the co-funders of this study, and to the readership of the Journal for any inconvenience caused."}
{"text": "A 31-year-old male amateur bodybuilder presented with a 2-year history of chronic pain over the sternum and a clicking sensation in the chest wall on movement. Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed no cause for his symptoms. Dynamic ultrasound scan performed at a specialist sports center revealed pseudoarthrosis of the manubriosternal joint (MSJ). After a period of conservative management , he failed to improve and underwent debridement and fusion of the MSJ with plates and screws. At follow-up 23 months later, he remains pain-free and has returned to weight lifting and bodybuilding. Motor vehicle crashes and chest seat belt restraints are the most common causes of sternal fracture. Reports of sternal injury among sportsmen and athletes are less common, however, with fracture resulting from non-contact trauma described in only sporadic cases in the literature \u20135.While surgery for sternal fracture after acute trauma is rare, surgical repair of painful chronic non-union after sternal fracture has been described , as has We describe the management of painful manubriosternal joint (MSJ) disruption in an amateur weight lifter and describe the challenge of diagnosis, pitfalls in imaging, and a technique of repair to render the patient symptom-free and able to resume his hobby.A 31-year-old man, a bodybuilder, presented with a 2-year history of chronic sternal pain and clicking on movement. On examination, he appeared pain-free and had an athletic body with very well-developed muscles of the torso and upper limbs. On the chest wall, a non-tender, bony thickening was palpable at the MSJ. After repeat consultation and a normal thoracic ultrasound scan, computed tomography (CT) and magnetic resonance imaging (MRI) scans were reported to show no abnormality. The patient's symptoms remained, and after 2-years of repeated consultations  and non-locked (2.7 cm) screws to increase stability while permitting initial slight movement with breathing. Autologous bone graft was performed by harvesting cancellous bone from the iliac crest and inserting this into the defect at the MSJ. At the end of the procedure, a stability check was performed with no pathological movement of the MSJ. The patient made an uneventful postoperative recovery and was discharged 7 days later after completion of a course of physical therapy. He was pain-free and without any limitation of movement. He returned to normal activities 2 weeks later. After 1 month, he was regularly lifting weights at preinjury levels. At 23 month follow-up, the patient remains pain-free and has returned to regular exercise and weight lifting.While much has been written about the management of sternal fractures after blunt trauma and non-union after median sternotomy for cardiac surgery, guidance on the management of MSJ pseudoarthrosis remains relatively scarce.The first challenge is in understanding the pathology in the absence of a single traumatic incident:There are two known mechanisms of MSJ dislocation or disruption; both entail the high-energy trauma expected in a motor vehicle crash. The first type of injury results from direct impact with posterior displacement of the body of the sternum. The second and more common injury type follows flexion\u2013compression trauma of the thorax and neck where the neck is forcefully hyperflexed while the chin, clavicles, or ribs displace the manubrium posteriorly.In the absence of a single incidence of major trauma, a careful history of how and when the pain started is important: the mechanism here is repeated low-level trauma or stress on the chest wall. A key feature of the symptoms is clicking of the fibrocartilaginous pseudoarthrosis on movement of the unstable MSJ [also reported by , in a ruThe strength and stability of the MSJ rely on the attachment of the clavicles and first rib to the body of the manubrium and the strong ligamentous attachments of the second ribs to the MSJ. These attachments result in a non-mobile joint. In our patient, years of bodybuilding and weight lifting resulted in these muscles and ligaments stretched repeatedly under considerable force in opposite directions. Cranial stretching involved the attachment of the manubrium to the spine through the first and second ribs and the attachment to the shoulders through the clavicles, the sternal head of the sternocleidomastoid and part of the pectoralis major attached anteriorly to the manubrium and sternum, and the sternohyoid and sternothyroid muscles attached posteriorly to the manubrium. Caudally, stretching in the opposite direction involved the transverse thoracis muscle attached to the posterior surface of the body of the sternum and the strong rectus abdominis attached to the distal part of the sternum . RepetitBilateral first rib fractures and pseudoarthrosis and callus formation at the thoracic inlet were described by Satija et al.  in a 17-Rarer still are reported non-traumatic inflammatory lesions of the manubriosternal synchondrosis reported among athletes complaining of chronic post-exercise pain at the MSJ . While cImaging findings of MSJ dislocation have been described , but pseThe final challenge was in selecting an appropriate operative technique to render the patient pain-free with a fused stable MSJ able to withstand the resumption of sporting activity:While most sternal injuries are managed conservatively, there are three key indications for surgery: (I) the presence of a sternal deformity, (II) loss of sternal continuity for a period of more than 6 weeks, and (III) persistence of chest pain for 2\u20138 weeks after trauma.Surgical fixation of the dislocated MSJ using plates and screws has yielded demonstrably better results than that achieved with wire fixation . The supTwenty-three months after surgery, the patient reports no further clicking or pain, and, on examination, there is no further evidence of movement at the MSJ.ronitbarh@gmail.com.The datasets presented in this article are not readily available because they are stored in confidential patient medical records. Requests to access the datasets should be directed to Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We read with a deep interest Messina et al.\u2019s meta-analysis focusing on goal-directed therapy (GDT) in major visceral/non-cardiac surgery . This reThe 21 studies included in the analysis can be divided into two subgroups: on the one hand those which only protocolized the fluid management and on the other hand those which protocolized a complete hemodynamics bundle of care including fluid management but also vasopressor or inotrope use. The second subgroup of studies (complete bundle of care) appears to have the most beneficial effect on perioperative complications found in the meta-analysis. This subgroup also included five of the only six studies of the meta-analysis which found a significant effect of GDT on perioperative complications by themselves. Moreover, the two studies with the greatest benefit of GDT also included a mean arterial pressure goal and the use of vasopressors and dobutamine in their protocols .In our opinion, the additional benefit of bundle protocols could be explained by the reduction in hypotension episodes occurrence and duration, thanks to a more frequent screening and a more aggressive treatment of these episodes in such protocols. In fact, even if the optimal blood pressure target remains controversial, hypotension is a well-known risk factor for complications in the perioperative period . To corrIn conclusion, all GDT protocols are not equivalent, and complete hemodynamics GDT protocols seem to be more efficient than fluid management only protocols. We suggest exploring the possible benefit of complete hemodynamics GDT protocols on morbidity and mortality in major visceral and non-cardiac surgery."}
{"text": "Working memory (WM) is essential to daily-life activities as it allows maintaining information in the short-term while processing concurrent information , the spatial location (where) and the temporal context of the scene (when). The recall of the spatial or temporal context associated to each element provided a binding score. As compared to a condition without concurrent processing, a verbal concurrent task (memorizing the number of garbage containers) only impaired memory performance of what information and a visuospatial concurrent task  impaired memory performance of what, when, and what-where-when binding information. These results suggest that construction of memory traces rely on verbal and visuospatial maintenance mechanisms and were interpreted as reflecting an involvement of both phonological loop  and the binding of these features. A passive exploration of the environment would allow determining the time-course of the task and controlling temporal parameters and require no control nor planning for traveling. Motor and planning actions required by active traveling can constitute an attentional cost . To enhance ecological validity, events should occur at a non-isochronous pace. Temporal parameters related to to-be-memorized and to-be-processed events  should be fixed and participants' behavior  should be measured. Studies of interdependence between WM processes and other cognitive functions will also benefit from VR paradigms. Long-term memory and semantic representation seem to contribute to refreshing and WM (Loaiza et al., Developing virtual-reality-based paradigms to investigate WM would be useful to identify the neural basis of WM mechanisms in ecological situations. To date, as for behavioral studies, neurophysiological studies of maintenance in WM (Vogel and Machizawa, VR is a powerful experimental tool that allow creating multimodal and naturalistic environments to assess memory for rich and complex information while keeping a strong experimental control. VR will allow testing theoretical assumptions with enhanced ecological validity and interactive fidelity and explore new hypothesis as whether and how traveling affects WM. In addition, VR allows us to examine some of the basic properties of the situated and embodied approach through exact control of methodological factors and go further into the understanding of the role of presence and consciousness in memory. Yet, using VR paradigms in WM studies require to compromise between a strong control of temporal parameters and immersion through active exploring. We recommend fixing temporal parameters of the experiment and to measure behavior, especially response times, as precisely as possible. Future studies will need to determine the minimum immersion and interaction conditions to explore WM with VR to limit the attentional cost of active navigation and facilitate the combined use of VR and neurophysiological measurements. Moreover, some other technical aspects of VR such as the risk of cybersickness, photorealistic level of environment, type of interaction and way of navigation, level and mode of the embodiment need further investigations to test their impact on WM as suggested by some authors in the domain of memory studies Smith, .Future studies should also assess metric properties of VR-based measurements of WM to ensure a good construct validity and reliability. Besides the good equivalence between cognitive performance and physiological responses in the virtual and the real world (Sorita et al., WM is impaired in various populations such as healthy aging, age-related dementia (e.g., Baddeley et al., All authors conceptualized the manuscript. LF wrote the original draft. GP and PP reviewed and edited its intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Cryptococcus neoformans , necessitating an extensive work-up.AK contributed to patient care and drafting of this manuscript. All Authors were directly involved in clinical management of the patient and revision of the manuscript. All authors approved the final version of this manuscript.The authors report no declarations of interest."}
{"text": "The COVID-19 pandemic has exerted considerable impact on public mental health globally. With the pandemic rapidly rising in sub-Saharan Africa including Kenya, there is need to provide evidence to guide the mental health response in the region.The objective of this review is (1) to describe the mental health response to the COVID-19 pandemic in Kenya, guided by the Mental Health Preparedness and Action Framework (2) to offer context specific recommendations for improvement of the mental health response in Kenya. Such information could be useful in decision-making in Kenya as well as in the greater sub-Saharan Africa region.This narrative review is based on information obtained from official government documents released from 13th March 2020, the beginning of the pandemic in Kenya, up to 31st July 2020.The COVID-19 response in Kenya has no formal mental health response plan. There is an unmet need for psychological first aid in the community. While guidelines for the management of mental health conditions during the COVID-19 pandemic have been prepared, implementation remains a major challenge due to a poorly resourced mental health system. There is no mental health surveillance system in place limiting ability to design evidence-based interventions.We propose four key strategies for strengthening the mental health response in order to mitigate the harmful impact of COVID-19 on public mental health in Kenya: (1) preparation of a formal mental health response plan specific to the COVID-19 pandemic with allocation of funding for the response (2) training of community health workers and community health volunteers on psychological first aid to enable access to support for those in need during the pandemic (3) scaling up of mobile health to increase access to care (4) conducting systematic and continuous text message surveys on the mental health impact of the COVID-19 pandemic in order to inform decision-making. The ongoing coronavirus disease of 2019 (COVID-19) outbreak which was declared a pandemic in March 2020 . DiseaseThe World Health Organization (WHO) reports that by far, the largest public mental health impact has been in the form of stress and anxiety, and predicts a rise in depression, suicide and substance use in the coming days . AccordiThe recently developed Mental Health Preparedness and Action Framework (MHPAF)  providesThe cases of COVID-19 are rapidly rising in the sub-Saharan Africa with concerns being raised about its capacity to deal with the pandemic . In addiThe Ministry of Health (MOH) through its Division of Mental Health has nonetheless embarked on efforts to deliver mental health care during the pandemic. Unfortunately, the mental health response is occurring against a backdrop of an under-resourced mental health care system characterized by inaccessible services, an acute shortage of mental health workers and limited funding . This, cThe aim of this review is therefore (1) to provide an overview of the mental health response to COVID-19 by the Government of Kenya guided by the MHPAF. A literature search revealed no paper describing the mental health response to COVID-19 in a sub-Saharan Africa country  to offerThe aim of this narrative review is to describe the mental health response to COVID-19 by the Kenyan government. Documents for review were identified following consultation with experts working at the Division of Mental Health at the MOH. We additionally hand-searched the websites of the MOH and other ministries that were listed by the government as being key in the COVID-19 response  for docuAccording to the MHPAF , the menIn order to manage the distress and anxiety often witnessed during pandemics, the MHPAF  recommenLastly, \u2018preparation and co-ordination\u2019 entails the setting up of COVID-19 specific mental health services. In Kenya, a number of guidelines have been developed by the Division of Mental Health in partnership with professional bodies such as the Kenya Psychiatric Association to ensure provision of COVID-19 specific mental health services. The \u2018Interim guidelines for managing mental health conditions during the COVID-19 pandemic\u2019 [Two other documents that have been prepared by the Division of Mental Health include a guide for health care workers on how to offer mental health and psychosocial support to the public ; and staA major challenge likely to be faced despite the guidelines is that the number of mental health facilities and mental health workers available in Kenya is scarce. For example the psychologist to population ratio is 1:4,600,000. In addition, less than 1% of the public sector health care facilities offer any form of mental health care . Using mThe MHPAF recommends the setting up of a mental health surveillance system during the early phases of the pandemic. This is to ensure systematic and continuous collection of data on mental health in order to assist with planning and designing of appropriate interventions . Data coCurrently in Kenya, research studies seem to be the main strategy for collecting and analyzing information on mental health during the COVID-19 pandemic. The authors are aware of on-going online studies that are being conducted by mental health professionals to investigate the burden of mental health conditions among health care workers.An additional role of the mental health surveillance system is the dissemination of accurate and timely information and to address myths surrounding COVID-19. This has been shown to reduce anxiety and stress during pandemics . AccordiIn Kenya, the Ministry of Information Communication & Technology (ICT) has been tasked with communication functions during the pandemic with focus on dissemination of information on COVID-19, public education and dissemination of health messages . To achiThe MOH has been involved in providing information on COVID-19 to the public. Specifically, the MOH provides daily situation reports on COVID-19 which usually detail the number of cases, deaths, recoveries and offers key public health messages . The MOHDirect funding to the mental health response could not be ascertained. Given the lack of a formal mental health response plan, it is likely that funding for the mental health response is erratic and inadequate.In the post-pandemic period, Kenya should conduct a thorough evaluation of the five components of a mental health response as outlined in the MHPAF. Lessons learnt should be utilized in preparing a well co-ordinated mental health response plan specific for pandemic situations.Preparation of a formal mental health response plan for COVID-19 by the Division of Mental Health with allocation of funding to the response. This ought to be prepared by a team of mental health experts and guided by the five components of the MHPAF.Training of community health workers and community health volunteers on psychological first aid to enable access to psychological support for those in distress during the pandemic particularly at the grassroots level. Such trainings could be administered remotely via video conferencing given the good internet coverage and smart phone penetration rates in Kenya.Scaling up of mobile health to increase access to mental health and psychosocial support for the general public during the pandemic. We propose that the medical doctors manning the 24-hour call centre receive online trainings on mental health and psychological support following which the service is expanded to incorporate delivery of brief psychological interventions to the general public.In order to ensure proper surveillance of the mental health situation during the current pandemic, we propose that systematic and regular surveys are conducted to allow for monitoring of the mental health impact of COVID-19 in Kenya. Major mobile service providers in Kenya have survey platforms that use text messaging. These constitute potential means through which mental health surveillance could be conducted. Given, the existing partnerships between the MOH and local mobile service providers, such an initiative is likely achievable.Kenya has made attempts at instituting a mental health response to the COVID-19 pandemic despite underlying systemic challenges. However, major gaps remain. The country has no formal mental health response plan, there is an unmet need for psychological first aid, access to mental health care and psychosocial support during the pandemic remains a challenge and there is no systematic collection of data on the mental health impact of COVID-19. We therefore propose four key strategies for strengthening the mental health response in Kenya:"}
{"text": "This paper presents a novel method for the automated synthesis of probabilistic programs. The starting point is a program sketch representing a finite family of finite-state Markov chains with related but distinct topologies, and a reachability specification. The method builds on a novel inductive oracle that greedily generates counter-examples (CEs) for violating programs and uses them to prune the family. These CEs leverage the semantics of the family in the form of bounds on its best- and worst-case behaviour provided by a deductive oracle using an MDP abstraction. The method further monitors the performance of the synthesis and adaptively switches between inductive and deductive reasoning. Our experiments demonstrate that the novel CE construction provides a significantly faster and more effective pruning strategy leading to an accelerated synthesis process on a wide range of benchmarks. For challenging problems, such as the synthesis of decentralized partially-observable controllers, we reduce the run-time from a day to\u00a0minutes."}
{"text": "We read with great interest the recent research letter by Thevissen et al. who reported the findings of their international survey regarding the detection of influenza-associated pulmonary aspergillosis (IAPA), with a focus on the use of galactomannan (GM) in broncho-alveolar lavage (BAL) fluid and serum . They no"}
{"text": "Point-of-care (POC) diagnostic services are commonly associated with pathology laboratory services. This issue presents a holistic approach to POC diagnostics services from a variety of disciplines including pathology, radiological and information technology as well as mobile technology and artificial intelligence. This highlights the need for transdisciplinary collaboration to ensure the efficient development and implementation of point-of-care diagnostics. The advent of the novel coronavirus 2019 (COVID-19) pandemic has prompted rapid advances in the development of new POC diagnostics. Global private and public sector agencies have significantly increased their investment in the development of POC diagnostics. There is no longer a question about the availability and accessibility of POC diagnostics. The question is \u201chow can POC diagnostic services be integrated into health services in way that is useful and acceptable in the COVID-19 era?\u201d. Point-of-care (POC) refers to the location where healthcare interventions are carried out. These interventions can be carried out in a variety of settings including in the home, in the office, in the community and at a healthcare facility. Disease diagnosis or testing is one of the healthcare interventions that can be carried at POC and referred to as POC diagnostic services or POC testing. POC testing is performed using various POC diagnostics to enable the near-patient detection and monitoring of disease conditions in order to inform prognoses, guide treatment choices and predict treatment responses . The advThe development of new evidence-based POC diagnostics and the replication of these diagnostics to extend their reach is a global health priority. The appropriate integration of new POC diagnostics approaches is crucial for ensuring desirable outcomes. The implementation of POC healthcare interventions such as POC testing ought to be relevant to each specific context and sensitive to local culture. Factors such as infrastructure, resources, values and the characteristics of the participants can influence the implementation, scalability and sustainability of health interventions. A study conducted in Nigeria calls for community education, screening for schistosomiasis, and the enhancement of diagnostic capacity and strengthening of the capability of health workers through point-of-care diagnostics . Our preResearch suggests the need for training healthcare workers to improve POC diagnostic service delivery in resource-limited settings ,10,11. PThe integration of available POC diagnostics into our current healthcare service needs to be prioritized to aid the prevention and management of current pandemics and in preparation for future pandemics. It is clear that the successful implementation of point-of-care diagnostics requires a transdisciplinary approach. Investment in transdisciplinary research platforms for POC diagnostics is recommended. These platforms can also foster improved awareness and recognition of POC diagnostics services as a standalone healthcare service and development of POC diagnostics curricula for the training of a new cadre of healthcare workers, dedicated to POC diagnostic services. The successful implementation of such platforms requires multidisciplinary and multi-sectorial stakeholder involvement including higher education institutions, diagnostics and information and mobile technology developers and providers as well as implementers and users of POC diagnostic services."}
{"text": "In the US few research initiatives actively engage persons living with dementia (PLWD) as partners in the research. The 2017 Summit actively engaged multiple types of stakeholder groups, including one for Persons Living with Dementia (PLWD), and was the first large-scale US research meeting to actively engage PLWD in planning and conduct of the meeting. The PLWD conducted a self-evaluation of their work that yielded best practices, meeting the need for guidelines for engaging with PLWD. The 2020 Summit presented the opportunity to test best practices. Some were implemented by the group conveners, like use of video-enabled meetings. Others were implemented with the PLWD, including decisions about governance structure for the group. The use of learnings from the first Summit in engaging with PLWD in the following Summit supported refinement of some engagement practices, yielding a list of recommendations for future work."}
{"text": "Maternal and neonatal mortality are disproportionally high in low-and middle-income countries. In 2017 the global maternal mortality ratio was estimated to be 211 per 100\u2009000 live births. An estimated 66% of these deaths occurred in sub-Saharan Africa. Training programmes that aim to prepare providers of midwifery care vary considerably across sub-Saharan Africa in terms of length, content and quality. To overcome the shortfalls of pre-service training and support the provision of quality care, in-service training packages for providers of midwifery care have been developed and implemented in many countries in sub-Saharan Africa. We aim to identify what in-service education and training materials have been used for providers of midwifery care between 2000 and 2020 and map their content to the International Confederation of Midwives\u2019 Essential Competencies for Midwifery Practice (ICM Competencies), and the Lancet Midwifery Series Quality Maternal and Newborn Care (QMNC) framework.A search will be conducted for the years 2000\u20132020 in Cumulative Index of Nursing and Allied Health Literature, PubMed/MEDLINE, Social Sciences Citation Index, African Index Medicus and Google Scholar. A manual search of reference lists from identified studies and a hand search of literature from international partner organisations will be performed. Information retrieved will include study context, providers trained, focus of training and design of training. Original content of identified education and training materials will be obtained and mapped to the ICM Competencies and the Lancet Series QMNC.https://alert.ki.se/) a multi-country study in Benin, Malawi, Tanzania and Uganda.A scoping review is a secondary analysis of published literature and does not require ethical approval. This scoping review will give an overview of the education and training materials used for in-service training for providers of midwifery care in sub-Saharan Africa. Mapping the content of these education and training materials to the ICM Competencies and The Lancet Series QMNC will allow us to assess their appropriateness. Findings from the review will be reflected to stakeholders involved in the design and implementation of such materials. Additionally, findings will be published in a peer-reviewed journal, and used to inform the design and content of an in-service training package for providers of midwifery care as part of the Action Leveraging Evidence to Reduce perinatal morTality and morbidity (ALERT) study, (PACTR202006793783148; Post-results. This scoping review will give a comprehensive overview of the education and training materials used for in-service training for providers of midwifery care in sub-Saharan Africa.To our knowledge, this is the first review that aims to map the content of in-service education and training materials used for providers of midwifery care in sub-Saharan Africa to the ICM Essential Competencies and The Lancet Series Quality Maternal and Newborn Care framework.This scoping review may miss in-service training materials that have not been reported in journals or published in the grey literature.A transformative agenda for maternal and newborn health has been laid out as part of the Sustainable Development Goals (SDGs); \u2018to reduce the global maternal mortality ratio (MMR) to less than 70 per 100 000 live births by 2030\u2019 (SDG 3.1) and \u2018end preventable deaths of newborns, with all countries aiming to reduce neonatal mortality to at least as low as 12 per 1000 live births\u2019 (SDG 3.2).et alThe workforce providing midwifery care is diverse. A study by Hobbs Box 1Definition of provider of midwifery careProviders of midwifery care are competent maternal and newborn health professionals educated, trained and regulated to national and/or international standards. They provide skilled, evidence-based and compassionate care to women, newborns and families.Providers of midwifery care:Promote and facilitate normal physiological, social and cultural processes throughout the childbearing continuum with a continuity of care philosophy.Seek to prevent and manage maternal and newborn complications.Consult and refer to other health services when required.Respect women\u2019s individual circumstances and views, providing sensitive and dignified care.Substantial heterogeneity exists in the length, content and quality of training that different providers of midwifery care receive to prepare them for the workforce, as well as in their ability to perform obstetric and neonatal functions.17It is imperative that in-service education is evidence based, of high quality and promotes both autonomy and multidisciplinary team working. The International Confederation of Midwives20This review is a component of the Action Leveraging Evidence to Reduce perinatal morTality and morbidity in sub-Saharan Africa (ALERT) project .No patient involvedDue to the nature of the research question a scoping review design was chosen to allow for identification and mapping of existing in-service education and training materials. This scoping review follows the steps as outlined by Arksey and O\u2019Malley.2310.1136/bmjopen-2020-047118.supp1Supplementary data10.1136/bmjopen-2020-047118.supp2Supplementary dataThe objectives of our study are to identify, and map in-service education and training materials designed for providers of midwifery care in sub-Saharan Africa from 2000 to 2020. The scoping review aims to address the following questions:What in-service education and training materials are available and have been used for providers of midwifery care in sub-Saharan Africa from 2000 to 2020?How does the content of these in-service education and training materials align with the International Confederation of Midwives Essential Competencies for Midwifery Practice as well as in relation to the Lancet Midwifery Series QMNC framework?The research questions will be assessed, and studies will be selected specific to the following Population, Concept, Study Design and Context criteria presented in Articles will not be eligible for inclusion in the scoping review if:The country in which the in-service education and training has taken place is not located within sub-Saharan Africa.The health personnel who have undertaken the in-service education and training is not considered to be a provider of midwifery care.The content of the in-service education and training does not relate to the provision of midwifery care.The in-service education and training materials were developed before 2000There are no details provided on the content of the education and training sessions.The search strategy will be conducted for all relevant existing literature, without language restrictions, based on search terms relating to the research questions and restricted to the years 2000\u20132020 using the following online bibliographic databases: Cumulative Index of Nursing and Allied Health Literature (CINAHL), PubMed/MEDLINE, Social Sciences Citation Index, African Index Medicus and Google Scholar. Grey literature searches will be performed and include organisations known to be active in global health improvement , International Federation of Gynecology and Obstetrics, International Pediatric Association). The reference list of all eligible studies will be hand-searched to identify any additional relevant studies. Examples of the preliminary search terms and strategy to be conducted in CINAHL are outlined in 10.1136/bmjopen-2020-047118.supp3Supplementary dataFollowing the aforementioned comprehensive search strategy, article titles and abstracts will be screened and eligibility for inclusion assessed independently by two reviewers (A-BM and JW). Any disagreements will be resolved by a third reviewer. Screened abstracts identified for inclusion will have their full texts independently screened by A-BM and JW. As the scoping review aims to map the content of in-service training materials we will not assess the quality of the studies reporting on the in-service training. All studies meeting inclusion criteria will therefore be included in the review. Full-text articles that are excluded at the screening stage will have reasons for exclusion documented. The CovidenceA data collection tool will be used to extract required information see . Informa10.1136/bmjopen-2020-047118.supp4Supplementary dataEducation and training materials identified in the scoping review will be sought by the reviewers. If the reviewers are unable to access the materials, they will contact the authors and ask them to share materials. This will allow original content to be mapped to the ICM Essential Competencies for Midwifery Practice10.1136/bmjopen-2020-047118.supp5Supplementary dataScoping reviews collect and examine data from existing literature and therefore do not require prior ethical approval. This scoping review will give a comprehensive overview of the education and training materials used for in-service training for providers of midwifery care in sub-Saharan Africa. To our knowledge, this is the first review that aims to map the content of education and training materials used for providers of midwifery care in sub-Saharan Africa to the ICM Essential Competencies and The Lancet Series QMNC framework. To ensure future in-service education and training materials are of quality and designed to adhere to the ICM Essential Competencies and the Lancet Series QMNC framework, findings from the scoping review will be reflected to stakeholders involved in the design and implementation of such materials and will be used to inform the development of the ALERT in-service midwifery training package. The authors aim to disseminate findings from the scoping review by publication in a peer-reviewed journal."}
{"text": "One of the first neurological symptoms of a COVID-19 infection that has been frequently described is the loss of smell and taste. A large number of neurological problems following the infection have been reported to date  reportedWe describe the case of a 69-year-old female patient with a moderate  COVID-19This symptom seems to be rare; at the time of submission of the manuscript, 105 patients with COVID-19 infection had been treated in our clinic; no patient had previously reported this symptom. However, in more severe courses of the disease, this pathology may have been disregarded. The two cases previously reported  also seeThe authors declare that they have no competing interests.There was no financial support.The patient gave informed consent to the reporting of her case."}
{"text": "We examine how the presence of long-term care insurance (LTCI) spills over to family outcomes, including informal care, co-residence, and labor supply of adult children. We instrument for long-term care insurance with changes in state tax policies to address the endogeneity of LTCI coverage. We find that for tax-filing families in the top third of the income distribution, LTCI coverage leads to a 50 percent reduction the parents\u2019 perceptions of the willingness of people to care for them in the future, including their adult children. We also find that LTCI causes changes in the residential decisions of adult children, with lower co-residence rates and higher likelihood of living within 10 miles of the parent. We also find small decreases in part-time work among adult children. Our findings provide empirical support for the presence of family spillovers of LTCI on the economic behaviors of family members. Part of a symposium sponsored by the Economics of Aging Interest Group."}
{"text": "This article discusses how decision-makers can be supported to strengthen a culture of prevention. This article presents an example of the United Nations Office on Drugs and Crime\u2019s (UNODC) work to engage with decision-makers to create readiness, demand, and capacity for evidence-based prevention programming among them, particularly in low- and middle-income countries. First, we utilized two of the UNODC\u2019s data sources to describe the context where the UNODC\u2019s prevention efforts take place. Analysis of the first dataset on prevention activities implemented globally revealed a gap in translating evidence into practice on a global scale. The second dataset consisted of UNODC policy documents mandating and guiding global action to address substance use. The analysis showed that at the level of political frameworks, prevention is gradually gaining more attention but is still frequently left in the shadow of health- and law enforcement-related issues. In addition, these guiding documents did not reflect fully the current scientific understanding of what constitutes an effective prevention response. Against this background, the feasibility of the UNODC\u2019s efforts to bridge the science\u2013practice gap in the field of prevention was discussed by presenting the results from the UNODC\u2019s regional capacity-building seminars focused on the role of monitoring and evaluation in prevention programming. The results showed potential of this capacity building to affect the attitudes and knowledge of targeted decision-makers. Such efforts to increase decision-makers\u2019 readiness and ultimately their endorsement, adoption, and ongoing support of evidence-based preventive interventions should be continued and intensified.The online version of this article (10.1007/s11121-020-01088-5) contains supplementary material, which is available to authorized users. Increasing efforts to use scientific knowledge to inform policymaking in the fields of health, education, and welfare have been observed in various contexts , inter alia, is to support all its member states, especially low- and middle-income countries (LMICs), in fulfilling their commitment to eliminate or significantly reduce the non-medical use of controlled substances  and adapting and transferring them into real-world settings without losing their efficacy or effectiveness (stage 3). However, the effective scale-up and institutionalization of evidence-based prevention (stage 4) is a less developed research field. This is especially true in regard to the last stage (stage 5) of the translation process, which is geared toward influencing global policies and generating environmental change across multiple cultures and societies. This last stage includes shaping international behavioral health priorities and agendas and supporting large-scale population-level shifts in well-being via evidence-based practices  is the governing body of the UNODC and serves as the policymaking body that formally discusses and agrees upon the global drug policy agenda. The resolutions and decisions made by the member states\u2019 representatives on the CND provide guidance for addressing the issue of drugs to all the member states and the UNODC. While adopted by consensus, these resolutions are not binding but merely guide the member states and provide a normative framework for their actions. In the present article, the work of the UNODC is portrayed against developments in global cooperation on drugs over 2009\u20132017. The heads of the UNODC member states set goals for this period for countering the world drug problem in the 2009 Political Declaration (CND 2009) calling for greater commitment on drug demand reduction as part of these shared goals. They also adopted a revised annual report questionnaire  legislative and institutional frameworks; (2) comprehensive approaches to drug demand reduction and supply; (3) extent and patterns of drug use; and (4) extent and patterns of trends in drug crop cultivation and drug manufacture and trafficking. The second part of the ARQ requests information on the prevention and early intervention responses implemented in the reporting year by each member state, among other demand, and supply reduction issues. We describe trends in the prevention practices implemented globally by presenting data from this part of the ARQ across its three reporting cycles: 2010\u20132011 (reported in 2012), 2012\u20132013 (reported in 2014), and 2014\u20132015 (reported in 2016).The ARQ section on prevention offers a list of different prevention approaches from which the member states can choose to indicate which of these readily defined types of prevention activities they are implementing. The member states are also asked to provide information on the size of the population they are reaching with these activitiesA composite score was then generated to summarize the information about the actual implementation of a given type of prevention (yes/no) and, if yes, at what level of coverage of the target population . This score for the level of implementation was generated for each of the three strength-of-evidence categories and was normalized between 0 and 1 to enable cross-comparison  provided the ARQ part II data in all three biannual cycles reported in this article, these respondents were mostly from Europe, Asia, and the Americas , with only a few responses from Africa. Thus, the ARQ data do not allow us to draw solid conclusions about the trends in prevention programming, and the data are not necessarily representative of all geographical regions. Additional work remains to be done to further develop this data collection instrument because this tool remains the only source of information depicting the global state of prevention programming and the translation of prevention research into practice.Finally, the data gathered with this instrument also reveal a significant gap in evaluation. The ARQ shows that a majority of the reported prevention activities (55%) were not evaluated at all in 2010\u20132011, and process evaluation was far more common than outcome evaluation for those activities reported to be evaluated. For example, only 1.9% of the member states implementing life skills education in schools reported evaluating its impacts  knowledge of the key learning goals of the training; (2) attitudes concerning the usefulness of evaluation; and (3) self-efficacy to utilize research for their professional benefit. Data were collected from participants in three of the regional workshops. A total of 55 participants from 25 countries returned both the pre- and the post-questionnaire, and the changes between the pre- and post-measurements were analyzed. The number of answers to each individual question varied because many respondents left some blank answers.p\u2009<\u20090.05; 29.8%; Table The questionnaire first asked the participants to read different examples of evaluation study results and to identify the types of evaluation research that might produce such results . The aim was to assess whether the training had helped the participants comprehend the different applications of evaluations correctly Table . Before The policymakers were also presented with different statements to assess their perceptions of the potential benefits of evaluating prevention and to measure their self-efficacy to conduct and use evaluations in ways benefitting their professional tasks and roles. The participants were asked to indicate to what extent they agreed with each statement , and the results are presented in Table The previous discussions and research point to the need to translate and transfer the knowledge derived from the abundant prevention-related research into the complex environments of real-world policies and programs and to promote readiness for and appreciation of evidence-based prevention globally, particularly in LMICs  should be continued.In the Sustainable Development Goal 3.5, UN member states have committed to strengthen the treatment and prevention of substance use. It has created invaluable momentum to advance prevention practices globally. However, the two indicators used to measure progress in achieving this goal by 2030 focus on the availability of treatment and on the prevalence of harmful alcohol use, and do not reflect the availability or quality of prevention practices UN DESA . This isWork to advocate for rigorous goals and commitments and to promote prevention efforts higher on the global policymaking agenda should be continued and broadened. During the 2019 CND, representatives of the UNODC member states set new goals to address substance use globally. This effort provides important momentum to strengthen the dialog between the scientific and political communities and to capitalize on the latest scientific knowledge about what works best to address substance use prevention. Capacity building is another key component of advancing evidence-based prevention. Various capacity building activities targeting prevention practitioners, coordinators, and decision-makers have been implemented globally, for example in the context of Universal Prevention Curriculum,ESM 1(DOCX 22 kb)"}
{"text": "We present a new wave-type model of saltatory conduction in myelinated axons. Poor conductivity in the neuron cytosol limits electrical current signal velocity according to cable theory, to 1\u20133\u00a0m/s, whereas saltatory conduction occurs with a velocity of 100\u2013300\u00a0m/s. We propose a wave-type mechanism for saltatory conduction in the form of the kinetics of an ionic plasmon-polariton being the hybrid of the electro-magnetic wave and of the synchronized ionic plasma oscillations in myelinated segments along an axon. The model agrees with observations and allows for description of the regulatory role of myelin. It explains also the mechanism of conduction deficiency in demyelination syndromes such as multiple sclerosis. The recently observed micro-saltatory conduction in ultrathin unmyelinated C fibers with periodic ion gate clusters is also explained.The online version of this article (10.1007/s00249-020-01442-z) contains supplementary material, which is available to authorized users. The input must be however larger than some threshold voltage, otherwise the response of the ion gate block does not occur . Such a behavior is called the all-or-none principle. Various modifications of HH models have been developed to include additional effects like e.g., leakage of ions due to the natural permeability of the membrane to ions beyond the voltage-gated channels, or in more detail, complex geometries of dendrites and axons, thermodynamic  mechanism at nodes of Ranvier with the cable model diffusion at internodal myelinated segments results in the estimation of the AP propagation velocity ,z direction, as illustrated in Fig.\u00a0T, m is the mass of the ion, C is a constant on the order of unity (to account for the type of scattering of carriers by the system boundary) and a is the radius of a sphere. The first term in the expression for a. According to Eq.  . If this mechanism (as described in the next paragraph) is included the required frequency of plasmon is achieved at the realistic diameter of the axon cord.The bulk plasmon frequency is The insulating, relatively thick myelin coverage creates a periodically broken channel (corrugated conductor-insulator structure) required for plasmon-polariton formation and its wave-type propagation. To reduce the coupling with the surrounding inter-cellular electrolyte and protect against any leakage of plasmon-polaritons, the myelin sheath must be sufficiently thick, much thicker than what is required merely for electrical insulation.Here, we considered an initial model of the dielectric surroundings. In the electrolytic surroundings, plasmon oscillations in separated myelinated segments have strongly red shifted self-frequency due to non-radiative damping of plasmons. The dipole oscillating in a segment induces the oppositely oscillating dipole in the surrounding electrolyte, which dissipates energy into heat eventually. This large effect causes the reducing of the on Jacak . Inclusia) and for small chain separations of k determines the group velocities of the plasmon-polariton modes. The results are presented in Fig.\u00a0For the resulting plasmon self-frequency in each segment, k as shadowed in the right panel of the figure) which can propagate with the appropriately high velocity. This subset of k determines also the frequency of plasmon-polariton as visualized by shadowing in the left panel in the figure. The mechanism which selects the appropriate k range is the HH mechanism at nodes of Ranvier and the thickness of the myelin sheath. The frequency of the plasmon polariton must be adjusted to the characteristic time of the triggering of the opening of Nak region right-shifts, which causes lowering of the velocity of plasmon-polariton\u2014cf. Fig.\u00a0k region left-shifts, which also causes lowering of the velocity on the left side of the maximum.From Fig.\u00a0The regulatory role is played here by the thickness of the myelin layer (as detailed in the next section). The dipole oscillating in a myelinated segment of the axon cord induces in the outer intercellular electrolyte the opposite dipole. Both dipoles coupled across the myelin layer of thickness kd and k domain and thus are unimportant for the considered ionic system. Hence, the quenching of the radiative losses  for the plasmon-polariton modes in the axon model occurs practically throughout the entire Note that for es Jacak  are chares Jacak  with denAlthough the ionic system chain model for a myelinated axon appears to be a crude approximation of the real axon structure, it can serve for the comparison of the energy and time scales of plasmon-polariton propagation implied by the model with the observed kinetic parameters of nerve signals. In the model, the propagation of a plasmon-polariton through the axon chain, excited by an initial AP on the first Ranvier node , sequentially ignites the consecutive Ranvier node blocks of NaThe plasmon-polariton scheme described above for the ignition of AP spike formation in the ordered chain of Ranvier nodes along an axon is thus consistent with the saltatory conduction observed in myelinated axons. The observations that firing of the AP can simultaneously move in two opposite directions if a certain central node of Ranvier of a passive axon is ignited, as well as the observation of the maintenance of the firing traverse despite small breaks in the axon cord or a few damaged Ranvier nodes also agree with the collective wave-type plasmon-polariton model of saltatory conduction in contrast to the lack of satisfactory explanations in models based on the cable theory. The maintenance of the plasmon-polariton kinetics despite discontinuities in the axon cord agrees well with the discrete chain model.In Fig.\u00a0n in the volume of the spheroid with semiaxes a,\u00a0b,\u00a0c, n equals to, a,\u00a0b,\u00a0c for a spheroid). The first isotropic term in the expression for z direction. The dipole coupling is independent of the shape of the chain elements. The mutual independence of dipole oscillations with distinct polarization described above follows from the linearity of the dynamics equation (versus the dipole) regardless of the metal or electrolyte conducting elements.To comment on the appropriateness of the chain model for axons, let us note that even though the thin core of the axon is a continuous ion conducting fiber, the surface electromagnetic field can be closely pinned to the linear conductor similarly as to the Goubau line (well-known from microwave technology) Goubau  and if pentclass1pt{minimaBecause the dynamics equation is not affected by the anisotropy, the solutions of the equation for each polarization have the same form as that for the spherical case with the exception of the modification of the related frequency of the dipole oscillations in each direction and the small correction of the orientation dependent contribution of the scattering ratio . Thus, we can independently renormalize the equation for dipole oscillations for each polarization direction, introducing the oscillation self-frequency for each direction q governed by the periodicity. The wave-type propagation has the form of synchronic dipole oscillations of myelinated sectors. These dipole oscillations are equivalent to periodic polarization of Ranvier nodes. The model allows for quantitative estimation of the relevant propagation characteristics and verification of whether plasmon-polariton dynamics fits the observed features of the saltatory conduction in myelinated axons.The periodic structure of a myelinated axon does not form a chain of electrolyte spheres but rather is a thin electrolyte cord with periodically distributed myelinated sectors separated by very short unmyelinated intervals of Ranvier nodes. The periodic corrugated structure of the dielectric isolation allows, however, for collective plasmon wave-type oscillations, The polarization of Ranvier nodes induced by plasmon-polaritons initiates opening of NaPlasmon-polaritons do not interact with external electromagnetic waves or, equivalently, with photons (even at adjusted frequency), which is a consequence of the large difference between the group velocity of plasmon-polaritons and the velocity of photons . The electrical fields induced by dipoles in the near-field zone are, It is known that the thickness of the myelin layer is an essential factor deciding on the proper functioning of myelinated axons. This thickness is greater than that needed for simple isolation because the role of myelin is more specific and not related with electrical isolation. In the case of a plasmon dipole oscillating in the myelinated segment, as part of the plasmon-polariton, the ion oscillations in the axon cord excite the oppositely directed also oscillating dipole of ions in the outer electrolyte, in the cave surrounding the myelinated segment, cf. Fig.\u00a0For the initial condition suitable for excitation of the considered segment of the axon, i.e., The frequency for a longitudinal plasmon is reduced in a strongly elongated axon rod segment with the aspect ratio trans-myelin beating. Via synchronization with HH cycle ignition time scale, this selected mode of plasmon-polariton is continuously supplemented in energy by HH cycles and simultaneously is able to ignite the HH cycle on consecutive Ranvier nodes along the chain of myelinated segments on arbitrary large distances. This explains why only the myelinated segments oscillate and the frequency of the related plasmon-polariton wave packet is precisely tuned by the myelin thickness, At the Ranvier node, the inner and outer cytosol are separated by the thin bare cell membrane, thus dipole coupling across the thinner barrier is stronger and the corresponding beating quicker. The quick component of this beating is also quenched as not synchronized with the time scale of electrically gated NaThe described mechanism of selection of the low self-frequency of plasmon oscillations of the myelinated fragment allows for accommodation of the frequency of plasmon-polariton . Not alis Figs.\u00a0, 9.Fig. Recently, it has been discovered that in the thin (ca. 0.1\u00a0The AP formation at lipid rafts (similarly as at nodes of Ranvier) is of major importance for the selection of an appropriate mode of plasmon-polariton\u2014that one which is synchronized with HH cycles at consecutive nodes. Only such a mode will be persistent due to energy supplementation at HH cycles. Other, non-synchronized modes are quickly quenched due to strong damping of plasmon-polaritons on short distances. The plasmon-polariton is not a local effect in contrast to the diffusion current described by cable theory. The plasmon-polariton is disjoint with the HH mechanism at nodes but triggers the HH cycles via depolarization of NaThis scenario explains the micro-saltatory conduction in C fibers. The absence of the myelin sheath causes the frequency of the plasmon-polariton in C fibers to be larger than in myelinated axons and mitigated only by the strong damping of surface plasmon oscillations in periodic segments. This damping is caused by the large Ohmic losses in the inner neuron cytosol and by a strong coupling to outer electrolyte across the membrane. The latter is especially large in the absence of myelin as in C fibers. Thus for these fibers we get the self-frequency for plasmons at a single segment, It is thus evident that the cable theory (coupled with HH cycle of AP formation) is helpful only in small short dendrites and unmyelinated axons without any periodic structure of ion gate clusters. Periodicity  of the conduction velocity. This coincidence together with the immunity of plasmon-polaritons to external e-m perturbations or detection support the reliability of the new model proposed for the saltatory conduction in myelinated axons, which is very efficient, quick and energy efficient despite the poor ordinary conductivity of axons.Plasmon-polariton kinetics of the triggering signal along the myelinated axons has the observed velocity and exceeds by 1\u20132 orders any estimations based on the conventional cable theory. The role of myelin thickness is elucidated as the regulatory factor in a different manner than for diffusion of ions. The plasmon-polariton is a nonlocal effect decoupled from HH cycles at Ranvier nodes, though the latter select the appropriate mode of plasmon polariton via synchronization with triggering of NaA plasmon-polariton model of the saltatory conduction explains also the recently observed micro-saltatory conduction in unmyelinated ultra thin C fibers in the PNS which possess the periodic structure of rafts with clusters of NaIt is worth noting some quantum aspects of plasmon-polaritons, which are synchronized in a wave form simultaneous for plasmon oscillations in all segments of a chain. The plasmon oscillations in a particular segment are, however, of quantum nature (regardless of whether electrons or ions), though seem to be quite ordinary oscillations of charge fluctuations. Plasmons are coherent oscillations of all charges in the subsystem and this coherence can be understood exclusively in quantum terms (e.g., of random phase approximation by Pines, Bohm Pines Supplementary MaterialBelow is the link to the electronic supplementary material."}
{"text": "In our recently published meta-analysis, due to an oversight, we treated urinary As concentration data reported by Tsinovoi et al.  instead We corrected both We also made the required corrections in Lastly, we note that the corrections to the linear and non-linear dose-response models for combined fatal and non-fatal risks of strokes as a function of drinking water arsenic concentration show the same trends as in the original publication and, in particular, over the relatively low concentration range in the scope of the study, there remains no significant association in the data collated between drinking water As concentration and the combined fatal and non-fatal risks of stroke."}
{"text": "We read with interest the recent meta-analysis by Chang et al. who investigated the role of neuromuscular blocking agent (NMBA) use in moderate-to-severe acute respiratory distress syndrome (ARDS) and discuss the potential mechanisms involved in the identified improvements due to the use of NMBA in ARDS . They co"}
{"text": "The authors wish to make the following corrections to this paper :The funding information was missing in the original version. The following acknowledgement of funding support should be included: Funding: This work was partially supported by American Cancer Society Internal Research Grant #126771-IRG-14-194-11-IRG.These changes do not affect the scientific results. The manuscript will be updated and the original version will remain online on the article webpage, with a reference to this erratum. The authors would like to apologize for any inconvenience caused to the readers by this change."}
{"text": "Food insecurity is an under-recognized geriatric syndrome that has extensive implications in the overall health and well-being of older adults. Understanding the impact of food insecurity in older adults is a first step in identifying at-risk populations and provides a framework for potential interventions in both hospital and community-based settings. This symposium will provide an overview of current prevalence rates of food insecurity using large population-based datasets. We will present a summary indicator that expands measurement to include the functional and social support limitations , which disproportionately impact older adults, and in turn their rate and experience of food insecurity and inadequate food access. We will illustrate using an example of at-risk seniors the association between sarcopenia, the age-related loss of muscle mass and function, with rates of food security in the United States. The translational aspect of the symposium will then focus on identification of psychosocial and environmental risk factors including food insecurity in older veterans preparing for surgery within the Veterans Affairs Perioperative Optimization of Senior Health clinic. Gaining insights into the importance of food insecurity will lay the foundation for an intervention for food insecurity in the deep south. Our discussant will provide an overview of the implications of these results from a public health standpoint. By highlighting the importance of food insecurity, such data can potentially become a framework to allow policy makers to expand nutritional programs as a line of defense against hunger in this high-risk population."}
{"text": "In this paper, we consider an information bottleneck (IB) framework for semi-supervised classification with several families of priors on latent space representation. We apply a variational decomposition of mutual information terms of IB. Using this decomposition we perform an analysis of several regularizers and practically demonstrate an impact of different components of variational model on the classification accuracy. We propose a new formulation of semi-supervised IB with hand crafted and learnable priors and link it to the previous methods such as semi-supervised versions of VAE (M1 + M2), AAE, CatGAN, etc. We show that the resulting model allows better understand the role of various previously proposed regularizers in semi-supervised classification task in the light of IB framework. The proposed IB semi-supervised model with hand-crafted and learnable priors is experimentally validated on MNIST under different amount of labeled data. We will denote a joint generative distribution as The deep supervised classifiers demonstrate an impressive performance when the amount of labeled data is large. However, their performance significantly deteriorates with the decrease of labeled samples. Recently, semi-supervised classifiers based on deep generative models such as VAE M1 + M2) [ + M2 [1]Hand-crafted latent space priors impose constraints on a distribution of latent space by fitting it to some targeted distribution according to the variational decomposition of the compression term of the IB. This type of latent space priors is well known as an information dropout  dropout . One can dropout . In contWe demonstrate that several state-of-the-art models such as AAE , CatGAN We evaluate our model using standard dataset MNIST on both hand-crafted and learnable features. Besides revealing the impact of different components of variational IB factorization, we demonstrate that the proposed model outperforms prior works on this dataset.Our main contribution is three-fold: (i) We propose a new formulation of IB for the semi-supervised classification and use a variational decomposition to convert it into a practically tractable setup with learnable parameters. (ii) We develop the variational IB for two classes of hand-crafted and learnable priors on the latent space of classifier and show its link to the state-of-the-art semi-supervised methods. (iii) We investigate the role of these priors and different regularizers in the classification, latent and reconstruction spaces for the same fixed architecture under the different amount of training data.Regularization techniques in semi-supervised learning: Semi-supervised learning tries to find a way to benefit from a large number of unlabeled samples available for training. The most common way to leverage unlabeled data is to add a special regularization term or some mechanism to better generalize to unseen data. The recent work M1 + M2)  is an exIn contrast to the above approaches and following the IB framework, we formulate the semi-supervised classification problem as a training of classifier that aims at compressing the input Summary: The considered methods of semi-supervised learning can be differentiated based on: (i) the targeted tasks ; (ii) the architecture in terms of the latent space representation (with a single representation vector or with multiple representation vectors); (iii) the usage of IB or other underlying frameworks (methods derived from the IB directly or using regularization techniques); (iv) the label space regularization ; (v) the latent space regularization (hand-crafted regularizers and priors or learnable priors under the reconstruction and constrastive setups) and (vi) the reconstruction space regularization in case of reconstruction setup .In this work, our main focus is the latent space regularization for the hand-crafted and learnable priors under the reconstruction setup within the IB framework. Our main task is the semi-supervised classification. We will not consider any augmentation and adversarial techniques besides a simple stochastic encoding based on the addition of data independent noise at the system input or even deterministic encoding without any form of augmentation. The regularization of the label space and reconstruction space is solely based on the terms derived from the IB framework and only includes available labeled and unlabeled data without any form of augmentation. In this way, we want to investigate the role and impact of the latent space regularization as such in the IB-based semi-supervised classification. The usage of the above mentioned techniques of augmentation should be further investigated and will likely provide an additional performance improvement.We assume that a semi-supervised classifier has an access to According to the above IB formulation the encoder However, since optimal Thus, the IB  can be rThe considered IB is schematically shown in The first mutual information term  in  can be dStochastic encodingmultiplicative encoding applied to the input additive encoding applied to the input concatenative/mixing encodingIt should be pointed out that the encoding  dropout ; (b) addPixelGAN , or in ts in VAE  or (c) cs of AAE .In this section, we factorize the second term in  to addreFinally, the conditional entropy is defined as Since er bound  as I\u03d5a,\u03b8Summarizing the above variational decomposition of  with theSupervised training without latent space regularization (baseline): is based on term Semi-supervised training without latent space regularization is based on terms Supervised training with latent space regularization is based on term Semi-supervised training with latent space regularization deploys all terms in ( Dcc^ in (7)LS\u2212Nond Dc in :(8)LSS\u2212N Dcc^ in  and eithnd Da in :(9)LS\u2212Reterms in  and 6)::SupervisIn this section, we extend the results obtained for the hand-crafted priors to the learnable priors. Instead of applying the hand-crafted regularization of the latent representation y the IB  and showg from A , Data Pr from A The targeted tasks: auto-encoding, clustering,  generation and classification.The architecture in terms of the latent space representation: the stacked combination of models M1 and M2 is used as discussed above.The usage of IB or other underlying frameworks: VAE M1 + M2 is not derived from the IB framework but it is linked to the regularized ELBO with the cross-entropy for the labeled samples. The corresponding IB Lagrangian of semi-supervised VAE M1 + M2 under the assumption of end-to-end training can be defined as:The label space regularization: is based on the assumption of categorical distribution of labels.The reconstruction space regularization in case of reconstruction loss: is only based on the MSE.D indicates the deterministic setup (i) and symbol S corresponds to the stochastic one (ii). To choose the optimal parameters of systems, e.g., the Lagrangian multipliers in the considered models, we used 3-run cross-validation with the randomly chosen labeled examples as shown in The tested system is based on (i) the deterministic encoder and decoder, (ii) the stochastic encoder of type stimator  is used Additionally, we performed a 10-run cross-validation on the SVHN dataset . We usedhttps://github.com/taranO/IB-semi-supervised-classification. The analysis of the latent space of trained models for the MNIST dataset is given in We compare the considered architectures with several state-of-the-art semi-supervised methods such as AAE , CatGAN The deterministic and stochastic systems based on the learnable priors clearly demonstrate the state-of-the-art performance in comparison to the considered semi-supervised counterparts.Baseline Neural Network (NN): the obtained results allow concluding that, if the amount of labeled training data is large, as shown in \u201call\u201d column (\u201d column , the latNo priors on latent space: to investigate the impact of unlabeled data, we add the adversarial regularizer \u201d column , allows Hand crafted latent space priors: along this line we investigate the impact of hand-crafted regularization in the form of the added discriminator Learnable latent space priors: along this line we will investigate the impact of learnable priors by adding the corresponding regularizations of the latent space of auto-encoder and data reconstruction. We investigate the role of reconstruction space regularization based on the MSE expressed via In the SVHN test, we did not try to optimize the Lagrangian coefficients as it was done for MNIST. However, to compensate for a potential non-optimality, we perform the model training with the reduced learning rate as indicated in We have introduced a novel formulation of variational information bottleneck for semi-supervised classification. To overcome the problem of original bottleneck and to compensate the lack of labeled data in the semi-supervised setting, we considered two models of latent space regularization via hand-crafted and learnable priors. On a toy example of MNIST dataset we investigated how the parameters of proposed framework influence the performance of classifier. By end-to-end training, we demonstrate how the proposed framework compares to the state-of-the-art methods and approaches the performance of fully supervised classifier.The envisioned future work is along the lines of providing a stronger compression yet preserving only classification task relevant information since retaining more task irrelevant information does not provide distinguishable classification features, i.e., it only ensures reliable data reconstruction. In this work, we have considered IB for the predictive latent space model. We think that the contrastive multi-view IB formulation would be an interesting candidate for the regularization of latent space. Additionally, we did not use the adversarially generated examples to impose the constraint on the minimization of mutual information between them and class labels or equivalently to maximize the entropy of class label distribution for these adversarial examples according to the framework of entropy minimization. This line of \u201cadversarial\u201d regularization seems to be a very interesting complement to the considered variational bottleneck. In this work, we considered a particular form of stochastic encoding by the addition of data independent noise to the input with the preservation of the same class labels. This also corresponds to the consistency regularization when samples can be more generally permuted including the geometrical transformations. It is also interesting to point out that the same form of generic permutations is used in the unsupervised constrastive loss-based multi-view formulations for the continual latent space representation as opposed to the categorical one in the consistency regularization. Finally, the conditional generation can be an interesting line of research considering the generation from discrete labels and continuous latent space of the autoencoder."}
{"text": "Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for diversification of the natural products and improvement of the biological activities. For a decade, the characterization of enzymes and enzymatic synthesis of prenylated compounds by using ABBA-type and DMATS-type PTases have been demonstrated. Here, I introduce several examples of the studies on chemoenzymatic synthesis of unnatural prenylated compounds and the enzyme engineering of ABBA-type and DMATS-type PTases. The prenylated indole alkaloids and prenylated aromatic compounds isolated from plants and microorganisms show broad structural diversity and various biological activities \u20136. The p2+ ion and diphosphate that is also conserved in the isoprenyl diphosphate synthases . . 107]. FThe development of the sequencing technology and the improvement of methodology to characterize the enzymes have accelerated the understanding of the biosynthesis of secondary metabolites. By using these techniques, dozens of ABBA-type and DMATS-type aromatic PTases were functionally and structurally characterized. The accumulation of the knowledge in enzymes provided the chance for the application and engineering of these aromatic PTases. The results presented in this review would be the model cases toward utilization of the secondary metabolite enzymes to generate structurally diversified and biologically active unnatural novel molecular scaffolds for drug discovery."}
{"text": "Health and work are two key determinants of economic insecurity and wellbeing. Since economic insecurity may rise with age due to the deterioration of health and work ability, it is essential to study the causal relationship between health and labor market outcomes among older people. In Korea, the size of the older population has grown rapidly in recent decades but the pension system remains limited in terms of its reach and generosity, leaving a considerable number of older people suffering from economic insecurity. To investigate the two-way causal links between health and labor market outcomes, we use unique data on middle-aged and older Koreans from 12 waves of the Korea Welfare Panel Study (2006-2017) and two dynamic modeling approaches: the Arellano-Bond Generalized Method of Moment Model (AB-GMM) and the Maximum Likelihood Structural Equation Model (ML-SEM). Results point at gender differences regarding the direction of the causal link between health and labor market outcomes. Men are more likely to be in good health due to higher income or paid work. Women are more likely to earn a higher income and to work as paid employees because of good health. These effects particularly hold for Koreans aged 55-74 in urban areas."}
{"text": "Defining complexity in quantum field theory is a difficult task, and the main challenge concerns going beyond free models and associated Gaussian states and operations. One take on this issue is to consider conformal field theories in 1+1 dimensions and our work is a comprehensive study of state and operator complexity in the universal sector of their energy-momentum tensor. The unifying conceptual ideas are Euler-Arnold equations and their integro-differential generalization, which guarantee well-posedness of the optimization problem between two generic states or transformations of interest. The present work provides an in-depth discussion of the results reported in arXiv:2005.02415 and techniques used in their derivation. Among the most important topics we cover are usage of differential regularization, solution of the integro-differential equation describing Fubini-Study state complexity and probing the underlying geometry."}
{"text": "An increasing number of studies evinces the significant role of sleep in health outcomes including physical symptoms, cardiometabolic functioning, and chronic health conditions. To further advance the field\u2019s knowledge on sleep and health in adulthood, it is necessary to have an integrative understanding of this topic that pulls together short-term determinants to long-term health consequences of sleep. As such, this symposium places diverse aspects of sleep across multiple contexts, ranging from predictors and consequences of sleep in daily life to the role of sleep in long-term changes in health across adulthood. The first paper by Lee and colleagues examines the role of daily positive and negative events as precursors of concurrent and next-day sleep duration. The second paper by Joo and colleagues addresses the moderating role of nightly sleep duration in the association between daily stressor severity and intensity of headaches. The third paper by Chai and colleagues explores how the association between daily emotional well-being and cardiometabolic syndrome differs by sleep deficiency and by age. The fourth paper by Sin and colleagues focuses on daily affective vulnerability to short sleep duration as a risk factor for developing chronic conditions 10 years later. The final paper by Reither and colleagues assesses within-person changes and between-person differences in restorative sleep and their associations with body mass trajectories across 15 years. The discussant, Dr. Soomi Lee, will integrate key points from the studies, discuss the utilization of diverse measurements of sleep, and address considerations for future research on sleep and health."}
{"text": "We develop a frailty index (FI) from continuous valued biomarker measurements that does not use thresholds to binarize deficits. In this work we construct a quantile frailty index (FI-Q) directly from risk quantiles, without binarizing the deficits. FI-Q is the average risk quantile for an individual in the population with respect to the set of measured biomarkers. We show that FI-Q predicts adverse health outcomes better than either a quantile-based cutpoint approach or an FI-Lab method used in previous studies. We also address practical questions such as how to use longitudinal data. We use data from the English Longitudinal Study of Ageing (ELSA) for longitudinal analysis and data from the National Health and Nutrition Examination Survey (NHANES) and the Canadian Study of Health and Aging (CSHA) to compare predictive value of FI-QM with previous FI-Lab studies."}
{"text": "The CASPMI project includes whole-genome sequencing data  from \u223c1000 healthy individuals of the CASPMI cohort. To facilitate the usage of such variations for pharmacogenomics studies, star-allele frequencies of the drug-related genes in the CASPMI and 1KGP populations are calculated and provided in CGVD. As one of the important database resources in BIG Data Center, CGVD will continue to collect more genomic variations and to curate structural and functional annotations to support population-based healthcare projects and studies in China and worldwide.Precision medicine calls upon deeper coverage of population-based sequencing and thorough gene-content and phenotype-based analysis, which lead to a population-associated genomic variation map or database. The Chinese Genomic Variation Database (CGVD;  The authors of the above-cited article request its retraction. The authors have not received approval from the relevant authorities to use Chinese genomic data and therefore have to suspend the CGVD database."}
{"text": "Age-Friendly Community Initiatives (AFCIs) are expanding throughout the United States to make social and built environments within local communities more responsive to population aging. With over 450 initiatives affiliated with the AARP Network of Age-Friendly Communities, Cities, and States (125 of which began in 2019-early 2020), rapid growth on the ground necessitates that theory and research develop alongside practice innovations. This symposium showcases the intersection of cutting-edge scholarship with community-based efforts to generate knowledge of community change processes that is immediately actionable by community leaders. Collectively, these papers emphasize the benefits of action research and developmental evaluation in community gerontology towards building the theories of age-friendly change that will set the stage for outcomes research. The first paper will present on work with 83 AFCIs in rural Maine involving interviews with organizational leaders to inform which types of supports could stimulate age-friendly changes to communities\u2019 built and social environments. The second paper will share a mixed-methods approach used to develop a global toolkit for dementia-friendly communities. The third presenter will describe the collaborative development and utilization of social network analysis to help age-friendly leaders plan their work, while simultaneously advancing research on variation in AFCI implementation. The final paper will present an evaluative framework that identifies roles and outcome measures for collective impact at the intersection of public health and age-friendly communities."}
{"text": "Marriage or other types of partnerships are consequential for health in later life, but its association to self-perceptions of aging remains a relatively unexplored area of research. This study used three waves of panel data from the Health and Retirement Study  to examine how changes in the health status and relationship quality over time contribute to self-perceptions of aging for married/partnered men and women. Multilevel models showed that women demonstrated more positive self-perceptions of aging than men, but there was no gender difference in how self-perceptions of aging became more negative over time. The findings on the main and moderating effects of health and relationship quality give evidence that changes across time, as well as average differences in individual characteristics, may affect self-perceptions of married/partnered men and women differently. The context in which gender shapes key aspects of life contributes to self-perceptions of aging in later life."}
{"text": "In the original article, there was a mistake in the legend for Figure 1 as published. The figure, which was previously published in the article cited below from the Japanese Journal of Radiology, was reused without appropriate acknowledgment in our article. The correct legend appears below.Figure 1 The concept of the diffusion tensor image analysis along with the perivascular space (DTI-ALPS) method for perivascular diffusion. (A) The DTI superimposed color display shows the distribution of projection fibers (z-axis: blue), association fibers (y-axis: green), and subcortical fibers (x-axis: red). Three regions of interest (ROIs) were placed in the area with projection fibers (projection area), association fibers (association area), and subcortical fibers  to measure the diffusivities in three directions . (B) Schematic diagram showing the relationship between the direction of the perivascular space (gray cylinder) and the direction of the fibers. Note that the direction of the perivascular space is perpendicular to the projection and the association fibers. The figure has been reprinted with permission from Taoka et al. .The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "The paper\u2019s goal is to assess whether and, if so, the extent to which prevalence in disability of adults near retirement ages in the US increased over time compared to their peers in England and examine income group differences in the relative trends. This study uses 2002-2016 Health and Retirement Study (HRS) and English Longitudinal Study of Ageing (ELSA) focusing on adults aged 55-64. Annual percent changes over the period of 2002-2016 for limitations in instrumental activities of daily living (IADL) and activities of daily living (ADL) are estimated for each survey (HRS and ELSA) using multivariable logistic regressions to adjust for individual-level characteristics While disability prevalence of adults ages 55-64 in England improved over the years of 2002-2016 , disability prevalence of US adults has not improved and in fact even worsened in terms of IADL . There are substantial variations in the IADL/ADL trends by income groups. In the US, the adverse trends in disability were more pronounced among the lowest income groups . In England, the disability status improved over time for all but the lowest income group. We will examine further to identify specific factors contributing to divergent/convergent trends in disability between the US and England."}
{"text": "Background and Purpose: Addressing issues of quality of life of nursing home residents based on the human rights-based approach has been a top priority in the long-term care system in Korea but no study has yet examined the relationship between self-determination of nursing home residents and their quality of life. This study aimed to examine whether greater levels of self-determination in the provision of daily care were associated with higher levels of quality of life of the residents. Methods: We collected data from 332 residents (+65) at 20 nursing homes in a metropolitan city. We measured residents\u2019 right to self-determination using the autonomy scale of the Client-centered Care Questionnaire. We also included quality of life, socio-economic characteristics, ADLs, depressive symptoms, and social networks. We ran multiple regression analysis using SPSS 26.0. Results: The findings of this study revealed that greater levels of residents\u2019 right to self-determination were associated with higher levels of quality of life . Older residents who were higher levels of depressive symptoms were likely to have lower levels of quality of life . Conclusions and Implications: This study adds to the growing literature on the ways nursing home residents\u2019 self-determination contributes to their quality of life. More opportunities for self-determination in their treatment should be given to promote recovery and to encourage participation in the decision-making process. Nursing practitioners and policymakers in Korea should develop programs and/or services that enhance residents\u2019 self-determination to improve their quality of life."}
{"text": "We derive the minimum divergence portfolio, which generalizes the Markowitz\u2019s (mean-divergence) approach and relying on the information geometrical aspects of the distributions the Capital Asset Pricing Model (CAPM) is then derived under the geometrical characterization of the distributions which model the data, all by the consideration of principal curves approach. We discuss the possibility of integration of our model into an adaptive procedure that can be used for the search of optimum points on finance applications.This paper proposes a method for the beta pricing model under the consideration of non-Gaussian returns by means of a generalization of the mean-variance model and the use of principal curves to define a divergence model for the optimization of the pricing model. We rely on the  We point out however that the criticality of a principal curve is usually defined in terms of the Euclidean distance. Hence, although Considering statistical divergences as Kullback\u2013Leibler or Bregman divergence allows us to deal with random variables with probabilities given by exponential and deformed exponential distributions. In the context of exponential and q-exponential distributions that includes q-Gaussian distributions, defined in details by Plastino and Vignat \u2212q-Gaussian distribution, it holds thatq-variance matrix The Fisher information metric The results we have quoted in N risky assets D is the vector of payoffs A portfolio composed by The matrixN distinct eigenvalues and iterating this same optimization procedure in subspaces orthogonal to the span of the already given eigenvectors, one obtains the principal directions Setting the LagrangianR byWe then define a matrix p diagonal elements in the generalized covariance matrix in diagonal form, that is,Next, we restrict ourselves to the projections of portfolios onto the  affine subspace spanned by the first Hence, we obtain a multi-factor linear model of the formp-principal portfolioThe expected return of the p-principal portfolio with expected return We claim that the To prove this claim, we denoteThe first order condition isWe conclude thatTheorem\u00a04.The p-principal portfolio with minimum generalized variance is given bywhere"}
{"text": "As these lines were written, the Covid-19 pandemic crisis was continuing to threaten countries around the globe. The worldwide consensus that physical distancing is an effective instrument for mitigating the spread of the virus has led policymakers to temporarily limit the freedom of movement of people between and within countries, cities, and even neighborhoods. These public health-related restrictions on human mobility yielded an unprecedented fragmentation of international and national food distribution systems. Focusing on food retailing - usually being modestly oligopolistic - we take a micro-economic perspective as we analyze the potential consequences this disruption has for the physical as well as for the economic access of households to food at the local level. As the mobility constraints implemented substantially reduced competition, we argue that food retailers might have been tempted to take advantage of the implied fragmentation of economic activity by exploiting their temporarily raised market power at the expense of consumers and farmers. We illustrate our point by providing empirical evidences of rising wholesale-retail as well as farm-retail price margins observed during the Covid-19 crisis. Subsequently, we review existing empirical approaches that can be used to quantify and decompose the micro-economic effects of crises on food demand and supply as well as the size and structure of the market, costs of trade, and economic welfare. The employment of such approaches facilitates policymakers\u2019 understanding of micro-economic effects of public health-induced mobility restrictions on economic activity. The world is currently undergoing a global pandemic that threatens societies and economies at the global, national, regional, and local levels. Covid-19 appears to be a covariate shock simultaneously challenging many countries of unprecedented magnitude and geographical comprehensiveness unknown in modern history. The livelihoods of millions are challenged by tangible effects as exemplified by the occurrence of extensive hoarding and panic-buying in many Western countries during the first half of March 2020, when most people witnessed empty supermarket shelves for the first time in their lives  fragmented food retail markets. Oligopoly models can be adjusted to verify whether and in which ways the transiently improved bargaining positions of selected players in food markets enlarge crisis ramifications. Demand planning (Swierczek"}
{"text": "The application of cryo-EM methods to study SARS-CoV-2 proteins provides a convincing demonstration of the power of cryo-EM in the arsenal of structural biology. With the advent of direct electron detectors, the number of depositions in the EM Data Bank ]. What is noteworthy about these advances is that protein complexes of this kind are often flexible and conformationally heterogeneous, making them challenging to study by X-ray crystallography. The advent of \u2018single particle\u2019 methods such as cryo-EM and XFELs offer the exciting prospect to transcend the description of proteins in terms of static structures, and instead derive conformational landscapes that may provide a much better way to understand their biological function . I enthusiastically endorse their appeal to the structural biology community to deposit COVID-19-related raw cryo-EM data in EMPIAR to enable more in-depth analysis following initial publication of the data given the rapid growth in our collective knowledge of this pandemic.The critical role played by the EMDB over the last two decades in the dissemination and impact of cryo-EM cannot be underestimated. Established at a time far before the wider recognition of the cryo-EM revolution, the access provided by the repository of structures to both specialists and non-specialists has catalyzed the growth of the field enormously. The recent launch of EMPIAR as an archive where authors are able to deposit raw cryo-EM data has enabled crowd-sourcing of data analysis ] of a sample referred to as B814 and the iconic recent image of the SARS-2 coronavirus [Fig. 1c)] produced by scientists at the NIAID laboratories in Montana is remarkable. Looking ahead, a major goal of structural virology will be to bridge the gap between the knowledge of atomic resolution structures of individual viral components and the critical macromolecular interactions that define their assembly along with RNA into an intact, infectious virus. These kinds of integrative structural studies, combined with biological analyses of the processes involved in viral replication will be essential to understand the molecular mechanisms by which SARS-CoV-2 enters cells to cause its devastating effects on human health.The resemblance of June Almeida\u2019s image from 1966 [Fig. 1"}
{"text": "The aim of this study was to estimate incidence of self-harm presentations to hospitals and their associated hospital costs across England.We used individual patient data from the Multicentre Study of Self-harm in England of all self-harm presentations to the emergency departments of five general hospitals in Oxford, Manchester and Derby in 2013. We also obtained cost data for each self-harm presentation from the hospitals in Oxford and Derby, as well as population and geographical estimates from the Office for National Statistics. First, we estimated the rate of self-harm presentations by age and gender in the Multicentre Study and multiplied this with the respective populations to estimate the number of self-harm presentations by age and gender for each local Clinical Commissioning Group (CCG) area in England. Second, we performed a regression analysis on the cost data from Oxford and Derby to predict the hospital costs of self-harm in Manchester by age, gender, receipt of psychosocial assessment, hospital admission and type of self-harm. Third, the mean hospital cost per age year and gender were combined with the respective number of self-harm presentations to estimate the total hospital costs for each CCG in England. Sensitivity analysis was performed to address uncertainty in the results due to the extrapolation of self-harm incidence and cost from the Multicentre Study to England.There were 228 075 estimated self-harm presentations  by 159 857 patients in 2013 in England. The largest proportions of self-harm presentations were in the age group 40\u201349 years (30%) for men and 19\u201329 years (28%) for women. Associated hospital costs were approximately \u00a3128.6 (95% CI 117.8\u2212140.9) million in 2013. The estimated incidence of self-harm and associated hospital costs were lower in the majority of English coastal areas compared to inland regions but the highest costs were in Greater London. Costs were also higher in more socio-economically deprived areas of the country compared with areas that are more affluent. The sensitivity analyses provided similar results.The results of this study highlight the extent, hospital costs and distribution of self-harm presentations to hospitals in England and identify potential sub-populations that might benefit from targeted actions to help prevent self-harm and assist those who have self-harmed. They can support national as well as local health stakeholders in allocating funds and prioritising interventions in areas with the greatest need for preventing and managing self-harm. The overall provision of mental health-related care is funded through general government funds allocated to NHS England. With regards to self-harm, the National Institute for Health and Care Excellence (NICE) recommends provision of a psycho-social assessment for all patients who present with self-harm to the emergency departments of general hospitals NICE, . This asAdopting the working definition of the Multicentre Study of Self-harm in England, which is used nationally in England NICE, , self-haThe data included individual patient level data for all self-harm presentations to the emergency departments of five general hospitals  between 1 April 2013 and 31 March 2014. The information collected included: overall self-harm method , specific self-harm method , hospital admission and patient socio-demographic characteristics . It also included the provision of psychosocial assessment. We also obtained the actual hospital cost  of each self-harm presentation in our dataset  from the finance departments of the hospitals in Oxford and Derby. Mid-year 2013 population estimates for the study catchment areas by single year of age and gender, as well as suicide rates and proportion of the catchment area populations living in rural areas were retrieved at Clinical Commissioning Group level from the Office for National Statistics (ONS). Data on the Market Forces Factor (an index that adjusts price differences across the country) in Oxford, Manchester and Derby were retrieved from NHS England.The number of self-harm presentations was divided by the total population in the catchment area of the three centres of the Multicentre Study for single age years and gender to estimate the rate of self-harm presentation to hospital by age and gender in 2013. This rate was multiplied by the population per age year and gender in each local health service commissioning area  in England to estimate the number of self-harm presentations in each CCG nationally by age and gender. The total number of self-harm presentations per CCG area in England was calculated by summing all self-harm presentations by age and gender.et al., Heterogeneity in costs among hospitals may be explained by patient case-mix , mix and quality of services provided  and production constraints    was calculated by dividing the age standardised suicide rate in each CCG area by the average age standardised suicide rate in the three centres of the Multicentre Study. The underlying assumption for performing this sensitivity analysis was that suicide  and self-harm have common risk factors  million. In absolute terms, the majority of costs were for episodes involving women and were greatest in the Midlands and East regions . The totThis study provides the first detailed estimates of self-harm presentations to hospitals and their associated hospital costs across England. The results of this study may assist national and local health decision makers in planning the distribution of funds for self-harm and prioritising interventions in areas with the highest need for tackling self-harm. Providing the incidence of self-harm presentations in each CCG by gender and age highlights sub-populations potentially where additional resources might be targeted to interventions that may prevent self-harm and assist those who have self-harmed, reducing therefore suicide deaths.et al., et al., et al., et al., et al., et al., et al., Using our incidence estimates and considering that there were 4727  deaths by suicide in England in 2013  is close to previously reported more crude estimates of 200\u00a0000 episodes per year   presenting to a general hospital in Nottingham were estimated using NHS reference costs to be \u00a31.64 million or \u00a31026 per poisoning; the authors noted that if repeated across England costs per annum would be much higher than our estimate for all self-harm costs at approximately \u00a3170 million (\u00a3192 million at 2013/14 prices)  the lack of hospital cost data in Manchester, (b) cost data being limited only to care received in general hospitals, which is only a part of the overall long-term costs of self-harm (Sinclair Our analysis can help to identify specific population groups to support within localities and also draw more attention directly to self-harm when developing local suicide and self-harm prevention and reduction strategies. A key element of our approach has been to measure resource use and costs rather than simply use published health system charges, which usually do not reflect actual costs. This will also help in more accurate evaluation of the cost-effectiveness of any interventions that may reduce self-harm events.et al., et al., et al., et al., et al., There is certainly a need to build on recent albeit relatively small-sized economic evaluations of actions to increase the use of psychosocial assessments (Opmeer Due to constraints on the data sharing permissions of the data in the Multicentre Study of Self-harm in England, we are not allowed to share the data for public use."}
{"text": "This narrative review aims to critically analyze the effects of exercise on health in aging. Here we discuss the main clinical and biomolecular modifications induced by long-term recreational football training in older subjects. In particular, the effects induced by long-term recreational football training on cardiovascular, metabolic and musculo-skeletal fitness, together with the modifications in the muscle expression of hallmarks related to oxidative metabolism, DNA repair and senescence suppression pathways and protein quality control mechanisms will be provided. All these topics will be debated also in terms of preventing non-communicable metabolic diseases, in order to achieve successful aging over time. In partVery recently, Mancini et al. have investigated the effects of lifelong football training on the autophagic process in the skeletal muscle from VPG and CG subjects . The aut2max, lowest blood pressure at rest, healthier metabolic profile and musculo-skeletal fitness (lower-limb muscle strength and BMD) in trained compared to active untrained subjects. One of the limits of these studies is the low number of participants and the systemic transposition of the positive results obtained in skeletal muscle. It is possible that other factors in addition to training may influence these results. However, considering the background homogeneity of the examined subjects , we can assume that the positive effects observed in muscle and systemic level could be ascribed to the specific football training.Molecular studies on football training and health are rather few, to the best of our knowledge those reported in this manuscript - one conducted on adults and two on older subjects ,92,100 -Over the past decade, growing evidence has demonstrated the efficacy of recreational football training in the improvement of metabolic, CV and musculo-skeletal fitness, thus promoting football as a useful tool for health promotion at all ages, also in terms of CV and metabolic non-communicable disease prevention.Most recent studies have demonstrated that long-term football training counteracts the decline in oxidative capacity in muscle mitochondria and positively affects the expression of molecular biomarkers involved in DNA repair and senescence suppression pathways, promoting successful aging.The strength of this review is linked to a comprehensive analysis of the clinical-metabolic and molecular studies conducted on older players of long-term recreational football. Here we provide an holistic analysis of the effects mediated both at molecular (muscle) and systemic level associated with the improvement of health in long-term football older players. The molecular studies discussed in this review represent a novelty in that, even if they only refer to a limited number of subjects, no other data are present in the literature to the best of our knowledge.The interest in these topics lies in the promising findings deriving from reported studies that could in turn stimulate future scientific research devoted to broadening and deepening insight into the systemic improvements induced by ball-games training in older subjects mediated by muscle molecular modifications. Finally, we hope that this review will also focus research on the minimum volume of exercise that can induce improvement at local and systemic level for successful aging."}
{"text": "As the COVID-19 pandemic causes a record number of people to work from home, this disruptive event will likely have a long-lasting impact on work arrangements. Given existing research on the effects of working from home on hours worked and wages, an increased availability of working from home may provide a chance for women to catch up with their male counterparts. Yet, the need to simultaneously care for children during the COVID-19 lockdown may also revive traditional gender roles, potentially counteracting such gains. We discuss the likely effects of the COVID-19 pandemic on gender gaps in the labour market and at home in light of recent empirical findings and novel statistics on the heterogeneous structure of work arrangements among couples. We construct a novel teleworkability index that differentiates between fully teleworkable, partly teleworkable and on-site jobs and find that in about a third of households the COVID-19 shock is likely to induce shifts in the intra-household allocation of tasks from mothers to fathers."}
{"text": "Asians are the largest and the fastest growing segment of the world population, and the second largest immigrant population in the U.S. A high proportion of Asians live in developing countries or are immigrants to developed countries. Studies on age-related social and health issues of Asians have lagged. To advance research into aging among Asians living in the U.S. and elsewhere in the world, sound methodologies can be adopted from those well-developed in other settings while novel methodologies are to be developed to meet the unique needs of Asian studies. This symposium brings together five abstracts that address a variety of innovative methodological issues in social and health studies among Asian older adults. The topics range from use of wearable devices to measure travel patterns, life space and physical activity in late-life Asian immigrants in the U.S.; use of Ecological Momentary Assessment method to examine influences of social contact satisfaction on neighborhood affect in Chinese in mainland China; use of multilingual age-friendly touch-screen device for cognitive intervention in Singapore; use of GIS to evaluate potential influences of accessibility to neighborhood living resources on attitudes towards aging among the oldest old in Shanghai; and use of a multi-phase complex mixed methods to evaluate a Chinese cancer screening program in Taiwan. Together, these studies showed that innovative methods can be adapted for context relevance and linguistic and cultural appropriateness, and successfully executed in studies on aging among Asians. This symposium is a collaborative effort of the Aging Among Asians Interest Group."}
{"text": "A colon is missing in the article title. The correct title is: Associations of end-of-life preferences and trust in institutions with public support for assisted suicide: Evidence from nationally representative survey data of older adults in Switzerland"}
{"text": "Emerging evidence demonstrates that gut-derived signals contribute to whole body metabolic control. The interest in searching for the mechanisms underlying such contributions has been particularly fostered over the past 15 years by the remarkable efficacy exhibited by different modalities of bariatric surgery on improving glucose homeostasis and lowering body weight, since those improvements correlate with dramatic changes in circulating levels of myriad gut-derived signals.Among those signals there are peptides from the glucagon family, which includes glucagon itself, glucagon-like peptide 1 and 2 (GLP-1 and 2), and the related hormone gastric inhibitory peptide (GIP). In one way or another, these peptides play a key role in the control of glucose homeostasis and in the control of energy stores. As a matter of fact, mouse models with congenic global disruption of the receptors for those peptides (with the exception of GLP-2 receptor) exhibit a lean phenotype and resistance to diet-induced obesity. This has led to evaluation of the contribution these peptides make to the metabolic benefits of bariatric surgery. Furthermore, GLP-1 has become the foundation of a novel class of peptide-based therapeutics for the treatment of diabetes and obesity  and by observations on in vitro systems. These and other aspects suggesting a role for these peptides in regulating fat stores by directly acting on adipose tissue have been comprehensively examined in a recent review by Beaudry and Drucker . SupportThus, a general corollary extracted from the review by Beaudry and Drucker  is that In the interim, analysis of the role of the action of the glucagon peptide family on other cell types, such as the role of GIP receptor in immune cells, has recently revealed itself as an unexpected but critical site of action for the control fat stores . Hence,"}
{"text": "Correction to: BMC Public Health 20, 1576 (2020)https://doi.org/10.1186/s12889-020-09649-7It was highlighted that in the original article  the AcknIncorrectStapenhill Dental Practice and the dental team who facilitated completion of the study \u2013 Burton on Trent.Knights Pharmacy and the pharmacy team who facilitated completion of the study - Bromsgrove.CorrectNova Biomedical - The team at Nova Biomedical generously provided testing equipment and consumables for completion of the project in addition to providing staff training in the appropriate use of all testing equipment.Siemens Healthineers \u2013 Mr. S Carey, Mr. A Sheppard and the team at Siemens Healthineers who generously provided testing equipment and consumables for completion of the project in addition to providing staff training for the appropriate use of all testing equipment.Stapenhill Dental Practice and the dental team who facilitated completion of the study \u2013 Burton on Trent.Knights Pharmacy and the pharmacy team who facilitated completion of the study - Bromsgrove."}
{"text": "Large-scale population-based data collecting repeated measures of biomarkers, follow-up data on events , and extensive genetic data provide excellent opportunities for applying statistical models for joint analyses of longitudinal dynamics of biomarkers and time-to-event outcomes that allow investigating dynamics of biomarkers and other relevant factors (including genetic) in relation to risks of diseases and death and how this may propagate to the future. Here we applied one such model, the stochastic process model (SPM), to data on longitudinal trajectories of different variables , other relevant covariates , and data on onset of Alzheimer\u2019s disease (AD) in the Health and Retirement Study. We observed that different aging-related characteristics estimated from trajectories of respective variables in SPM are strongly associated with risks of onset of AD and found that these associations differ by sex, APOE status (carriers vs. non-carriers of APOE e4) and by PGS groups. The approach allows modeling and estimating time trends  in relevant dynamic characteristics in relation to the disease onset. These results provide building blocks for constructing the models for forecasting future trends and burden of AD that take into account dynamic relationships between individual trajectories of relevant repeatedly measured characteristics and the risk of the disease. Such models also provide the analytic framework for understanding AD in the context of aging and for finding genetic underpinnings of such links between AD and aging."}
{"text": "Gerontologists have the opportunity to step into an increasingly significant role as public educators who convene gatherings focused on expanding aging awareness and literacy, inter-generational inquiry and collaboration, and age inclusion, equity and justice. The purpose of this presentation is to share creative design principles and keen take-aways from several ongoing community-based educational interventions connected to these themes. As well, we will discuss the role such public-facing initiatives might play in making a compelling case for the importance of supporting and participating in various kinds of formal educational pathways in the field of aging. Part of a symposium sponsored by the Community College Interest Group."}
{"text": "The second stage of the CMS Region IV project involved a series of 20 half-day workshops and five follow-up webinars to introduce Go to the Hospital or Stay Here?, the training resources available , and strategies for implementation. Altogether 1124 representatives from long-term care facilities, state agencies, ombudsman groups and hospitals attended these interactive workshops. Polled participants reported that resident and family insistence on transfer to the hospital was a major barrier to successful reduction of acute care transfers for them. Those who implemented the Guide facility-wide reported an average 28% reduction in transfers. Primary barriers to facility-wide implementation were lack of leadership, making a choice to absorb the cost of financial penalties and failure to distinguish the goal of Guide use from those of existing transfer reduction programs. The facilities found the workshops helpful preparation for effective implementation of the Guide."}
{"text": "Cytidine triphosphate (CTP) is at the crossroad of the processes allowing SARS-CoV-2 to multiply, because CTP is in demand for four essential metabolic steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope, it is a critical building block of the host transfer RNAs synthesis and it is required for synthesis of dolichol-phosphate, a precursor of viral protein glycosylation. The CCA 3\u2019-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. This unique metabolic setup allowed us to highlight and provide a"}
{"text": "Mobility limitations are the most prevalent late life disability and are strongly associated with negative health outcomes. Research suggests that 1 in 5 older adults with limitations in activities of daily living report needing more help than is received. The objective of this study is to address a gap in the literature by directly examining the relationship between adverse consequences  of unmet in-home mobility care needs and hospital stay for a national sample of community-dwelling older adults. Data was analyzed from round eight (2018) of the National Health and Aging Trends Study (NHATS), an epidemiologic panel study of nationally representative Medicare beneficiaries ages 65 and older living in the communities . Community dwelling adults with one or more adverse consequence due to in-home mobility limitation had 1.931 times odds of hospital stay in the last 12 months, compared to the counterpart with no in-home mobility limitation , after adjusting for the covariates. Community-dwelling older adults who have adverse consequence due to unmet in-home mobility care needs are more likely to be immobile and are more likely to have hospital stays. By addressing the needs of this population, the rate of hospitalization can be decreased resulting in fewer stressful events and better quality of life. Policies to improve long-term services and supports and reduce unmet need could benefit both older adults and those who care for them."}
{"text": "Whenever one looks plant -made chemicals, everyone is fascinated with their huge chemodiversity, being estimated at over one million metabolites . The impacts of natural climate and geography on the metabolome of tobacco is reported by Ma et al.. The paper by \u0160amec et al. deals with the metabolome of the Psilotales, which exhibit unique anatomical character in the fern lineage.Metabolomics has now maturely held an indispensable position to decipher the chemodiversity of plants. However, peak annotation of acquired data by untargeted analysis is still challenging. Kusano et al. provides an evolutional perspective regarding two transferases often involved in plant secondary  metabolism; another perspective paper by Shirai and Hanada discusses the effects of copy number variations on functional divergence in the cross-species and inside-species diversity. Shoji proposes the evolutional model based on recruitment of genes by focusing on jasmonate-responsive transcription factors. The Mini-Review article by Maeda provides insight on the evolutional diversification of plant primary metabolism concerning the robustness of plant metabolism and further diversification in specialized metabolism.Several articles deal with an evolutionary consideration in the expansion of plant chemodiversity. Two Perspective articles discuss on evolution aspects: The report by Schwachtje et al. discusses the imprinting and priming plant metabolism against upcoming environmental challenges as a novel concept for adaptation and diversification of plant metabolism responding to stresses. To obtain further insights on mechanisms of plant natural products biosynthesis, computational chemistry may play a central role\u2014Sato et al. present an overview of cutting-edge aspects of application of computational chemistry on the biosynthetic mechanisms of plant specialized metabolites.Two papers deal with the novel concept and approach to extend our understanding of plant metabolism. The Hypothesis and Theory article by Yonekura-Sakakibara et al. discuss the origin of flavonoid biosynthetic enzymes with functional genomics implication in their comprehensive Review Article. Another Review Article  provides the current information about the flavonoid pathway in the bryophytes . The role of the flavonoid metabolons formed by specific protein-protein interactions of the biosynthetic enzymes is discussed in the Review Article . The Original Research Article by Cheevarungnapakul et al. reports the genes for the biosynthesis of caffeoylquinic acids in sunflower.The rest of the 13 articles focuses on relatively the pathway-specific metabolism or metabolites with some generalization across the biosynthetic pathways. Four papers deal with flavonoids and phenylpropanoids. Karunanithi and Zerbe provides up-to-date knowledge on the functional diversity and molecular evolution of the plant terpene synthases widely across the plant kingdom. The Original Article contributed by Muchlinski et al. reports biosynthesis and emission of mixtures of monoterpenes and sesquiterpenes triggered by the generalist herbivore in Switchgrass. Three papers focus on triterpenoid saponins. Lei et al. studied the large-scale profiling of saponins in 201 ecotypes of Medicago truncatula. The Original Article by Fanani et al. reports the detailed investigation on the molecular basis for C-30 oxidation of triterpenoids leading to the production of high-value saponins such as glycyrrhizin in Legume licorice. C\u00e1rdenas et al. in their Mini-Review Article discuss convergent and divergent evolution in triterpenoid biosynthesis, and the mechanisms increasing structural diversity within and across plant species.Terpenoids form the largest sub-family of specialized metabolites with their immense possibility in the expansion of structural diversity. The Review Article by Morris and Facchini(a); Morris and Facchini(b) provide an overview of the functional diversification of methyltransferases in the biosynthesis of benzylisoquinoline alkaloids. The Review by Chhajed et al. discusses the cellular and subcellular organization of the glucosinolates -myrosinase system, its chemodiversity and functions in different cell types, emphasizing single-cell-type studies. Sugiyama and Hirai provide an up-to-date information on the diversity and the role of atypical myrosinases beyond the classical model of glucosinolates -myrosinase system.Three contributions dealing with nitrogen- and sulfur-containing specialized metabolites are included. Overall, this Research Topic becomes an excellent anthology to exhibit state-of-the-art on the theme of Topic by contributions from world-experts of this field. The Research Topic can play a role as a sort of flagship topic of the Specialty Section of Plant Metabolism and Chemodiversity. The curiosity-driven fundamental research on the origin and evolution of diversification of plant chemicals is primarily essential. Besides, the basic knowledge obtained could contribute to solving the current global problems such as climate crisis and pandemic diseases. I hope this Research Topic could be a landmark of future research in this field.KS contributes entirely to the paper.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Significance: Photothermal optical coherence tomography (PT-OCT) has the promise to offer structural images coregistered with chemical composition information, which can offer a significant impact in early detection of diseases such as atherosclerosis.Aim: We take the first step in understanding the relation between PT-OCT signals and the endogenous tissue composition by considering the interplay between the opto-thermo-physical properties of tissue as a function of its lipid composition and the ensuing effects on the PT-OCT signals.Approach: Multiparameter theoretical estimates for PT-OCT signal as a function of composition in a two-component lipid\u2013water model are derived and discussed. Experimental data from various concentrations of lipid in the form of droplets and injections under bovine cardiac muscle align with theoretical predictions.Results: Theoretical and experimental results suggest that the variations of heat capacity and mass density with tissue composition significantly contribute to the amount of optical path length difference measured by OCT phase.Conclusion: PT-OCT has the potential to offer key insights into the chemical composition of the subsurface lipid pools in tissue; however, the interpretation of results needs to be carried out by keeping the nonlinear interplay between the tissue of opto-thermo-physical properties and PT-OCT signals in mind. Only when PT-OCT imaging is carried out on aqueous samples containing relatively low amounts of exogenous agents or dissolved moleculesOnce x change  and the Here, tems see , the qua,,To get a better understanding of the predictions of the developed model, we simulated the PT-OCT responses of various ratios of mayo\u2013water mixtures. The opto-thermo-physical properties used for pure mayo and water , employing broadband light of a superluminescent diode centered at 1310\u00a0nm . The scattering of the 0% mayo sample was adjusted to those of other mayo concentrations using titanium dioxide powder. For the dilution experiments, the average of the pixels in the PT-OCT B-mode images were normalized to that of the 100% mayo sample, as seen in ,Imaging results of the artificial lipid-rich plaques are shown in In summary, this work provides a theoretical model and a preliminary experimental study demonstrating the feasibility of obtaining insights into the chemical composition of biological tissues using PT-OCT. The developed model and experimental results suggest that the relation between PT-OCT signals and the concentration of an absorbing component in the tissue is nonlinear, and that the degree of this nonlinearity is determined by the contrasts of a component\u2019s opto-thermo-physical properties Click here for additional data file."}
{"text": "We thank Charre and colleagues for spotting the mis-annotation of sequences in our database, which was caused by human error. The problem has been corrected. In the future, we recommend submitting bug reports directly to one of the e-mail addresses indicated on the HDVdb Web page."}
{"text": "Myocardial infarction (MI) consists of a central fibrous scar surrounded by a heterogeneous region of viable and non-viable myocytes. The peri-infarct gray zone provides the potential substrate for lethal ventricular arrhythmias via the reentry phenomena. The extent of the gray zone, characterised by delayed-enhancement MRI (DE-MRI), has been shown to be a strong predictor of mortality  and to tIn this work, preliminary results are presented examining the relationship between the extent of gray zone and inducibility of VT as well as VT cycle length.Eight patients  with an ischemic cardiomyopathy referred for implantable cardioverter defibrillator (ICD) implantation  and non-inducible in five patients. Imaging results within the two patient groups are shown in Table These results confirm that inducibility for VT is correlated to the size of the peri-infarct gray zone as assessed by MCDE. The higher variability in the IR-GRE analysis may contribute to the lack of a significant difference in the gray zone size between inducible and non-inducible patients in this small group of patients. We have also shown that the VT cycle length is correlated to the size of the MCDE-derived gray zone, consistent with previous results showing a positive correlation between VT cycle length and isthmus size measured during programmed electrical stimulation ."}
{"text": "International comparisons of the aging experience offer a unique opportunity to understand how much the aging process varies according to differences in social environments. Despite the potential knowledge gained from global comparisons of health and aging, conducting cross-national comparisons can be challenging. The HRS-family of surveys, which have been harmonized within the Gateway to Global Aging, provides remarkable opportunities for cross-national comparative analysis. The papers in this session use harmonized data to compare the aging experience across different social dimensions in multiple countries from around the world, including examinations of: 1) the role of social engagement among married couples in cognitive function in Mexico and the United States; 2) the importance of work histories and macro-economic policies on later life health in England and Europe; 3) gender differences in the receipt of informal care in the U.S., Korea, and China; 4) the association between sensory impairment and disability-free life expectancy in England and the U.S.; and 5) end-of-life care arrangements and health care utilization in the context of different health systems across multiple countries."}
{"text": "We report on the source of  We computed the The high intensity of the event at STB is evident from the \u201csnow storm\u201d visible in Figures\u00a0mentclasspt{minimaet al.  in radio and hard X-ray bursts, while protons produce the impulsive-phase The shock is another source of energetic particles that have access to the open field lines threading through the shock and hence travel both toward and away from the Sun. The shock-accelerated particles thus occupy a volume much larger than that of the PEA and flux rope and surround the flux rope. Electrons escaping the shock front produce type II radio bursts at the local plasma frequency and harmonics. The bursts can start typically at a frequency of Figure\u00a0Recently Hudson  criticizet al.  and the average speed in the coronagraph FOV of et al. The SGRE and type II burst durations in the SOL2014-09-01 backside eruption are consistent with the linear relationship between the durations found in all (ii)The magnetic structures in the eruption  inferred from observations suggest a large east\u2013west extent making it possible for the presence of the particle-precipitation region on the frontside solar disk in Earth view.(iii)The largest extent of the SGRE source is inferred as the separation between the shock sheaths at the flanks of the flux rope. This means if limb is within the face-on angular half width of a behind the limb flux rope, one can still see (iv)The large extent of the SGRE source implies that part of it is hidden in the case of limb events.(v)The CME/shock kinematics, the hard SEP spectrum, and the association with type II radio bursts over a wide range of wavelengths imply a very energetic CME with copious production of high-energy (up to GeV) particles needed for the production of SGRE via neutral pion decay. This is consistent with the fact that some (vi)The SGRE ended when the shock reached a heliocentric distance of (vii)The equivalent flux of We performed a detailed investigation of the SOL2014-09-01 behind-the-limb eruption that resulted in the fourth largest SGRE event (in"}
{"text": "I present a review on the book \u201cThe Story of Catch\u201d by Ruslan C. Pashayev a wrestling history enthusiast from Columbus, Ohio, United States who is also an expert-member of the Traditional Sports Team of the Instytut Rozwoju Sportu i Edukacji (the Institute of Sport Development and Education), Warsaw, Poland. Meticulous research and attention to detail have made Ruslan C. Pashayev one of the foremost authorities on the history of Western European Catch-Hold traditional styles of wrestling (folk wrestling styles), particularly the Lancashire Catch-as-Catch-Can style.\u201cThe Story of Catch\u201d is the only major book ever to cover this subject or the time period that began a variation of professional wrestling which is known around the world as \u201cLancashire Catch Wrestling\u201d or simply \u201cCatch.\u201d Besides that \u201cThe Story of Catch\u201d covers the history of various Western European traditional catch-hold wrestling styles which predated and \u201cfathered\u201d Lancashire catch-as-catch-can as well as tracing the origin and explaining the evolution of modern International Olympic styles of wrestling such as Graeco-Roman and Freestyle. The purpose of his work was to establish the truth about the origin of Lancashire catch wrestling and explain the evolution of this cultural phenomenon.Seven years of research in various libraries, local studies, historical societies, archives, registration and record offices, and museums in Great Britain in particular those located in the towns of East Lancashire  and in West Yorkshire, as well as in the British Library, American Library of Congress, and many others. The memoirs of individuals, historical books, documents, newspapers, and magazines all have played a part in the overall success of the studies that led to this work.This book presents a pivotal study in restoring the history of Lancashire catch-as-catch-can wrestling. Ruslan C. Pashayev's research clearly is both revolutionary and eye-opening. The author has done an amazing work of research in tracking down and documenting the true origins of catch-as-catch-can wrestling. He cuts through the myths and legends that have evolved around this wrestling style over the decades and presents irrefutable evidence as to its introduction to the Lancashire County of England and its amazing growth in the mid and late nineteenth century. By analyzing thoroughly historical documents, including newspapers of the time, the author has successfully challenged much of the traditionally perceived history of the sport. His inquiries resulted in an absorbing revelation of the foundations and development of a sport that was destined to become a social phenomenon of the twenty-first century. His investigations have unveiled the ethnic and geographical origins of the Lancashire Catch-as-Catch-Can style, the wrestling styles that preceded Catch in the region of East Lancashire, and the emergence of a professional category in this sport. Like a modern day detective Ruslan C. Pashayev has pieced together the forensic evidence to weave an absorbing chronicle of Lancashire wrestling's fascinating history. Besides that it is written clearly, with attention to detail and humor that only one with a deep understanding of the wrestling sport could even appreciate.The book starts with the author giving very detailed information and analyses of the various traditional wrestling styles (both catch-hold and fixed-hold styles of wrestling) which were historically practiced in different parts of England in particular in the areas of East Lancashire and West Yorkshire. Then author explains the history of the term of Catch-as-catch-can (catch/take a hold of someone as one pleases) wrestling in England throughout the centuries and resumes by providing a great account of two kinds of catch wrestling styles which were around in the early 1800s, the London Catch-as-catch-can and Lancashire Catch-as-catch-can styles of wrestling.Among the revolutionary discoveries made by the author was the introduction of the up and down catch-as-catch-can wrestling by the immigrants (textile workers) from Continental Europe  in East Lancashire and West Yorkshire in the fourteen to seventeen centuries  and its transformation into a professional Lancashire up and down fighting and establishment its major centers in the towns of East Lancashire (Pre-1800s). Tracing the roots of Lancashire catch-as-catch-can wrestling to the \u201cFlemish weavers\u201d the immigrants from the Medieval County of Flanders who brought their free-for-all traditional style of wrestling called Stoeijen to East Lancashire was instrumental in explaining two major features of Lancashire catch wrestling (catch hold of any part of the body above and under the waist and ground wrestling) which significantly differed from those of the traditional English styles of wrestling and weren't found anywhere else in England outside the areas of East Lancashire and West Yorkshire. Those two features of Lancashire catch wrestling previously remained without any explanation for so long until the author of this book successfully resolved this major historical paradox.Further in the book the author talks about the abolition of illegal pro Lancashire up and down fighting and introduction of the modern pro catch wrestling in East Lancashire which happened in the 1820s. The information about the establishment of the Rules of the Game which occurred in the 1840s-50s (the time period which produced the first generation of Lancashire pro wrestling superstars) was uniquely interesting. Arguably the most important part of the book from the historical point of view is the one which talks about the Golden Era of Catch Wrestling, the 1860s. In this the section of the book the author provides previously unknown detailed information about the earliest pro wrestling promotions (championship titles), the great champions and championship lineages of the most glorious epoch of catch. The Author fully and completely explains the rules according to which the pro wrestling business was operated in East Lancashire and how it affected and shaped the modern day pro wrestling.In the second part of the book the author highlights pro wrestling during the so-called Era of Claimants, the epoch which followed the heyday of Lancashire wrestling and the immigration of Lancashire Superstars to America in the 1870s-1900s.In the very end of the book the author is giving a descriptive analyses of the early 1900s situation in pro catch wrestling in Britain during the era called the Wrestling Boom or the music halls era of catch (1899- Pre-WW1) as well as he speaks about the destiny of catch wrestling in twentieth century  and prophesizes about it's future.traditionalsports.org), Wrestling Heritage of UK (wrestlingheritage.co.uk), Pro Wrestling Historical Society , and Wrestling Titles History (wrestling-titles.com).The research presented in this book was rated as being of high historical value by the foremost American (such as Mark Hewitt and Steve Yohe) and British (such as Alan Bamber and Ron Harrison) wrestling historians. \u201cThe Story of Catch\u201d was very well received all around the world and is now promoted on the various wrestling history studies websites such as Traditional Sports (\u201cThe Story of Catch\u201d also presents numerous historical photos, captions, and illustrations, some of which have never been seen before. Whether one is a wrestling fan, wrestling history scholar, wrestling and MMA enthusiast, or practitioner the research of this indefatigable historian and his \u201cThe Story of Catch\u201d are a must read.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Recent advances in noninvasive Brain-Machine Interfaces (BMIs) have demonstrated the potential impact of directly interfacing the brain with machines. The ultimate translational goal of BMI systems is to enable people suffering from severe motor disabilities to control a new generation of neuroprostheses and, thus, (re)gain their own independence.Many studies have already demonstrated the feasibility of the BMI technology with different kinds of assistive devices, designed to restore communication  or to enable the control of robotic applications . However, despite great progress, the integration of the BMI and robotics is still in its infancy and translational impact is low.The BMI community has predominantly focused on exploring novel algorithms to decode the user\u2019s intentions from neural patterns with a focus on enhancing the robustness and the reliability of the BMI system. However, the process of how the estimated intentions of the user are translated by the intelligent robotic device into real and daily-based situations is often neglected. This largely affects the translational impact of the BMI technology. The latest advances in the field of robotics may help address this challenge by exploiting novel human\u2013robot interaction theories and by providing insights and solutions from a new and different perspective.This special topic sought original contributions that explicitly take into account the cross-cutting aspects in BMI and robotics research including but not limited to BMI control of navigation robots, BMI control of robotic prosthetic limbs, BMI-driven assistive technology for end users, translational aspects in BMI-controlled devices, shared-control strategies for the BMI, contextualized robotic behaviors, long-term human\u2013robot interaction (BMI\u2013robot interaction), semi-autonomous robot behaviors, evaluation of BMI-driven robotics in real-world scenarios, and real-time detection of possible targets in real-world scenarios. All typologies of closed-loop BMI systems  were solicited if they focused on the integration of BMI and robotics devices. We are pleased with the interest in the topic and the collection of studies presented, which include two state-of-the-art reviews, one on neural driven rehabilitation robotics for lower limb gait rehabilitation and another human affective states when interfacing with robotic devices, as well as five novel studies investigating a range of BMI robotic learning scenarios and signal decoding in invasive and noninvasive BMIs, all of which highlight opportunities and challenges to advance the integration of Brain-Machine Interfaces and Robotic devices.Alirmardani and Hiraki focused on the current employment of BMIs in human\u2013robot interaction applications. They illustrated the state of the art of passive BMIs and the current challenges to monitor and decode cognitive load, attention level, perceived errors, and emotional states in real time.In their review, Kim et al. investigated the influence and the effect of human supervision on robot learning during pick-and-place tasks. In the proposed experimental scenario, two human\u2013robot interfaces were provided: the first one based on human gestures to decode the human\u2019s intent and the second based on error-related potentials to provide the human\u2019s intrinsic feedback of the performed robot action. They demonstrated that such a human\u2013robot interaction promoted robotic learning and the concurrent online adaptation, especially when prior knowledge about the task was provided.Wirth et al. showed the possibility of exploiting a single-trial P300-based BMI to discriminate when a virtual robot has reached a predefined destination during navigation tasks. They proposed this approach as part of a learning-based system to enhance the efficacy and efficiency of BMI-driven applications for navigation.Monitoring robot behavior through the evaluation of possible mistakes may be not the only way to foster the learning process of intelligent devices. Kolkhorst et al. showed that a robotic agent could improve the usability of an event-related potential BMI by obviating the traditional need of an external screen for stimulus presentation. They exploited a robotic arm to present stimuli by highlighting objects in a realistic environment with a laser pointer. The proposed classification method, based on specialized classifiers in the Riemann tangent space, reported not only high accuracy but also robustness to both heterogeneous and homogeneous objects.Similarly, Huang et al. proposed a hybrid BMI system to control an integrated wheelchair-robotic arm system. A motor imagery BMI was used to deliver navigation commands to the wheelchair and an electrooculogram-based interface for the control of the robotic arm. Interestingly, the system allows the users to voluntarily renew the classification parameters during online operations by means of a specific sequence of commands.Beyond exploiting the \u201chuman-in-the-loop\u201d approach to monitor robot behaviors, BMI systems can be also used to directly control the movement of robotic actuators. While most studies to date demonstrated the feasibility of mentally driving a single assistive device, Kim et al., authors proposed a new decoding algorithm based on deep canonical correlation analysis and neuronal firing rate activities that improves the kinematic reconstruction in a 2D arm reaching task performed by nonhuman primates. The algorithm was designed to identify the best kinematics-related canonical variables of neuronal activity via deep learning\u2013based approaches. As highlighted in the study, the prediction of kinematic parameters of a prosthetic device from neural activities can have profound consequences in BMI clinical applications.In Lennon et al. conducted a systematic review of the current state of the art and limitations of neural driven robotic gait devices in stroke rehabilitation. Despite identifying a limited number of promising studies to date, the review highlighted wide heterogeneity in the reporting and the purpose of neurobiosignal utilization during robotic gait training after a stroke and the lack of standardized protocols. A quick reference guide (the DESIRED Checklist) is proposed to identify a minimum reporting data set as a standard for future studies in order to maximize the translational impact of the technology.Finally, In summary, in the BMI field, the role of the robotic intelligence is often underestimated by relegating the robotic device to a mere actuator of the user\u2019s commands. This collection highlighted challenges to be addressed and potential solutions, standards to adhere to when undertaking studies, and the importance of further investigating the potential bidirectional human\u2013robot interactions in BMI applications in order to improve the overall efficiency of these novel interfaces and to design a new generation of neuroprosthetic devices."}
{"text": "Compared with normal strength concrete (NSC), ultra-high-performance steel fiber-reinforced concrete (UHPFRC) shows superior performance. The concrete damage plasticity (CDP) model in ABAQUS can predict the mechanical properties of UHPFRC components well after calibration. However, the simulation of the whole structure is seriously restricted by the computational capability. In this study, a novel multi-scale modeling strategy for UHPFRC structure was proposed, which used a calibrated CDP model. A novel combined multi-point constraint (CMPC) was established by the simultaneous equations of displacement coordination and energy balance in different degrees of freedom of interface nodes. The advantage is to eliminate the problem of the tangential over-constraint of displacement coordination equation at the interface and to avoid stress iteration of the energy balance equation in the plastic stage. The expressions of CMPC equations of typical multi-scale interface connection were derived. The multi-scale models of UHPFRC components under several load cases were established. The results show that the proposed strategy can well predict the strain distribution and damage distribution of UHPFRC while significantly reducing the number of model elements and improving the computational efficiency. This study provides an accurate and efficient finite element modeling strategy for the design and analysis of UHPFRC structures. Concrete is currently the most widely used building material. Although many structures are built with concrete, the use of normal strength concrete (NSC) still has some limitations, such as low tensile strength and low ductility. Improving the mechanical properties of concrete to obtain higher strength and higher ductility has been widely of concern. Ultra-high-performance steel fiber concrete (UHPFRC) is a new type of fiber concrete, with high strength, fracture toughness, and ductility. Its compressive strength and tensile strength are generally over 150 MPa and 7 MPa, respectively ,3,4,5, aExtensive tests are required at the material and structural levels in order to develop standard analytical procedures and design specifications for UHPFRC, which will take a lot of time and cost. Therefore, verifying the concrete material models in the existing finite element software by conducting a limited number of well-formulated tests on the material and structure levels is a way to save time and cost. The verified concrete material model and finite element modeling method can be used to establish extended analysis of various design parameters. In addition, the influences of changes in geometry, load cases, and reinforcement on mechanical properties of UHPFRC can be investigated. The finite element software ABAQUS is equipped with the concrete damage plasticity (CDP) model developed for NSC, which is a mature and reliable tool for predicting the mechanical behavior of NSC ,30,31. CSimilar to the investigations of NSC, the investigations of UHPFRC need to be developed to the structural level as well as the material and component level. However, it is very expensive to establish a full-scale structural test, which is seriously restricted by the test conditions. When the calibrated CDP model is used to simulate a single UHPFRC component, the reduction of mesh size and the increase of number of elements will significantly increase the calculation time, while larger mesh size will lead to convergence problems . TherefoIn order to promote the development of finite element simulation of UHPFRC structure, a novel multi-scale finite element modeling strategy was proposed in this study. A novel combined multi-point constraint (CMPC) based on displacement coordination and energy balance was established, aiming at the problems of the tangential over-constraint and the requirements for nonlinear stress iteration existing in the single multi-point constraint method. The nonlinear constitutive relationship of UHPFRC is considered. The multi-scale models of UHPFRC components under various load cases were established in the finite element software ABAQUS. The comparative analysis results show that the proposed multi-scale modeling strategy can well predict the strain distribution and damage distribution of UHPFRC components while significantly reducing the number of model elements and improving the computational efficiency. This study provides an accurate and efficient finite element modeling strategy for the design and analysis of UHPFRC structure, which can promote the application and development of UHPFRC in the construction industry.The concrete damage plasticity (CDP) model is a concrete material model for NSC in the finite element software ABAQUS. It is a mature and reliable tool for predicting the mechanical behavior of NSC ,30,31. IIn this study, the UHPFRC beams named as B25-1 and B25-2  are chosAccording to the design diagram of UHPFRC beam specimen and the design of loading device, the corresponding finite element model of the test was established in ABAQUS with mesh size of 25 mm. The details of the reinforcement, mesh and load boundary condition of the finite element (FE) model are shown in The test results and simulation results of the four point bending test of the two UHPFRC specimens are shown in iS  signifies micro element nodes with 3 degrees of freedom and B signifies macro element node with 6 degrees of freedom.In the multi-scale model, the interface connection of different scale elements can be established by the constraint equations according to the degrees of freedom of interface nodes. The sketch of the interface connection of multi-scale model shown in C is the coefficient matrix of interface constraint equations.According to the coupling relation of degrees of freedom of nodes, the unified form of the constraint equations of the multi-scale interface connection is as follows:C. If the constraint equations can effectively simulate the actual deformation coordination, a better effect of the coupling can be obtained.The accuracy of multi-scale simulation depends on the rationality of coefficient matrix ib, ih are the distances from the node i of the micro element to the macro element node; The solution of multi-point constraint equations is usually based on the single constraint relation such as displacement coordination  or energIn the Equation set (2), the first equation is the axial and rotational constraint equation, which is established by displacement coordination. The last three equations are tangential constraint equations, which are established by energy balance. The aim is to eliminate the limitation of the single constraint relation in the plastic stage and improve the simulation accuracy of the multi-scale model.Based on the multi-point constraint relation of displacement coordination, the tangential deformations of all micro element node at the interface are assumed to be consistent, and the displacement constraint relation of each node is established one by one. The deformation diagrams of displacement coordination are shown in In the CMPC equation set, the displacement constraint equation in the tangential direction of the interface nodes can be obtained after the stress is eliminated by substituting the formula for the shear stress distribution:The interface deformation under axial compression at the plasticity stage of the multi-scale model is shown in The multi-point constraint relation based on energy balance is established by the virtual work principle. It is assumed that the nodal force of the macro element and the nodal forces of the micro elements do equal work at the interface in the rotational direction. The equation is as follows:The normal stress distribution of UHPFRC section under bending moment is shown in The CMPC method establishes the multi-point constraint equation of the interface in rotational direction based on the displacement coordination. The axial displacement of each node of the micro elements can be obtained through the s constraint equation (see the first equation in Equation set (2)). After entering the strain-hardening stage, this multi-point constraint equation avoids the problem that the formula for stress distribution needs to be updated iteratively. Therefore, the CMPC method proposed in this paper combines the advantages of displacement coordination method and energy balance method. The multi-point constraint equations conform to the transfer relations of displacement and stress between the interface nodes. It can achieve good constraint effect in axial, tangential, and rotational directions. It is applicable to the analysis of UHPFRC components under complex loads.According to Equation set (2), displacement vector b and h are the width and height of the rectangular section, respectively.In the Equation set (6), the first equation is the constraint equation of axial and rotational displacement, which can be solved according to the displacement coordination. The last three equations are the constraint equations of tangential displacements, which need to be solved by substituting the formula for stress distribution. For example, the formula for shear stress distribution of the rectangular section in the y direction is as follows:After solving the Equation set (6), the following can be obtained:The CMPC multi-scale modeling strategy with the same parameters selected above is adopted to establish the multi-scale models of reinforced UHPFRC components, as shown in In the micro element model, C3D8R elements are used to model UHPFRC with the calibrated CDP model which is the same as that in the second section. The reinforcement is simulated by T3D2 element. In the macro element model, B31 elements are used to simulate UHPFRC and the reinforcement net. The uniaxial stress-strain relationship of the material subroutine (UMAT) of UHPFRC is the same as that of the calibrated CDP model. The section size of the B31 element of the reinforcement net is calculated equivalent to total reinforcement area. The material model parameters of reinforcement are the same as those in Under the axial compression load, the stress distributions of UHPFRC of the multi-scale models and the connection interface are shown in Unidirectional concentrated moment loads is applied to the loading point at the top of the models under the bending load case. The stress distribution and tensile damage distribution of UHPFRC of the models are shown in In shear load case, a concentrated horizontal force is applied to the loading point at the top of the models. The stress distribution and tensile damage distribution of UHPFRC of the models are shown in Under unidirectional load cases, the multi-scale model of UHPFRC component established according to the proposed multi-scale modeling strategy achieved good accuracy. The performance of this multi-scale model under multidirectional composite load case will be studied below.In this load case, the axial compression force, the bidirectional moments and the bidirectional horizontal forces are applied composited at the loading point at the top of the models. The diagram of multidirectional composite load is shown in Under the multidirectional composite load case, the stress distributions of UHPFRC of the multi-scale models and the connection interface are shown in Through comparison, it can be seen that the CPMC equations established based on the proposed multi-scale modeling strategy achieve good connection effect under the multidirectional composite load case. The calculation accuracy of the CMPC model for UHPFRC is consistent with that of the solid element model, which is better than the displacement coordination model and the energy balance model. The multi-scale modeling strategy proposed in this study can be effectively applied to the multi-scale finite element analysis of UHPFRC structures with accuracy and efficiency.The applicability of concrete damage plasticity (CDP) model in finite element software ABAQUS to UHPFRC was verified according to the four-point bending test results of reinforced UHPFRC beams. The simulation results show that the calibrated CDP model used in the multi-scale modeling strategy in this study can accurately and effectively predict the load-displacement curve and plastic damage distribution of UHPFRC components.A novel combined multi-point constraint method was established by the simultaneous equations of the displacement coordination equation and energy balance equation in different directions of the interface. The CMPC method eliminates the problem of the tangential over-constraint of displacement coordination equation at the interface and avoids stress iteration of energy balance equation in the plastic stage. The multi-point constraint equations conform to the transfer relations of displacement and stress between the interface nodes.The expression of the constraint equations of the multi-scale connection of beam-solid element by CMPC method was derived. The multi-scale model of the reinforced UHPFRC component was established in ABAQUS with this expression and the calibrated CDP model. The axial compression load case, bending load case, shear load case, and multidirectional composite load case are analyzed.The simulation results of the multi-scale model under each load case show that the multi-scale model established by the CMPC method can significantly reduce the number of model elements and improve the calculation efficiency. The CMPC models have good simulation accuracy in the analysis of each load case compared with the displacement coordination model and the energy balance model. In the strain-hardening stage of UHPFRC, the CMPC method can still accurately simulate the stress distribution and damage distribution of the connection interface. It can be applied to multi-scale finite element analysis of UHPFRC structures with accuracy and efficiency.This study proposed a novel multi-scale modeling strategy for ultra-high-performance steel fiber-reinforced concrete (UHPFRC) structures. The main work and conclusions are summarized as follows:"}
{"text": "The international literature presents growing evidence of the impact of life transitions in older age on experiences of social exclusion, and place in general and as well as housing in particular potentially play a mediating role in this interrelation. However, the specific mechanisms through which the older adult place relationship mediates exclusionary outcomes of life-course transitions remains poorly understood in the study of ageing. This contribution investigates how older adults\u2019 relationship to their home is interlinked with life-course transitions and old-age social exclusion. To do so, we present case studies from three different countries , focusing on the individual experiences of retirement and bereavement, and analyze them by drawing on the concepts of the person-environment exchange processes of agency and belonging. Finally, we draw conclusions about how spatial agency and belonging can protect and empower older people at critical junctures in their lives."}
{"text": "Reliable quality of life assessment is important for identification of health problems, evaluation of health interventions and planning of optimal health policies and care packages. Due to lack of a psychometrically robust measurement tool for quality of life appraisal among the Iranian older population, this study was aimed to investigate psychometric properties of the Persian version of the World Health Organization quality of life-old module (WHOQOL-OLD-P) for use on the Iranian and other Persian-speaking aged populations.The standard translate/back-translate procedure was applied to convert the English version of the WHOQOL-OLD into Persian. The face and content validities were assessed by a panel of experts including 15 specialists in geriatrics and allied fields. The Cronbach\u2019s alpha and intra-class correlation (ICC) coefficients were estimated to assess internal validity and reliability of the translated version. Factorial structure of the WHOQOL-OLD-P was also tested using confirmatory factor analyses in a sample of 400 Persian-speaking older adults (aged 60\u2009years of old and above) residing in the city of Yazd, the capital city of Yazd province, center of Iran.The internal consistency and reliability indices of the WHOQOL-OLD-P were in the vicinity of acceptable range . The confirmatory factor analysis outputs confirmed the six-factor solution of the WHOQOL-OLD-P .The study findings support validity and reliability of the WHOQOL-OLD-P for use on Iranian and possibly other Persian-speaking older populations. Further cross-cultural and comparative multinational studies are recommended to provide more vigorous evidence about feasibility and acceptability of the translated tool in diverse and multicultural Persian-speaking communities. Quality of life (QOL) assessment is considered by health scholars as an important requirement for evidence based health care decision making and policy formulation for ageing population of the world. Therefore, QOL assessment is a part of routine health care packages in many countries to ensure effectiveness of health care or innovative interventions that targeted aged populations , 2.The ratio of aged to overall population of Iran as a transitional country is rapidly increasing and based on the 2016 demographic census\u2019s results aged people constituted about 9.3% of the country\u2019s population .QOL according to the World Health Organization (WHO)\u2018s definition is the self-perception of individuals\u2019 current standpoint position in life with respect to what goals, expectations, standards, priorities, culture and value system they might have in their living ambience . Thus, tApplication of a reliable and explicit tool to measure QOL of elder people is an imperative prerequisite in health systems and also for conduction of robust research projects . HoweverThe WHOQOL-OLD as an explicit measurement instrument for QOL assessment was introduced by the WHO  and has Preeminent advantage of the WHOQOL-OLD relative to other QOL assessment tools is its development through an extensive international cooperation  that makMain aim of this study was to translate and psychometrically appraise properties of the Persian version of the WHOQOL-OLD to provide a robust measurement instrument for application in akin studies of QOL on aged Persian-speaking populations in the Middle East region and other neighborhood countries. Thus, cross-cultural and international comparisons of the findings from studies in different populations will be applicable.The study sample consisted of 400 older adults  aged 60\u2009years old and above who were registered in the two primary health care center in the city of Yazd, the capital city of Yazd province, center of Iran. The sample size was decided based on the recommended sample size (8 people per each of the instrument\u2019s items)  which is somehow consistent with the findings of other psychometric studies of the WHOQOL-OLD module on other socio-cultural contexts , 19, 36.The calculated ICC measure of reliability over time for both the total WHOQOL-OLD-P and its subscales\u2019 scores were in the vicinity of acceptable range  and simiThe identified 6-factor solution that best fitted the study data was congruent with the reported priori factor structure of the original scale  and in tRegarding the obtained results in this validation study, it can be concluded that the WHOQOL-OLD-P\u2019s application is feasible since no problem encountered in the data collection stage and a relatively limited time frame (6\u20138\u2009min for older adults with academic education and 10\u201313\u2009min for the rest of interviewees) was required to complete the scale on every individual participant.The study sample in this research consisted of elder people with at least one to three diagnosed simultaneous chronic diseases who had been registered in the two primary health care centers in the city of Yazd, the capital city of Yazd province, central part of Iran. The purposively selected health care centers and therefore, non-probabilistic sample that was selected for inclusion might be limited representativeness of the study participants and restraint extrapolation and generalizability of the findings. Comparison of the within-subjects perceived QOL measures and association of the factors such as religion, age, gender, level of education and overall health status with the estimated QOL values were not speculated in this study. Therefore; interim data collection and analysis in future corresponding studies could add further detail and explanation about precipitating factors of QOL.Iran is a multi-cultural, multi-religious and multi-ethnic country and the study findings might not be generalizable to elder people residing in the country\u2019s other provinces and geographical areas due to socio-cultural diversities.There is also possibility of the reporting bias based on the respondents\u2019 willingness and ability to provide accurate responses especially concerning the length of the WHOQOL-OLD-P, although the concern was attempted to be mitigated by emphasis on the anonymity of the participants and allocation of proper time for interview.Elder people who suffer from multiple chronic diseases are more likely to develop depression and therefore; tend to report lower quality of life . Such anMultidimensional nature of QOL and the effects posed by certain underlying factors warrant further research to examine how these circumstances might relate to self-reported quality of life among older people. QOL assessment by use of measures that actually highlight specific domains e.g. physical, emotional and social functioning or over emphasis on health-related aspect of daily life experiences may also cause bias especially in measurement of elder population\u2019s QOL . Aged peIntroduction of a valid and reliable instrument for measurement of quality of life among Iranian and other Persian-speaking elder adults was the primary objective of this study. Taking into account all above mentioned limitations, the WHOQOL-OLD-P application could be recommended as an explicit instrument for measurement of perceived QOL as a proxy measure of aged people\u2019s overall health in the Iranian and other Persian-speaking elder populations across the world. The WHOQOL-OLD-P application could enhance reliability of QOL assessment by a wide range of healthcare providers (HCPs)  in primary health care centers, secondary and tertiary care providing settings . The instrument can be utilized in routine care provision activities or in assessment of influences a specific health condition or morbidity and also subsequent restorative therapeutic intervention might have on perceived overall QOL among the aged people. Other social care providing organizations could also use the WHOQOL-OLD-P for estimation of impacts their policies, services or targeted interventions might have on elder people within the Persian-speaking countries.The WHOQOL-OLD module was translated into Persian in this study and psychometrically tested for possible application in the research and practice settings within the Iranian context. The translated version indicated robust internal consistency, reliability and construct validity. Due to growing number of aged population in Iran presence of sound data collection tool for QOL assessment will add to the accuracy of scientific knowledge and intervention modalities that target elder people\u2019s quality of life in different socio-cultural and practice settings. The WHOQOL-OLD\u2013P utilization in future studies will also make comparison of cross-region and cross-border health status of elder people attainable and desirable."}
{"text": "This paper highlights some peculiar characteristics of the economic crisis induced by the spread of COVID-19. It suggests two intertwined policy measures in order to tackle the emergency phase of the crisis and to support the economy in the subsequent recovery phase. The proposed short-term policy measures offer policy responses in the event of a second wave of coronavirus infections in the coming months. In the aftermath of the emergency phase, the current proposal puts forward the implementation of a massive EU-wide recovery plan addressing the long-lasting technological and environmental challenges of these years, which will be financed by European institutions through the issuance of European Pandemic Recovery Bonds."}
{"text": "Despite its origins in the study of race in America in Gunnar Myrdal\u2019s American Dilemma, research on cumulative dis/advantage (CDA) and the life course has paid little attention to the significance of racism in the overall production and patterning of CDA. Building on recent work that has reviewed the life-course implications of the inscribing of racist interests in social policy, this paper explores the life-course implications of race bias in another domain, specifically the domain of medical diagnosis, where algorithm formulas have been shown to disadvantage black patients based on economic and other parameters. Even with training, experimental evidence comparing human and AI diagnostics have demonstrated that despite improvements, residual racism is evident in differential diagnoses. We consider the life-course implications of this and similar race-based differentials in organizational decision-making as a component in systems of cumulating dis/advantage."}
{"text": "Farkas certificates for lower and upper bounds on minimal and maximal reachability probabilities in Markov decision processes (MDP), which we derive using an MDP-variant of Farkas\u2019 Lemma. The set of all such certificates is shown to form a polytope whose points correspond to witnessing subsystems of the model and the property. Using this correspondence we can translate the problem of finding minimal witnesses to the problem of finding vertices with a maximal number of zeros. While computing such vertices is computationally hard in general, we derive new heuristics from our formulations that exhibit competitive performance compared to state-of-the-art techniques. As an argument that asymptotically better algorithms cannot be hoped for, we show that the decision version of finding minimal witnesses is This paper introduces"}
{"text": "We read with great interest the pilot single arm trial by Matsumoto et al , which eThe authors begin by explaining that difficulties with accessing CBT are due to the expense, number, and uneven urban distribution of therapists, and feel that telemental health has resolved these issues. We would comment that whilst distribution will have been addressed, the use of video conferencing alone would likely be insufficient to address the expense and the paucity of therapists. Therefore, this represents an apparent limitation on the scalability of such interventions. Varying the level of interaction with the therapist through the use of computer-assisted CBT  has already been described with positive results both in terms of outcomes and cost-effectiveness in a population of primary care patients undergoing treatment for depression . Future The equivalence of face-to-face CBT and ICBT in a meta-analysis of 1418 patients  further Although the single-arm nature of the trial limits the applicability of the conclusions, the authors describe a preference (83% of participants) for video conferencing over face-to-face CBT. More information as to the rationale belying this preference would help inform future intervention strategies. Furthermore, previous experience and perceptions toward face-to-face CBT before an intervention could also help further elucidate the validity of participants\u2019 preference toward video conferencing. One potential explanation could be that the method of participant recruitment and selection could introduce a bias of intrinsic preference of trial subjects toward seeking video-based CBT, given that one recruitment strategy employed by the authors was web-based advertising.Although a need for further clarification exists, the authors are to be commended on their unique contribution to the field, and it is with great excitement that we anticipate future works to further describe the potential benefits of ICBT and its applications."}
{"text": "A 30-year-old male presents to emergency medical services profoundly combative with a Richmond Agitation\u2013Sedation Scale of +4 after reported use of intravenous methamphetamines. A preliminary diagnosis of excited delirium syndrome is made based on the history obtained and the decision is made to chemically sedate the patient. While preparing for sedation, you wonder which pharmacological agent will produce the fastest and safest sedation in this patient population. A 30-year-old male presents to emergency medical services (EMS) profoundly combative with a Richmond Agitation\u2013Sedation Scale of +4 after reported use of intravenous methamphetamines. A preliminary diagnosis of excited delirium syndrome (ExDS) is made based on the history obtained and the decision is made to chemically sedate the patient. While preparing for sedation, you wonder which pharmacological agent will produce the fastest and safest sedation in this patient population.In patients presenting with ExDS in the pre-hospital environment, is the use of benzodiazepines, antipsychotics or ketamine superior in producing rapid and uncomplicated sedation?United States of America National Library of Medicine (up to September 2019):) AND Cumulative Index to Nursing and Allied Health Literature (up to September 2019):TX  AND TX Literature was considered relevant if it described a piece of primary research in the pre-hospital setting, with a focus on the pharmacological management of ExDS. Literature was excluded if the research was undertaken in a hospital-based setting, or if it was non-interventional in nature.United States of America National Library of Medicine:90 results, of which nine were considered relevant.Cumulative Index to Nursing and Allied Health Literature:145 results, of which eight were considered relevant. None in addition to those identified previously.See Despite the challenges which patients suffering from ExDS will present to practitioners, literature examining the management of these patients in the pre-hospital environment is exclusively from the United States or founded in the setting of an emergency department with regional variations in the optimal sedative recommended for use in this patient population. Although the pre-hospital and emergency department settings share a number of features, the pre-hospital environment is an unpredictable, profoundly resource-poor setting without consistent access to anaesthesia and advanced medical therapies potentially required for management of deteriorating patients with ExDS. This is of particular importance when considering not simply the efficacy, but the safety of pharmacological management of patients presenting with ExDS.There is insufficient evidence to recommend one pharmacological agent in the management of ExDS within the pre-hospital environment generally, and no evidence specific to specialist paramedic practice in the United Kingdom. Although ketamine is associated with the most rapid onset of adequate sedation in patients with ExDS, it is also associated with the highest rate of adverse events and its use is frequently reported to result in the requirement for endotracheal intubation. However, it is unclear whether the requirement for intubation is driven by clinical need or provider discomfort, given the number of intubations performed by single providers within multiple studies. Antipsychotic agents such as haloperidol and droperidol appear to have a superior safety profile when compared against ketamine and midazolam, although they are associated with a protracted time to adequate sedation, which is of particular relevance in the setting of an ExDS patient and in the setting of the resource-poor pre-hospital environment.The choice of pharmacological agent for sedation of the patient with ExDS will depend on the local legality of paramedic-led administration of scheduled medications, availability, clinician comfort and available resources to manage unexpected complications. Further high-quality controlled trials of benzodiazepines, antipsychotics and ketamine are required before any recommendation for widespread use of any agent can be made.None declared.None."}
{"text": "To this end, this project compares the socioeconomic status (SES) gradient in formal and informal care across Europe and over time. A particular effort is made to include macro-level indicators of LTC systems in cross-level analyses across countries. The first paper presented in this symposium by the UK team studied SES-inequality in care receipt across European nations with different care systems; the second paper presented by the German team studied the same question but now among caregivers, the third paper provides the analyses for caregivers in Japan, and the fourth paper by the Dutch team studies SES-inequalities in care use within the Netherlands over time (1995-2015). The symposium will start off with a short description of the IN-CARE project (2019-2022). Tine Rostgaard agreed to be our discussant.Ageing societies and recent reforms to long-term care (LTC) in many European countries are likely to make informal care by kin and nonkin increasingly critical for fulfilling the care needs of older people. To date, it is unknown whether informal care falls disproportionately on disadvantaged populations. The IN-CARE project (a collaboration of Dutch, UK and German research teams;"}
{"text": "The aim of this study was to assess differences in the effect of traumatic brain injury (TBI) on the onset of Alzheimer\u2019s disease (AD) and other dementias between veteran and non-veteran respondents of the Health and Retirement Study as well as to measure the sensitivity of these differences to the introduction of controls for groups of demographic, medical co-morbidity and polygenic risk scores reflecting AD hallmarks. Using the Fine-Gray proportional hazards model we found that TBI was a strong predictor of dementia in community dwelling residents age 65+: for AD associated risk was 181%  sample-wide and 142%  in veteran males. Effect magnitude decreased with the addition of risk-related control variables but remained associated with significantly increased risk. Large differences in risk were observed between veteran and non-veteran males for AD, vascular dementia, senile dementia, and dementia with Lewy Bodies"}
{"text": "About 41 million people die of chronic non-communicable diseases (CNCDs) each year, accounting for 71% of all global deaths. The high prevalence of CNCDs is particularly problematic for sub-Saharan Africa (SSA) since CNCDs are already a major cause of mortality in the sub-region. While the case fatality rate of COVID-19 is quite low, it is worth noting that people with underlying CNCDs constitute the majority of those who die from this virus. Underpinned by the chronic care model (CCM), we present a commentary on the implications of COVID-19 for the management of CNCDs in SSA. We realized that despite the World Health Organisation\u2019s guidelines for countries to maintain essential services while putting necessary measures in place to prevent and control the spread of COVID-19, myriad of health systems and community-level factors militate against effective management of the CNCDs in SSA. This results in disruptions in management of the conditions as well as possible long-term effects such as the deterioration of the health status of CNCD patients and even deaths. Without immediate interventions to salvage the status quo, SSA countries may not be able to achieve the Sustainable Development Goal 3.4 target of reducing by one-third, premature mortality from CNCDs by the year 2030. We recommend that financial constraints could be ameliorated through short- and long-term loan facilities from the International Monetary Fund and the World Bank to augment national efforts at strengthening health systems while combating COVID-19. We also recommend increased community engagement and public education by COVID-19 response teams to enhance community support for persons living with CNCDs and to reduce social stigmatization Coronaviruses constitute a large family of viruses which cause ailments ranging from the common cold to more severe diseases among humans such as the Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2012 . The higThis paper is underpinned by the chronic care model (CCM), which was developed by the MacColl Institute for Healthcare Innovation at Group Health Cooperative in 1992 . The CCMHealth systems: the health system forms the backbone of the management of CNCDs in SSA. To ensure effective management which improves the health outcomes of people living with CNCDs, the CCM admonishes a resilient health system that provides safe and high-quality care through a dedicated and motivated team of health professionals who are well-positioned to support improvement strategies and encourage open and systematic handling of errors through the provision of quality care [ity care . The heaThe increasing prevalence and mortality from COVID-19 with its rapidly increasing demand on health systems makes it almost impossible for the health systems of SSA countries to keep providing the CNCD management services as expected . This isAside from the fact that the existing inadequate number of beds in health facilities are being occupied by COVID-19 patients, the majority of the already inadequate health professionals previously designated to care for patients with CNCDs are redirected to focus on COVID-19 related activities such as attending to patients in isolation/intensive care and contact tracing. Besides, laboratories, which conduct specimen testing for CNCD patients have now focused on taking specimen for COVID-19 suspected cases as well as carrying out the test at the expense of CNCDs. Patients with CNCDs, thus, have limited access to these facilities. Moreover, infrastructure initially designated as special clinics for managing CNCDs patients are now being used as holding centres where suspected COVID-19 cases are quarantined. The meagre financial resources of health facilities have also been diverted towards the management of COVID-19 in terms of purchasing personal protective equipment (PPE) such as masks and hand gloves to the detriment of CNCDs. The diversion of health system resources towards the management of COVID-19 at the expense of CNCDs comes at the backdrop of the WHO\u00b4s recommendation and operational planning guidelines, which entreat countries to maintain the status quo regarding the provision of already existing health services to mitigate the risk of health system collapse and aggravation of patients\u00b4 health. Health systems in SSA are, however, unable to maintain the status quo due to their logistical, financial, and human resource challenges.In several SSA countries, people are encouraged to avoid presentation to hospitals unless it is absolutely necessary. Due to the existing inadequacy of health professionals and limited PPEs, the aim is to reduce the burden of CNCDs on the health systems of SSA countries as they are already overwhelmed by the COVID-19 pandemic, and to reduce the risk of contamination of patients with CNCDs attending routine visits at hospitals. In most SSA countries, patients with CNCDs themselves, for the fear of contracting virus, avoid going to the hospitals for their reviews. Individuals developing CNCDs and needing care for the first time also avoid going to the hospitals for diagnosis and subsequent management of their conditions. The implication of the myriad of health systems challenges, precipitated by the COVID-19 pandemic entail delays in seeking prompt care by CNCD patients, the disruption of CNCD management timelines, and the deterioration of the health status of persons living with CNCDs leading to needless deaths.Community: community as a tenet of the CCM entails self-management, resources mobilization and advocacy for policies that improve CNCD care [NCD care . Self-maNCD care . Self-maNCD care . HoweverNCD care . The impThe CCM also identifies coping strategies by patients with CNCDs as a major factor that helps in the management of the conditions . Coping Despite the WHO guidelines to all countries across the world to maintain essential services including those related to the management of CNCDs while putting necessary measures in place to prevent and control the spread of COVID-19, myriad of health systems and community-level factors militate against effective management of the CNCDs in SSA resulting in the disruptions in management of the conditions as well as possible long-term effects such as the deterioration of the health status of CNCD patients and even deaths. Without immediate interventions to salvage the status quo, SSA countries may not be able to achieve the SDG 3.4 target of reducing by one-third, premature mortality from CNCDs by the year 2030.Recommendations: to mitigate the immediate and long-term irreversible negative effects of COVID-19 on the management of CNCDs in SSA, the following recommendations have been proffered: 1) Financial constraints could be ameliorated through short- and long-term loan facilities from the International Monetary Fund and the World Bank to augment national efforts at strengthening health systems in SSA to enable them to continue being resilient to manage CNCDs even as they strive to end the COVID-19 pandemic. 2) More health professionals should be employed and deployed to continue providing care for other patients including those with CNCDs while the rest focus on effectively responding to COVID-19. 3) In countries where the recruitment and deployment of more health professionals becomes challenging due to the existing financial constraints, alternative measures for the follow-up of patients with CNCDs could be implemented. These include the use of telemedicine to check-up on patients\u00b4 progress and self-management practices. Also, courier services and drones could be used to deliver CNCD medications and urgently required documents where necessary. 4) Health professionals should be adequately provided with PPEs to improve their protection against COVID-19 infections. When this is done, they would encourage patients with CNCDs to come for reviews knowing they have minimal risk of exposure to the infection. 5) Health infrastructures in SSA should be expanded and equipped with donor support to accommodate Covid-19 patients and at the same time CNCDs patients. 6) There should be increased community engagement through their leadership and public education by COVID-19 response teams of the various SSA countries to enhance community support for persons living with CNCDs and to reduce social stigmatization.The authors declare no competing interests."}
{"text": "This thematic review includes short reviews on GH deficiency and insensitivity in children and adults from basic science to clinical significance. We are proud to present this thematic review on growth hormone (GH) deficiency and insensitivity in children and adults. It contains short reviews made by eminent experts in the field that together comprises a comprehensive assessment of the field from basic science to clinical significance.The activity of the GH-IGF-I axis is regulated by the amount and secretory pattern of the GH, the endocrine and paracrine/autocrine production of IGF-I and the interaction of GH and IGF-I at the tissue specific level. Additionally, GH and IGF-1 have both unique and overlapping actions related to growth and metabolism. Therefore, overall effects of the GH-IGF-axis on growth and metabolism is dependent on the amount of GH and IGF-I at the tissue level as well as the responsiveness/sensitivity of the GH and IGF-I receptors.Through clinical observation and experience, clinicians have observed variable responses to GH treatment in children. For example, the same GH exposure can produce a highly variable magnitude of growth. Similarly in adults, GH replacement in patients with hypopituitarism and severe GH deficiency can produce a response that is highly variable. In adults the efficacy of GH replacement varies from changes in body composition and lipid profile to improvement in well-being and quality of life. Additionally, it is also unpredictable to which of these endpoints an individual subject seems to respond most.The aim of this thematic issue was therefore to shed light on the clinical aspects related to GH deficiency and insensitivity in both children and adults. This issue also includes human models of extreme GH insensitivity induced by inactivating changes in the GH receptor as well as at the post receptor level. The careful phenotyping as well as the molecular discoveries in these patients have extended the findings on the physiology of the GH-IGF-I axis and some of the individual sensitivities attributed to either GH or IGF-I. These observations have also been useful in better understanding the consequences of long-standing GH deficiency in children and adults. In addition to human studies, animal models of GH deficiency and insensitivity have also improved our understanding on the impact of GH and/or IGF-1 on tissue specific metabolism and in the end its impact on health- and life-span. Related to this is the findings in adults with GH deficiency that showed reduced survival in the unreplaced state. The causal relationship with GH deficiency has been debated and is further reviewed and discussed in this thematic issue.The clinical challenges in the diagnosis of GH deficiency and various degree of insensitivity are further discussed together with strategies to improve outcome among these patients. With a perfect mix between basic, translational and clinical topics related to GH deficiency and insensitivity, we hope that the readers of this issue will enjoy and appreciate the science behind the short reviews. We also hope that the reader will improve their understanding of the molecular mechanism(s) of GH/IGF-1 action, the clinical consequences and the treatment strategies to improve each patient\u2019s outcome from childhood to adulthood."}
{"text": "The official installation of the European Reference Networks in 2017 formed the foundation to improve quality and safety and access to highly specialized health care across the EU for patients affected by rare or low prevalence and complex conditions. The European Reference Network on Rare Endocrine Conditions (Endo-ERN) covers specific expertise from birth to senescence with a specific governance structure characterized by both a pediatric and an adult chair, and equal responsibilities for patient representatives and health care providers. The introduction on the scope and mission of Endo describes the complexity of the Endo-ERN mission and will thrive toward the ultimate aim and mission of the network of reducing health care inequalities across Europe. Specific knowledge and medical expertise of the existing rare endocrine condition is urgently needed, and therefore, raising awareness for Rare Disease Day from the Endo-ERN perspective is imperative. The EU directive 2011/24 of patient\u2019s rights in cross border health care that was accepted by the European parliament in 2011 formed the foundation for the development of European Reference Networks (ERNs) [The European Reference Network on Rare Endocrine Conditions (Endo-ERN) was initiated by clinical committee members of both European endocrine societies: the European Society of Pediatric Endocrinology (ESPE) and the European Society of (adult) Endocrinology (ESE) that identified and nominated a pediatric and an adult chair as well as steering committee members who developed and decided upon the coordination and governance. On the landscape for rare endocrine conditions Endo-ERN was divided into eight organ- and physiology-based main thematic disease groups  which were included in five Work Packages .Endo-ERN, at present, is the largest ERN, representing 86 HCPs from 26 countries. Patient involvement is crucial to all ERNs, and Endo-ERN already integrated patient representation during the construction phase of the network, with equal responsibilities for patient representatives and HCPs . Each MTThis special and unique supplemental issue of \u2018Endocrine\u2019 has been compiled by Endo-ERN experts and encompasses a large array of specific features of rare endocrine conditions, covering specific activities carried out in the different work packages and main thematic groups of the network, and range from mini-reviews of a specific condition to manuscripts describing original novel data, including data on the use of virtual consultations, and on the educational and research needs from the patient\u2019s perspective, representing all work packages and main thematic groups. With this, we are confident that the complexity of the Endo-ERN mission is well described and we will thrive towards the ultimate aim of reducing health care inequalities across Europe.Written and compiled in the midst of the Covid-19 pandemic, raising awareness for Rare Disease Day from the Endo-ERN perspective is quite necessary. As we will see from the manuscripts, the specific knowledge and medical expertise of the existing rare condition was mandatory for battling corona infections in our patients. Furthermore, during the pandemic, the anxiety of chronically ill patients increased and their medical attention could often not be met. With the more specific medical but also societal approaches to Covid-19, it is time to turn again to all medical necessities of our European fellow citizen, so no one is \u201cforgotten\u201d."}
{"text": "International Journal of Cardiology 30384-3; DOI: 10.1016/j.ijcard.2020.04.013). Eight Italian high-volume centres of Paediatric Cardiology were involved in this observational, retrospective data collection and analysis. In this dataset, clinical and procedural characteristics of 1423 newborns submitted to 1551 interventional cardiac catheterization procedures were analyzed. Primary outcomes were considered procedure and in-hospital mortality as well as major adverse event and procedural failure rates. Secondary outcomes were considered minor adverse events and need for blood transfusion. Targets of this data analysis were: 1) to evaluate the overall major risk factors of interventional cardiac catheterization; 2) to identify the most hazardous interventional procedures; 3) to assess possible trends of individual procedures as well as their outcome over time; 4) to find possible relationships between the volume activity of any centre and the procedure and follow-up outcome. In particular, this Data in Brief companion paper aims to report the specific statistic highlights of the multivariable analysis (binary logistic regression) used to assess the impact of any potential risk factors on the type of procedure over a short-term follow-up.A comprehensive description of morbidity and mortality as well as risk factors of interventional cardiac catheterization performed in neonatal age was reported in our paper recently published on the  Specifications table\u2022Interventional cardiac catheterization is an increasing approach to treat newborns with critical congenital heart disease. No data about risk stratification of interventional procedures in this subset of patients are so far reported in literature. Our dataset aims to evaluate the intrinsic risk of trans-catheter interventional approach as well as the potential risk factors involved in any individual procedure performed at this age.\u2022The nationwide cohort dataset recently published in the related research article provides specific information on morbidity and mortality of newborns submitted to interventional cardiac catheterization. The Authors showed that the morbidity  is significantly related to the complexity of the intended procedure while the in-hospital mortality significantly depends on the clinical characteristics and hemodynamic stability of the patient. These data may be useful to cardiologists involved in the management of newborns affected by congenital heart disease to clearly understand patient's risk profile of any interventional procedure.\u2022The safety and effectiveness data of trans-catheter approach reported in this Data in Brief paper and its related research article may hopefully promote further developments in trans-catheter treatment of neonates with critical congenital heart disease. \u201cAd hoc\u201d-planned future researches aiming to specifically compare percutaneous and surgical approaches in this subset of patients will give further useful information to set the future guide-lines of management of critical, neonatal-onset cardiac malformations.\u2022Defining careful risk profile of newborns in whom an interventional cardiac catheterization is planned allows to improve pre-procedure counselling with parents and care-givers as well as gives further insights about the short-term prognosis of these frail patients. These data will hopefully improve timing and type of interventional approach  in this frail subset of patients.1-the -the -the -the -the -A) and the most performed procedures (B) on the primary outcomesthe -A) and, accordingly, the rate of composite outcome (B)the This dataset  gives relevant details and explanations about the enrolled population/procedures (catheterizations/procedures and adverse events) and statistical analysis techniques . These data are expressed as figures and tables as well as in form of RAW DATA in the SUPPPLEMENTARY FILE section:2In the related research article Multi-variable analysis was performed with a binary logistic regression The data reported in the The data were then divided for any centre in order to evaluate, by linear regression test, the impact of the volume of activity of any individual centre on the composite outcome. The same statistical analysis was also made by separating the higher-risk procedures (risk category 4) from the lower ones (risk category 3)"}
{"text": "The implementation of physical activity policies has been slow and uneven. As a remedy, the World Health Organization has recommended that national policy implementation should be supported with practical tools and guidance. The Physical Activity Environment Policy Index (PA-EPI) is a tool that allows the extent of policy implementation to be assessed. It comprises a list of good practice policy indicators. These are categorized into eight policy domains targeting aspects of the physical activity environment and seven infrastructure support domains for strengthening physical activity policy systems. This protocol provides researchers with guidance on how to use this tool.Guided by a protocol developed by the International Network for Food and Obesity / Non-communicable Diseases (NCDs) Research, Monitoring and Action Support (INFORMAS), the PA-EPI protocol. The INFORMAS protocol was modified based on the research teams experience carrying out the first study utilising the PA-EPI tool.A multi-step process is recommended. This process relies upon the identification of two groups of partners: national policymakers and independent stakeholders tasked with the promotion of physical activity directly and/or indirectly. During the early steps of the process the desk-based research is undertaken to identify information about and evidence of physical activity policy implementation- the PA-EPI Evidence Document. This mapped information is presented to the national policymakers to verify that it is valid and comprehensive. Subsequently, the evidence of implementation is presented to the stakeholders who, using a 5-point Likert scale (1-little or none to 5 high), individually rate the extent of policy implementation in practice. These individual ratings are aggregated and a implementation scorecard is generated displaying the extent of implementation of each of the good practice indicators Stakeholder then engage in an expert workshop to review implementation scores, and identify key policy implementation recommendations which are presented to government.The process of conducting a policy implementation assessment using the PA-EPI requires the cooperation of several stakeholders as part of a national coalition. It is envisioned that PA-EPI assessments will enable international cross comparison. This will promote learning from international best practice."}
{"text": "Sepsis is one of the most common reasons for admission to the intensive care unit, and its incidence continues to increase. However, the precise mechanism of sepsis has not yet been fully elucidated. Outer membrane vesicles (OMVs) present in the outer membrane of bacteria have been speculated to be one of the causes of sepsis. Direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) can be used as a means to remove OMVs. This study evaluated whether the use of PMX-DHP affects bacterial distribution.A total of 30 critically ill patients with severe septic shock were enrolled from intensive care unit of Haeundae Paik hospital. Plasma and urine samples were collected before and after the use of PMX-DHP. Sequencing-based metagenome analysis of the microbiome was performed, and changes in the distribution of various bacteria before and after the use of PMX-DHP were identified.Bradyrhizobium . Figure 3 shows the changes in the distribution of bacteria in urine before and after the use of PMX-DHP. No bacteria showed a statistically significant difference in distribution before and after the use of PMX-DHP in this distribution.A total of 30 patients were enrolled. Figure 1 shows the changes in the distribution of bacteria in plasma before and after the use of PMX-DHP. The only strain that showed a statistically significant difference in the pre-mean and post-mean values in this distribution was Figure 1Distribution of bacteria in plasma before and after the use of PMX-DHPFigure 2Changes in the distribution of Bradyrhizobium in plasmaFigure 3Distribution of bacteria in urine before and after the use of PMX-DHPBradyrhizobium was the only strain that showed a statistically significant decrease in the amount of outer membrane vesicles (OMVs) in plasma through hemoperfusion using PMX-DHP.All Authors: No reported disclosures"}
{"text": "Nature Communications 10.1038/s41467-023-38565-8, published online 23 May 2023Correction to: The original version of this Article contained an error in the order of names in the author list, which incorrectly listed the second author Chenxin Yu in the last position. This has now been corrected and the numbering of author affiliations has been updated accordingly in both the PDF and HTML versions of the Article."}
{"text": "Emphasising the importance of patient-centred outcome reporting to guide decision-making in this cohort of patients. This can only be achieved with the availability of high-quality patient-reported outcome data. Previous reviews have highlighted several limitations regarding studies reporting patient-reported outcomes in LRRC, including variability in the patient-reported outcome measures (PROMs) being used, and in the timing of PROM assessments, with the evidence being low in quality overall.6 The results identified several issues related to the quality of reporting of PROMs in LRRC, most importantly that none of the PROMs currently being used to report outcomes in LRRC have been validated for use in this group of patients. Methods for handling missing PROM data and defining the patient-reported outcome of interest are also poorly reported. However, the person completing the PROM and method of data collection, and conclusions and discussion of the clinical relevance of the patient-reported outcome data, were well reported.This systematic review focused on assessing the methodological quality of studies reporting PROMs in LRRC to identify the PROMs being used and to assess their psychometric properties using the COSMIN Risk of Bias checklist.The lack of disease-specific PROMs which have been validated for use in LRRC, is the most important issue to address to improve the quality of reporting PROMs in LRRC. Several approaches could be employed, including developing new disease-specific PROMs for patients with LRRC or undertaking content validity studies of the PROMs which are currently being used in LRRC."}
{"text": "AlZahrani  The authors regret that the funding information was incorrectly shown in the Acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.The authors extend their appreciation to the Deanship of Scientific Research at Northern Border University, Arar, KSA for funding this research work through the project number NBU-FFR-2023-0020.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "T-lymphocytes or T-cells) were able to transfer protection against infectious agents, allowing for the definition of cell-mediated immunity (CMI)  . Since tT-cells has been a topic of interest for immunologists for decades and the study of these cells has contributed to major observations on the immune system  is a chronic contagious disease caused by the bovine leukemia virus (BLV), which compromises lymphocyte activities and leads to immune response dysfunction. Most of studies on the pathogenesis of EBL have been focused on the analysis of B and chanisms . Howeverchanisms  raise quRainard et al. provide a broad review of reports on the adaptive immune response mechanisms in the mammary gland (MG) of ruminants, with an emphasis on cell-mediated immunity. Mammary gland is armed of physical and cellular defenses compatible with the production, storage, and secretion of milk, which differ from mechanisms found in other organs exposed to invaders. The immunological functions of mammary gland also varies greatly among mammals and this particularity limits extrapolations from one species to another  paved the way for a better understanding of multiple processes of immune response including host response to infections and cancer, as well as immunotolerance . AlthougT-cell exhaustion, which is caused by the expression of immune checkpoint molecules that limit cell-mediated protective immunity  non-antibiotic approaches covering the most critical period of the cow's life.The immune checkpoint blockade has revolutionized the therapeutic landscape in oncology. Its success in cancer therapy implies that targeting similar pathways may prove beneficial in preventing and treating infectious diseases. Indeed, persistent infections are sustained by immunity . In thisAs a whole, this Research Topic proposes alternatives to some drawbacks involving the study of cell-mediated immunity in ruminants and highlights the better understanding of this arm of immune response as a fundamental step for the development of improved vaccines and therapies for these species.Research Topic conception by RPM. Research Topic editing and editorial writing by RPM and FNS. Both authors contributed to the article and approved the submitted version."}
{"text": "Objectives: Candidemia has become one of the leading causes of healthcare-associated bloodstream infection, particularly in the intensive care unit. The management of candidemia remains challenging. We reassessed the protective effectiveness of a comprehensive care bundle on the management of candidemia and the effects of compliance with each element on the outcomes of patients. Methods: This network meta-analysis was conducted using the frequentist method. The participants included adult patients both infected with candidemia and who received bundle care. The primary outcome was the all-cause mortality among the patients included. Results: Studies in which a care bundle was created for patients with candidemia were identified, and 5 eligible studies with 5,808 participants were enrolled for further analysis. The random-effects model of the overall odds ratio (OR) revealed a significant reduction in the risk of all-cause mortality compared with that of the controls , as well as a reduction in the risk of developing persistent candidemia compared with the controls . In addition, no single element reached a protective effectiveness to improve the clinical outcome. Conclusions: This meta-analysis demonstrated that the combination of core elements in the care bundle resulted in protective effects, in that the all-cause mortality rates and incidence rates were effectively reduced among patients with persistent candidemia."}
{"text": "This presentation will talk about co-production findings from three completed studies to develop and evaluate a culturally appropriate Japanese version of the New Forest Parent Training Programme (NFPP), named Well Parent Japan (WPJ). Dr Shimabukuro will also present an on-going prospective study aiming to provide support for Japanese mothers and teachers of children with ADHD in a school setting. Dr. Shimabukuro will share the experiences worked with different stakeholders at the different stage of the study and highlight the benefits of co-production in the research and how WPJ was shaped. This presentation will also discuss difficulties and challenges when evidence-based parent training intervention is transferred from research to practice.None Declared"}
{"text": "A simple, robust and computationally inexpensive method of generating statistical representations of X-ray free-electron laser (XFEL) radiation is presented. Many coherent imaging applications that utilize ultrafast X-ray free-electron laser (XFEL) radiation pulses are highly sensitive to fluctuations in the shot-to-shot statistical properties of the source. Understanding and modelling these fluctuations are key to successful experiment planning and necessary to maximize the potential of XFEL facilities. Current models of XFEL radiation and their shot-to-shot statistics are based on theoretical descriptions of the source and are limited in their ability to capture the shot-to-shot intensity fluctuations observed experimentally. The lack of accurate temporal statistics in simulations that utilize these models is a significant barrier to optimizing and interpreting data from XFEL coherent diffraction experiments. Presented here is a phenomenological model of XFEL radiation that is capable of capturing the shot-to-shot statistics observed experimentally using a simple time-dependent approximation of the pulse wavefront. The model is applied to reproduce non-stationary shot-to-shot intensity fluctuations observed at the European XFEL, whilst accurately representing the single-shot properties predicted by FEL theory. Compared with previous models, this approach provides a simple, robust and computationally inexpensive method of generating statistical representations of XFEL radiation. The results from our model demonstrate the ease and effectiveness of our approach in replicating the temporal characteristics of the XFEL wavefield over a range of key experimental timescales.2.et al., 2020et al., 2019et al., 2020et al., 2022et al., 2022et al., 2022et al., 2019The European XFEL is the world\u2019s first high-repetition-rate XFEL facility   = 1 denoting fluctuations in pulse intensity that are perfectly correlated, g(2) = 0 denoting no correlation and g(2) = \u22121 denoting anti-correlation. The shot-to-shot correlation of the pulse trains whose intensities are presented in Fig. 1Intensity distributions with time-dependent shot-to-shot statistics have previously been recorded during operation on the SPB/SFX instrument , where r is the transverse position vector: r = . We write this wavefield as the superposition of two functions describing the transverse and longitudinal properties of the pulse wavefield, \u03c8\u22a5 and f(t). We assume the transverse properties to be a slowly varying function of time (microseconds) in comparison to the longitudinal components (femtoseconds), and subsequently treat each function independently. The pulse wavefield at a time t within a pulse train can be written as the Fourier integralWe construct a numerical representation of the source wavefield that is the product of two components: (i) a stationary Gaussian approximation of the fluctuations in the SASE pulse spectra  are the radius of curvature and spatial wavevector in the transverse plane, respectively, which both vary with time. We define the time-constant amplitude factor with respect to the peak intensity of the pulse, I0, 0 and \u03c3z are, respectively, the beam widths at the waist and in a transverse plane located a distance z downstream of the waist.In modelling the transverse characteristics of the pulse wavefront, we make the assumption that shot-to-shot fluctuations in the source phase are the primary origin of fluctuations in the observed pulse intensities. This assumption implies both a constant pulse amplitude and a time-dependent beam phase. The evolution of the XFEL source intensity along the axis of propagation is determined by the gradient and curvature of the source wavefront phase XFEL wavefields are highly paraxial. Estimates of statistics of the time-dependent components of the pulse wavefield x,\u2005\u0394y) relative to the mean centre of mass calculated over all pulses within a pulse train. These displacements correspond to horizontal and vertical deflections of the pulse intensity,Shot-to-shot phase tilts of the source plane wavefield lead to displacements in the time-dependent centre of mass . The single-shot properties of each pulse were assumed to be Gaussian and of the form given in equation (3)et al.  ] ]. Using these probability distributions, the temporal properties of the beam phase were determined iteratively. Fig.\u00a06Probability distributions were obtained by fitting a covariance ellipse enclosing 95% of the recorded data in the state space of each pulse property at sequential time points Each pulse within a pulse train was propagated independently through the SPB/SFX beamline model to a detection plane 3.644\u2005m downstream of the instrument focus, matching the parameters of the intensity measurements described in Section 2i.e.g(2), is a linear function of the mean pulse intensity and thus shares the same highly correlated statistics. Such an autocorrelation function depicts the decay in the correlation between the first pulse in a pulse train and sequential pulses, which is of primary interest for time-resolved imaging experiments The intensity statistics of the experimental and simulated pulse trains are highly correlated, yielding an average Pearson correlation coefficient The Pearson correlation between the experimental and simulated intensity statistics is time dependent and provides an indication of the conditions under which the geometric phase approximation of our model is suitable. Fig. 9b) illustrates that poorly correlated pulses are, on average, more truncated by the mirror aperture than highly correlated pulses. For a Gaussian beam truncated along one dimension, the true (prior to truncation) and recorded centres of mass deviate by a percentage beam width approximately equal to the percentage of intensity outside the mirror aperture. Consequently, the error in the calculated pointing angle increases linearly with pulse intensity losses  provides an indication of beamline instabilities that are not currently captured by the SPB/SFX model. These instabilities, such as thermal deformation of mirror surfaces and positional jitter of photon transport optics, may result in a nonlinear relationship between the beam pointing angle and the observed centre of mass. While our results suggest that these phenomena are not the primary contribution to wavefront fluctuations on the megahertz timescale, these effects, which can arise over long-duration operations, may be significant contributors to the intensity statistics between pulse trains (Petrov et al., 2022The overlap between the centres of mass of highly correlated and uncorrelated pulses in Fig. 95.Our phenomenological model of radiation at the European XFEL describes shot-to-shot fluctuations that are time dependent, and it requires no prior knowledge of the properties and operation of the accelerator and undulator. The mean intensity profile of our model is consistent with predictions based on FEL theory and, when paired with probabilistic models derived from experimental measurements, can be perturbed to replicate shot-to-shot wavefront statistics that these previous models do not describe. This model is a highly generalized approach to simulating XFEL radiation that can provide descriptions of the statistics of large ensembles of pulse wavefields under a broad range of operational conditions. The accuracy of these measurements is limited only by suitable estimates of the expected values of pulse width and divergence, and the quality of intensity data recorded. Our model provides a method of generating statistically accurate descriptions of the experimental pulse wavefield, in a manner that is robust to instrument operation and is suitable for users of XFEL facilities who may wish to carry out simulations of wavefront properties during an experiment.et al., 2020et al., 2022et al., 2022et al., 2021et al., 2017et al., 2015et al., 2016et al., 2017et al., 2011When paired with efficient wavefront propagation simulations (Chubar & Celestre, 2019et al., 2010tth pulses. In the case where pulse intensity or wavefront information can be recorded simultaneously during diffraction experiments, the development of filtering and classification algorithms (Rose et al., 2018Alongside the capacity to reproduce intensity distributions observed experimentally, our model provides new information on the shot-to-shot statistical properties of radiation at the European XFEL. In circumstances where the observed fluctuations in beam size and position are time dependent, our model predicts that the shot-to-shot coherence of the European XFEL is non-stationary. This implication of non-stationary spatial coherence between XFEL pulses has significant consequences in both imaging and wavefront characterization experiments, and is not captured in current descriptions of radiation at the facility (Geloni et al., 2020et al., 2020et al., 2021et al., 2019et al., 2014Regarding the characterization and remediation of the pulse wavefront, non-stationary shot-to-shot coherence has significant implications in a broad range of applications. Measurements of coherence from intensity correlations, for example via the Siegert relation (Ferreira et al., 2022et al., 2021Applications of our simplified representation of the XFEL source could prove highly beneficial as a photon diagnostic for the accelerator by providing a simple relationship between the stability of the observed intensities and the wavefront phase. This \u2018top down\u2019 approach may provide a route to optimizing operational parameters and could take advantage of machine-learning techniques in some cases to extract key factors of operation that determine FEL performance (Patel et al., 2022et al., 2020Finally, we expect that the residual disparity between the simulated and experimental shot-to-shot intensity fluctuations can be addressed in future applications by improving the experimental conditions under which fluctuations in the beam size and position are recorded. Specifically, it should be possible to achieve this by recording the shot-to-shot intensity distributions prior to photon transport. By further modifying the experimental setup used on the SPB/SFX beamline, our phenomenological model can be readily extended to represent shot-to-shot statistics of other pulse properties, including pulse energy, duration and spectra. This could be achieved using currently available photon diagnostics (Gr\u00fcnert We note that our model is intended to complement solutions based on theoretical descriptions of the SASE radiation process. For applications that are highly sensitive to pulse spectra, this model should be used in conjunction with these methods to describe highly nonlinear modes of operation.6.We have presented a phenomenological model of shot-to-shot wavefront statistics at the European XFEL. Our model maps the shot-to-shot statistics of intensity fluctuations observed experimentally to a geometric representation of the source phase. Unlike alternative models of XFEL radiation, our approach is robust with respect to non-fundamental practical effects caused by instrument operation, while requiring no prior knowledge of their physical origins. Using wavefront propagation simulations, we have demonstrated the capacity of our model to represent pulse wavefronts that reflect the time-dependent intensity statistics observed at the European XFEL."}
{"text": "The COVID-19 pandemic disrupted specialist training across Australia and New Zealand particularly in the area of assessments. Large-scale face-to-face exams were especially vulnerable to disruptions including lockdowns, travel and density restriction and required the Royal Australian and New Zealand College of Psychiatrists (RANZCP) to introduce alternatives.Following several small-scale Objective Structured Clinical Exams (OSCEs) in late 2020 and 2021 (both AV and multi-site), the RANZCP introduced an Alternative Assessment Pathway (AAP) after an exam cancellation in November 2021.To discuss the introduction of an Alternative Assessment Pathway at the RANZCP and share progress regarding the broader changes to assessment models under consideration.The AAP was co-designed with trainees and Specialist International Medical Graduates and introduced in December 2021 as an interim measure to assess clinical competence in the absence of an OSCE. It comprises a portfolio review of completed end-of-rotation forms and, if required, a case-based discussion held via Zoom.The AAP has been held over two rounds (December 2021 and March 2022) with 97% and 90% pass rates respectively (data correct as at 6 October 2022). An evaluation into the pathway is currently underway.In July 2022, the RANZCP introduced the Clinical Competency Assessment as a continuation of the AAP (with some modifications) for the remainder of 2022 and 2023.While the pandemic has become a catalyst for change, the RANZCP has been considering broader changes to the theory and practice of its assessments for some time. The presentation will provide an overview of its short-term clinical assessment model and share progress regarding change to the long-term assessment strategy.None Declared"}
{"text": "Introduction: COVID-19 is a disease that causes flu-like symptoms and difficulty breathing. Emerging in 2019, the COVID-19 pandemic has affected the entire world through restrictions and lockdowns. Multiple studies have compared the effects of COVID-19 on different types of head trauma, with each one producing different results. The goal of this study was to use state and hospital data to determine whether the COVID-19 pandemic had a significant impact on surgeries for traumatic brain injury (TBI).Methods: Public state data on COVID-19 incidence, sourced from the Virginia Department of Health, was compared to hospital data of 352 patients receiving surgeries for TBI from a single major level-one trauma hospital in Northern Virginia. We used data from the three years before COVID-19 and the two years during the pandemic, using t-tests and Pearson correlation to analyze the data. This is a retrospective case review study on the number and age of patients receiving TBI surgery from March 2017 through February 2022 at Inova Fairfax Hospital in Northern Virginia to determine the impact of the COVID-19 pandemic on these factors.Results: When comparing the data, there was a 60% reduction in cases of operative TBI during the peak months of COVID-19 compared to the same months in previous years (p<0.005). Comparing data on the number of Virginia and Northern Virginia COVID-19 cases and data on the age of individuals undergoing TBI surgery four weeks later showed a statistically significant negative correlation (p<0.05) in which the average age of individuals undergoing TBI surgery was lower in the four-week block following a four-week block of increased COVID-19 incidence.Conclusion: Our findings indicate a correlation between the period of decreased activity from COVID-19 restrictions in Virginia and a decline in both the number of TBI surgeries and the age of individuals undergoing these surgeries. A coronavirus emerged in December 2019 from the city of Wuhan, China . The COVTraumatic brain injury (TBI) is widespread, being one of the leading causes of death globally ,7. It isSeveral studies have shown an overall decrease in the incidence of TBI during the COVID-19 pandemic compared to prior years -19, wherTo determine the effects of the COVID-19 pandemic and its subsequent lockdown on the incidence of TBI surgeries performed in Northern Virginia, we compared hospital data from Inova Fairfax Hospital on patients receiving surgery for TBI to publicly available Virginia State data on new COVID-19 infections. We determined the number of TBI surgeries performed and the average age of the TBI surgery patients by month at our institution in the three years before the COVID-19 pandemic  and the two years following its start (March to February of 2020-2021 and 2021-2022). We chose to analyze the first two years following the outbreak of COVID-19 as this period of time represents the most significant impact of COVID-19 on the population, and we selected the three years prior for comparison to minimize the effects of annual variations. We compared the number of TBI surgeries performed at Inova Fairfax Hospital during the first two years of COVID-19 to the three years prior. We also compared the number of TBI surgeries performed at our institution during the four months of increased lockdown restrictions (March to June 2020) to the same four months of the previous three years. We compared the age of patients receiving surgery for TBI during the first two years of the COVID-19 lockdown to the three years prior. We also compared the age of patients receiving surgery for TBI during the four months of increased lockdown restrictions (March to June 2020) to the same four months of the previous three years. All of these comparisons were performed using t-test statistics.We further determined if there was a correlation between the number of new COVID-19 cases in Virginia and Northern Virginia with the incidence of performed TBI surgeries four weeks later, or if there was a correlation between the number of new COVID-19 cases in Virginia and Northern Virginia with the average age of patients receiving surgery for TBI four weeks later during the first two years of the COVID-19 pandemic. Our correlation was between the average incidence of COVID-19 and TBI injury data of the following four weeks because we assumed that it would be time for people to be aware of an increase in COVID-19 infections and change their behaviors. For this comparison, we used publicly available data from the State of Virginia on the incidence of new COVID-19 infections in the State of Virginia and the Northern Virginia area organized by four-week periods from April 2020 to February 2021. The data from Inova Fairfax Hospital on the number of TBI surgeries and the average age of TBI surgery patients were also organized by four-week periods from April 2020 to February 2021. We used Pearson correlation statistics for this analysis. Statistics were completed using Minitab Statistical Software  on a Hewlett-Packard personal computer . Values of p<0.05 were considered statistically significant.A comparison of the average number of performed TBI surgeries per month during the first two years of the COVID-19 pandemic to the average number of performed TBI surgeries per month during every month of the three years prior can be seen in Figure A similar result was seen when assessing the average age of patients receiving TBI surgery, but this comparison did not reach statistical significance. Figure Figure There was a statistically significant negative correlation when evaluating the mean age of patients receiving TBI surgery. Figure Our analysis revealed that during the peak four-month period of COVID-19 lockdown restrictions, there was a marked decline in TBI surgeries compared to the averages of the same four months over the preceding three years. We believe that this decrease in TBI surgeries performed during lockdown restrictions might be a byproduct of fewer opportunities for people to engage in activities that may be associated with TBI such as driving. A study done in Normandy, France, found decreased ICU admissions for TBI during the COVID-19 pandemic, linking it to a 74% decrease in motor vehicle accidents across France, but this study also found an increase in TBI surgery . HoweverOther studies showed more variance from our findings. A meta-analysis of 13 studies found a higher mortality rate from TBI during the pandemic but only in low- and middle-income countries . The autOur analysis indicated a notable shift toward an older demographic, with the average age of patients undergoing TBI surgery during the heightened COVID-19 lockdown months being 73.9, compared to an average of 66.9 in the same period over the previous three years. We believe this trend to be related to fall-induced TBIs common among elderly patients. While elderly patients continued to be susceptible to TBI-prone falls which frequently occur at home, during the four months of increased lockdown restrictions, patients of younger age groups were less susceptible to TBI-prone activities, such as operating motor vehicles, than they were during the three years prior. A study done in the Netherlands found a similar trend of increased age among TBI patients while lockdown restrictions were in place, linking it to a decrease in commuting among younger populations that might pose the risk of TBI . FurtherDuring the two years following the start of the COVID-19 pandemic, as the incidence of new COVID-19 cases in Virginia and Northern Virginia increased, we found that the average age of patients receiving TBI surgery decreased. We believe that this negative correlation might be a result of increased domestic abuse, especially among children. A study done on the rise of abusive head trauma (AHT) supports this idea, reporting an increase in AHT among children at their institution during the pandemic and linking it to the increased exposure of children to their parents .Another study that agrees with our overall findings observed a decrease in the mean number of TBI cases during the pandemic, linking it to a decrease in traffic accidents . HoweverAnother study done in Vento, Italy, observed an overall decrease in the incidence of TBI (approximately 49% less than expected TBI rates) in the year following the start of the COVID-19 pandemic . This isA primary limitation of our study is its retrospective design. Retrospective analyses, while valuable, might not account for all potential confounders as effectively as prospective studies. This may affect the generalizability and causative interpretations of our results. Another limitation of this study is that it does not compare the several years prior to the COVID-19 pandemic with each other to see if there was a preexisting, long-term, negative trend in TBI surgeries performed. An overall yearly decrease in operative TBI may inappropriately suggest this trend to be a result of the COVID-19 pandemic as the trend continues through the years analyzed following the emergence of COVID-19. Another limitation of this study is that it uses data from only one hospital in one country while attempting to draw conclusions about a global pandemic. As we have discussed above, other regions of the world have reported results different from our findings suggesting limitations in generalizability. It\u2019s also essential to note that our study centered primarily on operative TBIs. Thus, while our findings shed light on this subset of TBI cases, extrapolating these conclusions to encompass the entire TBI spectrum during the pandemic would require a more expansive analysis.With our study, we found an overall decrease in TBI surgeries performed and an increase in the average age of patients receiving TBI surgery during the four months of increased COVID-19 restrictions (March to June 2020). Our findings represent an example of how policy decisions and peoples\u2019 behaviors in reaction to environmental pressures can affect unrelated health conditions such as head trauma. This is important for us to keep in mind when making policies and addressing the concerns of the overall population. This also suggests that changes in society occurring during the COVID-19 lockdown that could be continued after the pandemic, such as an increase in working from home, may have the effect of decreasing severe TBI."}
{"text": "Micromachines retracts article [The journal  article  due to d article  will be Micromachines. This retraction was approved by the Editor-in-Chief of the journal The author agreed to this retraction."}
{"text": "Editorial on the Research TopicData driven and model based computational futures in cardiovascular practiceWith the turn of the millenium medicine has been witness to a tidal change in practices around real world evidence, and research, whose opportunity arose from the growing availability of computing resources, and the associated ever increasing ability to collect and store data. The value and perils of this new normal have become evident during the COVID-19  medicine, with a special focus on two apparently alternative approaches: machine learning, and physiological models.Enthusiasm about the promises of machine learning applications in the biomedical field is evergrowing, pushed by the amazing list of state-of-the-art works established by data-driven computational approaches in recent years , 3. NeveInterest in hypothesis driven computational model approaches has been growing, and in some notable cases  to provide proximal flow control.Reid et al. present the application of virtual imaging technology for diagnosis and planning of the aortic valve sparing procedure demonstrating that obtained information could be successfully applied to pre-operative surgical planning.The manuscripts we could map to machine learning applications to cardiovascular medicine appeared comparatively competitive on the technological solutions but somewhat less mature in terms of governance and technological solutions available to access the clinical settings.Cheng et al. present work to develop a reliable prediction tool of composite outcomes of postoperative complications using a minimum of easily accessible clinical parameters.Jiang et al. present the use of machine learning techniques to identify atrial fibrillation recurrence following Cox-Maze IV procedures.Baskaran et al. present an exploration of the generalisability of currently available predictors of major adverse cardiovascular events to under-represented populations.Cabrero-Holgueras and Pastrana present work to adapt the linear algebra operations of deep learning layers to packed homomorphic encryption demonstrating a speed-up in processing of convolutional layers compared to the existing proposals of privacy-preserving deep learning over encrypted medical data.Very interestingly with regards to making machine learning real-world ready, lowering barriers to data access, We believe this special theme will offer the readers a timely and strategic overview of the state-of-the-art in computational methods applied to cardiovascular medicine, offering a realistic and grounded insight into adjacent possibles they will soon be faced with in research and clinical practice."}
{"text": "The authors regret that the affiliations for Ji-Youn Kim and Hye-Ryeon Yu were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "Molecules entitled \u201cRole of Computer Aided Drug Design in Drug Development\u201d to present the most recent progress in this field. This Issue includes nine articles in total (two reviews and seven research articles), covering the research field of biomarker and ligand\u2013protein interaction prediction, drug repurposing, ligand binding site identification and largescale virtual screening.The introduction of computational techniques to pharmaceutical chemistry and molecular biology in the 20th century has changed the way people develop drugs. The computer-aided drug design method utilizes the 3D structures of potential drug targets  that are involved in the process of disease and the assembly of potential candidates to design novel molecules or modify existing agonists/antagonists against the target specifically ,2. As thAs previously mentioned, computer-aided drug design is an interdisciplinary field that involves a variety of techniques. The two review articles in this Special Issue provide us with a detailed introduction to commonly used methods and tools in drug design. Hasan et al.  not onlyFour out of seven research articles in this Special Issue present case studies of virtual screening and drug design using structure- and ligand-based computational methods. Rayevsky et al.  virtuallThe impressive progress of machine learning and artificial intelligence in the past decade is reshaping the field of rational drug design. Another three works in this Special Issue show how data-driven techniques accelerate drug discovery. Li et al.  developeBesides, Liu et al.\u2019s work  providesTo summarize, this Special Issue covers most of the computer-aided drug design techniques. It provides the readers with an overview of not only the application of structure- and ligand-based methods for drug discovery but also the development of machine learning methods for the prediction of biomarkers and potential ligands. We sincerely hope the articles in this Special Issue will draw researchers\u2019 attention to the field of rational drug design and prompt the development of novel computational methods for drug discovery."}
{"text": "Retraction Note: Journal of Autism and Developmental Disorders (2021) 52:2627\u2013264310.1007/s10803-021-05120-7The Publisher and the Editors-in-Chief are retracting this article. After publication concerns were raised with respect to the methodology used in this article. Post-publication review by a number of experts in the field has confirmed the following:Misrepresentation of the incidence of autism and insufficient attention given to various other factors that might account for apparent changes in ratesUse of unrepresentative dataNo valid justification for the mechanisms proposed for preventionArbitrary and insufficiently justified use of the birth cohort 1931 as an origin for the time trendUse of higher estimates and assumptions that inflated costs, together with failure to consider discrete events that occurred in referent years, including changes in definitions, alternative surveillance methods, and alternative explanations which may have contributed to changes in diagnosis.In addition, the Conflict of Interest statement does not accurately reflect the non-financial interests of the authors.The Editors-in Chief therefore no longer has confidence in the conclusions presented. Mark Blaxill, Toby Rogers and Cynthia Nevison disagree with this retraction."}
{"text": "In liver transplantation, a side-to-side anastomosis is one of the commonly performed techniques of the inferior vena cava reconstruction. The authors report a case of an application of an endoscopic vascular linear stapler for a side-to-side caval anastomosis during deceased-donor liver transplantation. The back table procedure was performed in a standard fashion for a side-to-side anastomosis. The linear vascular stapler was introduced during the temporary clamping of the recipient\u2019s inferior vena cava and the anastomosis was created without problems. Suturing of the resulting defect completed the anastomosis. The use of the stapler resulted in a shortening of the anastomosis time. The staple line after the reperfusion of the graft was completely sealed. The patient\u2019s postoperative course was uncomplicated and post-operative ultrasound and computed tomography confirmed the patency of the anastomosis. This case demonstrates a novel approach to a side-to-side caval reconstruction during liver transplantation that enables a shortening of the implantation time and may improve the quality of anastomoses. Since the first orthotopic liver transplantation was performed in 1963 by Starzl et al.  that preA 43-year-old male with hepatitis C virus (HCV)-related liver cirrhosis underwent elective deceased-donor orthotopic liver transplantation at the Department of General, Transplant and Liver Surgery of the Medical University of Warsaw. At the time of transplantation, his Model for End-Stage Liver Disease (MELD) and Child\u2013Pugh scores were 19 and 9, respectively. A hepatectomy with preservation of the recipient\u2019s IVC was performed. The whole-liver graft procurement from the brain-dead donor and preparation for piggy-back transplantation was performed as described previously . The livA one-centimeter incision was made in the distal part of the recipient\u2019s IVC and a corresponding venotomy was performed in the IVC of the liver graft A,B. Two No post-reperfusion syndrome was observed. The biliary ducts were anastomosed end-to-end with two running 6-0 polydioxanone sutures. The postoperative period was uneventful. An ultrasound examination on postoperative day (POD) one and POD 5 showed patent vascular anastomoses with typical flow characteristics. There was no stricture observed in the cavo-caval anastomosis and the maximal blood flow velocity (Vmax) equaled 73 cm/s. On POD 7, the patient\u2019s laboratory results revealed normalization of the liver function . Follow-A modified cavo-caval side-to-side anastomosis with a linear stapler and partial restoration of the IVC blood flow during orthotopic liver transplantation was presented. The authors chose the simplest possible technique of performing a stapled side-to-side cavo-cavostomy with a single linear cartridge application and closure of the resulting defect with a continuous suture. The authors believe this type of anastomosis most closely mimics the sutured piggy-back anastomosis and offers at least the same quality and safety of the resulting reconstruction . The impThe piggy-back technique reduces the risk of acute kidney injury (AKI) after transplantation compared to the caval-replacement technique due to the preservation of the IVC blood flow . This beLiu et al. in 2006 published an experimental study on an EndoGIA linear stapler for IVC anastomosis in dogs . The allStapled IVC anastomosis is a useful technique in voluminous liver grafts or cases of large caudate lobes when access to the proximal part of the IVC may be cumbersome. The placement of an EndoGIA stapler and suturing of the defect in the IVCs is performed from the caudal approach, which requires only minimal retraction of the liver to expose the infrahepatic IVCs. Moreover, sutured anastomoses in bulky grafts may be prone to excessive tension on the suture line, resulting in minimal lacerations in the vessel wall. This frequently leads to oozing from the anastomotic line after the restoration of blood flow through the liver and the IVC. Another possible problem with sutured anastomosis under tension may be its shortening and an increased risk of outflow obstruction. However, it has to be noted that the limitations of sutured modified piggy-back anastomosis also pertain to the stapled piggy-back technique. Anatomic limitations, abnormalities of the IVC, or severe adhesions between the liver and the retrohepatic IVC preclude safe preservation of the IVC during hepatectomy . VoluminThe stapled side-to-side cavo-caval anastomosis during orthotopic liver transplantation may offer some benefits, including shortening of the graft ischemia period, improved feasibility of anastomosis in large liver grafts or inconvenient caudate anatomy and better quality of the anastomotic line. However, some disadvantages and risks are possible, including less control of the anastomotic line, the lack of a way to adjust during the placement of staples, the risk of leaving loose staples in the venous lumen and the possible increased rigidity at the apex of the anastomosis. Well-designed randomized studies are needed to assess the clinical significance of the expected advantages and disadvantages of such an approach.Stapled cavo-caval anastomosis is a promising modification of the piggy-back liver transplantation technique. Other devices for vascular anastomosis may become future alternatives, including non-penetrating single staples  or even"}
{"text": "The glomerular filtration rate was obtained through an equation devised by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), which was derived from pooled data from clinical studies in the United States.The prevalence of CKD among apparently healthy people was analyzed among the participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).One point to emphasize is that ELSA-Brasil researchers did not correct the glomerular filtration rate for race in the manner proposed by the CKD-EPI consortium.Although the U.S. Preventive Services Task Force concluded that the \"evidence is insufficient to assess the balance of benefits and harms of routine screening for CKD in asymptomatic adults,\""}
{"text": "Correction: Biotechnology for Biofuels and Bioproducts (2023) 16:122 10.1186/s13068-023-02361-9Erysipelotrichaceae bacterium). However, ChPPK is the focus of research in this article and not EbPPK. The authors apologize for not being aware of the previous publication and have now cited the previous publication reporting the sequence [Following publication of the original article , it camesequence  in the asequence  in the Rsequence  previousThe authors also state that the correction does not affect the discussion or conclusions and that they sincerely apologize for the unintentional errors.The original article has been corrected."}
{"text": "Health system response to the co-incidence of epidemics and disasters: the importance of lessons learned during the COVID-19 pandemic\u201d was selected and notified by the journal \u201cFrontiers in Public Health\u201d to publish research papers that investigated and reported the different aspects of the health system response to the co-incidence of the COVID-19 pandemic and disasters across the world.The COVID-19 epidemic started in the Chinese city of Wuhan in December 2019 . In the Moslehi et al.). People's risk perception regarding the COVID-19 pandemic was investigated by Chinese researchers. They indicated that the older population, as a vulnerable group, had the highest risk perception score regarding the COVID-19 epidemic in China . Several authors investigated and analyzed the status of healthcare providers at the time of COVID-19. For example, the insufficient preparedness of nurses to respond to the COVID-19 crisis in Iran was extracted and reported (Moradian and Mahmoudi). In Germany, the self-images of ICU clinicians for crisis management during the COVID-19 epidemic were explored and reported as important perceptions that should be notified by policymakers . NGOs, as one of the important relief providers, can supply emergency relief resources with the support of the government through media publicity and policymaking encouragement in China (Lu and Wang). Regarding post-disaster recovery, resilient communities could cope with the effects of the COVID-19 epidemic better than vulnerable communities, which have insufficient communications and information . The surge capacity of healthcare facilities was an important issue at the time of the COVID-19 epidemic. Accordingly, the Arizona Department of Health Services has designed and implanted a surge line since the COVID-19 pandemic. This line was successful in facilitating patient transfer and benefiting marginalized populations . Medical performance evaluation and COVID-19 vaccination optimization were also investigated by Chinese authors, who published their research in this Research Topic .A total of 11 papers related to this Research Topic were accepted and published in the journal. None of the submitted papers addressed the co-incidence of the COVID-19 epidemic and natural disasters but considered the COVID-19 epidemic as a disaster and reported its various health aspects. For instance, regarding the social health aspect of COVID-19, social vulnerability indicators were developed to highlight the incidence of the COVID-19 epidemic in socially vulnerable regions in Iran (Although the impacts of disasters and epidemics on health systems have been reported by several studies, little is known about how to reduce the dual risk of disasters and epidemics. The COVID-19 epidemic provided a unique opportunity for identifying the emergent challenges and establishing innovative risk reduction and preparedness strategies to respond to similar crises in the future. The health sector has the main responsibility for people's health, and thus, plays special roles during the co-incidence of epidemics and disasters. Applying the lessons learned during the COVID-19 epidemic and establishing resilient health facilities and prepared healthcare staff can reduce deaths, injuries, and health system destruction after epidemics and disasters. Otherwise, all the adverse challenges and issues that the world experienced during the COVID-19 pandemic will probably repeat in any similar pandemic in the future. Thus, health systems need scientific collaborations and policymaking efforts at regional and international levels. The documentation and publication of effective lessons learned by health systems in the areas of prevention and treatment and disaster and emergency management should be considered as important measures and the first steps in future planning and policymaking.SS: Writing\u2014original draft, Writing\u2014review and editing. LM: Writing\u2014review and editing. MY: Writing\u2014review and editing. MZ: Writing\u2014review and editing."}
{"text": "Correction: Journal of Pharmaceutical Policy and Practice (2023) 16:158 10.1186/s40545-023-00652-yFollowing publication of the original article , it was dry ice. This unusual requirement necessitated training of physicians and pharmacists in the safe handling of dry ice and the support of the Swiss military pharmacy for logistics and distribution.This was achieved by shipping the vaccine vials in trays secured within thermal containers cooled with The original article has been updated."}
{"text": "The COVID-19 pandemic has radically changed our lives in every way. Since the beginning of the pandemic, more than 760 million cases and nearly 7 million deaths related to the COVID-19 disease have recorded worldwide . These p-Suicide risk related to isolation and financial stress;-The greater risk of domestic violence in the home environment;-The removal of young people from community relations within the school and other social fields;-Burnout within the healthcare community;-Difficulties in the surveillance and treatment of mental illnesses;-Reduced access to care for patients suffering from chronic alcohol and/or drug abuse;-The risk of stigma surrounding COVID-19-positive patients.According to the WHO , in the first year of the pandemic, there was a noted increase in the prevalence of mental disorders such as anxiety and depression, equal to approximately 25% . In the Although today, after approximately 3 years, we are witnessing a post-emergency period with a gradual recovery of all activities, scientific interest in the COVID-19 pandemic and its respective effects on mental health remain the subject of numerous studies, especially with respect to the long-term psychological effects of the disease. A recently published study by Xie et al. revealed an increase in the risk of mental illness in subjects who survived the acute phase of the COVID-19 pandemic . In 2023The evidence that has been offered leads us to further investigate the impact of the COVID-19 pandemic on our psychological states, both in the short and long terms . The pur"}
{"text": "Background: Following the establishment of Economic Community of West African States Medicines Regulatory Harmonization (ECOWAS-MRH) initiative in 2017, it was considered timely to carry out an evaluation of the current status of the initiative\u2019s operating model by the pharmaceutical industry users. This study examined the challenges being encountered and identified strategies that would strengthen the ECOWAS-MRH initiative moving forward.Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from manufacturers who have submitted applications to the joint assessment procedure and had identified recommendations for improving the performance of the ECOWAS-MRH initiative.Results: Ten pharmaceutical manufacturer participants  all reported that harmonisation of registration requirements was a major benefit, allowing submission of the same dossier to multiple countries, reducing the application burden and saving time and resources. Additionally, receipt of the same list of questions from several countries enables the compilation of a single response package, resulting in shorter timelines for approvals compared to the individualised country responses. Another benefit of a harmonised registration process was the simultaneous accessibility of medicines in various markets. Key challenges included a lack of centralised submission and tracking, differences in regulatory performance of the national medical regulatory authorities, a lack of detailed information for applicants and a low motivation to use the ECOWAS-MRH route with a preference for other regulatory pathways in the ECOWAS member states.Conclusion: This study identified several approaches to increase the effectiveness of this initiative: the implementation of risk-based approaches such as use of reliance pathways; establishment of a robust information technology systems, building assessor capacity to facilitate processing and monitoring applications; and priority review of ECOWAS-MRH products. It is the responsibility of every country to establish an effective and efficient medicine regulatory system in order to ensure timely patients\u2019 access to high-quality, safe and efficacious medicines . Vogel .The active engagement and co-operation of manufacturers with regulators in the medicine regulatory system is vital to the success of a national health system. Presently, there are multiple national jurisdictions that manufacturers have to contend with in order to obtain the requisite raw or starting materials, intermediate or semi-finished products, and where applicable, packaging materials from one country into another so as to manufacture a finished pharmaceutical product or vaccine. Furthermore, there are multinational pharmaceutical companies who conduct activities such as contract manufacturing across multiple countries worldwide, which underlines the complex nature of manufacturing of medicines and vaccines. The ideal regulatory environment that would benefit applicants would be one that multiple countries subscribe to under an umbrella of harmonisation. Furthermore, there is evidence to show that pharmaceutical applicants have a selective bias with regard to regulatory systems that provide transparency, accountability and predictability .There are various regulatory mechanisms available at this time that correspond to these parameters, such as the well-established centralised authorisation procedure of the European Union. In this procedure, applicants apply for a single centralised marketing authorisation for a product, which is valid throughout the European Union member states as well as Iceland, Liechtenstein and Norway . SimilarPresently, various diseases such as malaria and tuberculosis occur predominantly in Africa, with the WHO stating that in 2017, 92% of the 219 million cases of malaria reported worldwide were from Africa ; therefoThe challenges to the assessment of applications for marketing authorisation for new chemical entities and vaccines in Africa have been identified . Moran aMedicine regulatory harmonisation appears to be an effective mechanism for deploying technical, human and financial resources efficiently for the benefit of the population. According to the WHO, applicants who participate in the WHO prequalification programme enjoy various benefits such as increased sales or market access, improved image or brand, reduced manufacturing costs and increased capacity/skills. By extrapolation, applicants who participate in similar harmonisation initiatives like the ECOWAS-MRH can also experience their share of these benefits by having access to patients in all the 15 member states of ECOWAS, making this a win-win situation for both the applicants and patients .Started in 2017 by the West African Health Organization (WAHO), the ECOWAS-MRH initiative seeks to enhanced accessibility of high-quality, safe and effective medicines and vaccines in the ECOWAS . By the About a decade ago, Narsai and colleagues reported that there was inadequate information in the literature detailing the views of pharmaceutical manufacturers about the regulatory systems in Africa . This siAs a result of completing an earlier study aimed to assess the effectiveness and efficiency of the current operating model of the ECOWAS-MRH initiative by the national medical regulatory authorities (NMRAs) in the member countries , this prThe objectives of this study were to obtain the views of the pharmaceutical applicants or their local representatives of the ECOWAS-MRH initiative about the performance of the programme to date, identify the challenges experienced by the applicants throughout the life cycle of the ECOWAS-MRH initiative, determine the strengths and weaknesses of the initiative, identify the ways of improving the performance of the work-sharing programme and envisaging the strategy for moving forward.All ten pharmaceutical manufacturers who have submitted marketing authorisation applications for assessment of medicines at the regional level since the beginning of the ECOWAS-MRH initiative participated in the study. The study participants were classified as Innovator, Generics (foreign) -manufacturer outside ECOWAS and Generics - manufacturer within ECOWAS.Data for the study were obtained through completion of the Process Effectiveness and Efficiency Rating (PEER) questionnaire  by appliThe questionnaire consists of five sections namely; demographics, the benefits and challenges of the ECOWAS-MRH initiative, improving the performance (effectiveness and efficiency) of the work-sharing programme and envisaging the strategy for moving forward.Semi-structured interviews with a checklist were conducted with each manufacturer in order to validate and elaborate their responses in the PEER questionnaire. This also provided the study participants with an opportunity to discuss any difficulty they faced in responding to some of the sections of the questionnaire. In addition, this post-completion of the questionnaire was designed for the applicants to reflect both their experience of the initiative and that of the ECOWAS-MRH through a dialogue.For the purpose of clarity, the results of the study are presented in five parts: 1) Demographics; 2) Benefits of the ECOWAS-MRH initiative; 3) Challenges of the ECOWAS-MRH initiative; 4) Improving the performance (effectiveness and efficiency) of the work-sharing programme; and 5) Envisaging the strategy for moving forward.The respondents were mostly regulatory affairs managers, with varying years of regulatory experience ranging from 3 to 30. A summary of the manufacturers and their product categories is provided in Eight out of the 20 submissions have been issued with recommendation letters. The remaining submissions have either been deferred or are still in the screening phase for various reasons.Both the innovator and foreign generics are available in almost all the ECOWAS member states with the exception of Guinea Bissau; however, local generics are mostly available in Nigeria and Ghana . The assHalf of the number of manufacturers  keep a separate record of applications submitted for assessment under the ECOWAS-MRH initiative to facilitate tracking and adherence to deadlines.The benefits of the ECOWAS-MRH initiative that were identified by most of the applicants were the harmonisation of registration requirements across the region (80%), information sharing among regulators (50%) and capacity building (40%) for assessments. However, the benefits of leadership commitment/governance structure (30%) and shorter timelines for approval (30%) were identified by a few of the respondents .The strengths of the ECOWAS-MRH process for recommending the registration of products were identified as priority review of ECOWAS-MRH products, regular committee meetings enabling timely finalisation of products after ECOWAS-MRH recommendation, separate register and tracking of ECOWAS-MRH products and products approved under ECOWAS-MRH made available on each country\u2019s website. Medicines and vaccines eligible for the ECOWAS-MRH joint assessment are those included in the WHO Essential Medicine list, HIV/AIDS, malaria, tuberculosis, reproductive health, neglected tropical diseases, antibiotics, for public health emergencies, registered by stringent regulatory authorities, prequalified by WHO, registered under Swissmedic procedure for scientific advice and Marketing Authorisation for Global Health Products (MAGHP), granted a scientific opinion in line with the European Medicines Agency\u2019s Article 58 of Regulation (EC) No 726/2004, life-saving commodities by the UN Commission on life saving medicines for women and children and other priority medicinal products as determined by the WAHO.Upon completion of the ECOWAS-MRH joint assessment for such eligible medicines and vaccines, these are then granted marketing authorisation via the national registration system in the relevant country . PrioritThe benefits of the ECOWAS-MRH initiative identified by applicants (manufacturers) included: a reduced submission burden as applicants compile one dossier (modules 2\u20135) for submission to multiple countries; savings in time and resources as applicants receive same list of questions from multiple countries, enabling the compilation of a single response package; shorter timelines for approval compared with those for the individual countries and access to various markets at the same time. A better understanding of the individual country requirements was stated as an additional benefit of the ECOWAS-MRH initiative to applicants .Increased availability of medicines and quicker access to quality assured medicines were reported as benefits of the ECOWAS-MRH initiative to patients in the individual or in the ECOWAS region by the applicants.The lack of ability to mandate central registration; differences in the regulatory performance of the countries; dependence on the countries\u2019 processes for communication with applicants; absence of centralised submission and tracking and lack of detailed information on the process for applicants were identified as challenges of the ECOWAS-MRH initiative.Other challenges were also cited namely, lack of identified NMRA processes for movement from regional to local approval in the ECOWAS countries, no clear process for approval and lack of NMRA responsiveness in communicating updates of application status .Additional challenges identified by manufacturers submitting applications to the ECOWAS-MRH initiative included: low motivation and appeal to use the ECOWAS-MRH route as there are few success stories available or publicised; lack of clarity about the process for submission and follow-up in each country; differing labelling requirements in participating countries and low motivation to use the ECOWAS-MRH route because other review routes such as reliance on approvals from stringent regulatory authority or other ECOWAS countries now being used by individual countries are faster; failure by countries to adhere to promised timelines; the risk of losing access to all member states once a product is rejected by ECOWAS-MRH ; a lack of information on country and ECOWAS-MRH websites about the process, milestones or timelines; the absence of lists of pending and approved products; the perception that the ECOWAS-MRH process is more stringent than some country processes; and differences in time to implementation of ECOWAS-MRH recommendations by partner states .\u2022 Lack of enough personnel\u2022 Absence of proper knowledge of review process\u2022 Unharmonised system of review\u2022 Lack of information on country and the ECOWAS-MRH websites about the process, milestones and timelines for pending and approved products\u2022 Each member country has different requirements for Module 1 and applicants having to fulfil all countries\u2019 requirements\u2022 There is no clear process to follow once approval has been received from the ECOWAS- MRH procedure\u2022 Having to bring all the member countries regulators together in a timely manner to review the dossiers/applications\u2022 Delay in response time between applicants and reviewersComments by applicants to the challenges faced by the NMRAs in reviewing the ECOWAS-MRH applications were related to personnel and resources as well as the application and review process as below:Suggestions from applicants to improve the effectiveness of the ECOWAS-MRH initiative  were to The applicants suggested the following ways to improve the efficiency of the ECOWAS-MRH initiative: improved central tracking of ECOWAS-MRH products; specific and clear requirements made easily available to applicants; use of robust information technology (IT) systems; a centralised system for submission of applications and communication with applicants; compliance with target timelines by measuring and monitoring each milestone in the review process; and transparency in metrics and statistics such as percentage of reviews completed within timelines; and increased resources such as the number of assessors .Regarding possible strategies for moving forward, the applicants proposed that the establishment of a regional administrative body to centrally receive and track ECOWAS-MRH applications which would be responsible for allocating work, apportioning the applicable fees to countries, tracking of applications and communication with applicants was the most effective strategy to improve efficiency of the ECOWAS-MRH initiative. On the other hand, continuing with the current operation of the model without any changes was considered the least effective strategy to improve efficiency of the ECOWAS-MRH initiative. Seventy percent (70%) of the respondents agreed that the establishment of an ECOWAS regional medicines agency, if legally possible, will be the best strategy for improved performance going forward.\u2022 Implement a one-time payment process by ECOWAS, eliminating individual NMRA separate statutory registration fees\u2022 Harmonise labelling across all ECOWAS countries, eliminating individual country-specific labelling\u2022 Standardise and harmonise Module 1 dossier requirement across the ECOWAS countries to expedite the registration process\u2022 Require one Certificate of Pharmaceutical Product (CPP) for any of the member countries or for countries where commercialisation is being planned rather than separate CPPs for each country\u2022 Allow applicants to market their products across ECOWAS countries after ECOWAS-MRH approval to expedite the availability of medicines\u2022 Provide an online ECOWAS-MRH portal application system to expedite application submissions, tracking and evaluation\u2022 Ensure effective follow-up process and prompt communication to applicants\u2022 Confirm that a link to the application process is available on all country NMRA websites\u2022 Create a clear ECOWAS-MRH process pathway for applicants to follow\u2022 Include a drastic reduction in country good manufacturing process (GMP) fees for sites already evaluated through the process\u2022 Discourage the need for a new set of GMP fees for each NMRA, as this will have great impact on the ability to progress the application in each ECOWAS country\u2022 Concentrate the ECOWAS-MRH initiative solely on the quality and efficacy of the products, as decisions on products\u2019 commercial presentation should be left to individual countries for effective cost management\u2022 Improve communication of the multiple benefits of the ECOWAS-MRH initiative as it is presently poorly communicated among participating companies\u2022 Strengthen the regulatory function and inspection\u2022 Respond quickly to submitted documents, especially dossiers from applicantsFinally, the respondents provided strategies that could be considered in strengthening the ECOWAS-MRH initiative going forward.This study obtained the views of the both generic and innovator pharmaceutical applicants about the performance of the programme to date, identified the challenges experienced throughout the life cycle of the ECOWAS-MRH initiative, determined the strengths and weaknesses of the initiative, identified the ways of improving the performance of the work-sharing programme and envisaged the strategy for moving forward. The applicants expressed their views on all aspects of the ECOWAS-MRH initiative and offered very valuable suggestions for its improvement.The important benefit of harmonisation of registration requirements across the region was identified by almost all the applicants at this time. It is noted that in a similar study of the ECOWAS-MRH initiative by the authors , the benThe medicines regulatory harmonisation initiative in West Africa (ECOWAS-MRH) aims to improve the registration timelines without compromising the quality of regulatory decisions submitted for marketing authorisation. The joint assessment procedure, which is patronised by the NMRAs in the West African region and pharmaceutical manufacturers in other parts of the world is a classic example of this harmonisation initiative .As noted by the applicants, the strength of the ECOWAS-MRH initiative to prioritise the review of ECOWAS-MRH products for subsequent registration in the member states can be maximised to help make such medicines and vaccines available for public health use in a timely manner. The clearly identified benefits to applicants derived from the ECOWAS-MRH initiative  resultinSome of the challenges of the ECOWAS-MRH initiative namely, lack of centralised submission and tracking which were identified by the applicants in the study were also identified by the NMRAs in the previous study . SimilarThe challenges faced by manufacturers submitting applications to the ECOWAS-MRH initiative such as low motivation to use the ECOWAS-MRH route and preference for other regulatory pathways in the ECOWAS member states is reflected in the low number of applicants who have accessed the ECOWAS-MRH initiative to date . Other cSuggestions to improve the effectiveness of the ECOWAS-MRH initiative provided by the applicants were previously offered by the NMRAs, such as making publicly available any information that might help applicants in managing their submissions such as document templates, lists of questions and answers, timelines and milestones, decision-making transparency aids such as publishing Public Assessment Reports, consistency in application of guidelines and decisions, engagement and interaction with stakeholders, minimising the need for country-specific documents and publishing of pending and approved products. Use of risk-based approaches for example, reliance pathways was also suggested as another way that could be explored to improve the effectiveness of the ECOWAS-MRH initiative. The WHO Prequalification Programme success stories should be examined and piloted in the ECOWAS region .The suggestions presented by the applicants to improve the efficiency of the ECOWAS-MRH initiative, were also previously provided by the NMRAs, such as implementing robust IT systems and building capacity of assessors to facilitate processing and monitoring milestones of applications should also be explored . SimilarThe views of the NMRAs from the previous study  have beeProvide incentives to applicants in ECOWAS through fast-track processing of applications and reducing GMP inspection fees to encourage more submissions from applicants to the ECOWAS-MRH initiative.\u2022 Engage with the WHO Prequalification Programme to create a facilitated regulatory pathway for medicines and vaccines that have been issued with recommendation letters following successful completion of the ECOWAS-MRH joint assessment procedure.\u2022 Provide eligibility for international procurement agencies to source medicines and vaccines with recommendation letters for public health use in situations where there are no prequalified alternatives\u2022 Encourage training for applicants to develop their skills, knowledge, and competence\u2022 Convene stakeholder meetings on a biannual basis to engage with manufacturers and update them on requirements to ensure compliance with regulations\u2022 The authors\u2019 key recommendations for improving the ECOWAS-MRH initiative for both generic and innovator applicants are.This study identified the benefits and challenges of the ECOWAS-MRH initiative as experienced by the applicants as well as strategies available to improve its effectiveness and efficiency. If implemented by both generic and innovator applicants, the key recommendations that have been proposed should further strengthen this initiative to enable it to fulfil its mandate in the ECOWAS region."}
{"text": "The authors were not able to provide the raw data and the Editor-in-Chief and editorial board no longer have confidence in the reported results. The article is therefore retracted.Materials.This retraction was approved by the Editor-in-Chief of the journal The authors did not agree to this retraction."}
{"text": "Cultural intelligence can affect the cross-cultural adaptation of international students in China, but the mechanism of its influence is still unclear. This study examines the mediating effect of the psychological resilience of international students in China in the process of cultural intelligence affecting cross-cultural adaptation. We used the cultural intelligence scale, psychological resilience scale, and cross-cultural adaptation scale to measure 624 foreign students in China.(1) There is a significant positive correlation between the cultural intelligence, psychological resilience, and cross-cultural adaptation of international students in China. (2) Resilience plays a mediating effect in the influence of the cultural intelligence of international students in China on cross-cultural adaptation.The cultural intelligence of international students in China can directly affect their cross-cultural adaptation and can also affect their cross-cultural adaptation through the mediating effect of psychological resilience. As increasing numbers of foreign students choose to study and live in China, under the influence of foreign cultures, international students in China will suffer from maladjustment  to assess cultural intelligence. The CQS has 20 questions, including four dimensions: metacognition, cognition, motivation, and behavior  to explore the mechanism of cultural intelligence affecting cross-cultural adaptation, and the maximum likelihood method is used to estimate and test it. The results are as follows: \u03c7The purpose of this study was to explore the influence mechanism of cultural intelligence on the cross-cultural adaptation of international students in China. The results of this study show that the overall level of cross-cultural adaptation of international students in China is low, and there is a positive correlation between cultural intelligence and cross-cultural adaptation among international students in China, which is consistent with the previous study (Lin et al., The study also found that cultural intelligence has an impact on cross-cultural adaptation through the mediating effect of psychological resilience. This is consistent with previous research results Kumpfer, . Some stIn terms of theory, this study reveals the mechanism of cultural intelligence on cross-cultural adaptation and the applicability of the psychological resilience model supported by empirical evidence in explaining the relationship between cultural intelligence and cross-cultural adaptation. The results of this study also have a certain application value. This study has found that cultural intelligence can improve the psychological resilience of international students in China and promote their cross-cultural adaptation.However, this study has the following limitations: first, the study has highlighted that the micro-intervention model based on cultural intelligence can effectively improve cultural intelligence (Reichard et al., The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Academic Committee of Guangxi Science and Technology Normal University. The participants provided their written informed consent to participate in this study.KC is responsible for questionnaire distribution and data processing and paper writing. FZ is responsible for revising project management papers. Both authors contributed to the article and approved the submitted version."}
{"text": "Beta-lactam allergies (BLA) pose a challenge to the optimization of antibiotic therapy as some of these are not true allergies, are minor reactions, or instead may be adverse effects. This issue is further complicated by the fact that traditional methods of challenging allergies can be costly or time-consuming. The purpose of this study was to evaluate the safety of a protocol which directly challenges patients with a BLA via full dose administration of the challenge antibiotic based on the risk of cross-reactivity.This retrospective, observational, case-control study compared the incidence of hypersensitivity reactions following the administration of a beta-lactam antibiotic in patients with a reported BLA to that of those without a reported BLA. It included adults in the community hospital setting who received a beta-lactam antibiotic for any indication during an inpatient admission between March 2018 and October 2022. The treatment groups were separated by the presence or absence of a documented BLA. The primary outcome was the occurrence of a hypersensitivity reaction following the administration of a beta-lactam antibiotic.A total of 910 out of 1000 patients were eligible for evaluation, and 116 of those patients had a history of a BLA documented on the chart whereas 794 did not. The primary outcome of an IgE-mediated hypersensitivity reaction occurred in 1 out of 116 in the BLA group and 4 out of 794 in the non-BLA group  (see table).ResultsNo significant increase in the incidence of IgE-mediated allergic reactions was noted in the patients with a history of a BLA, however, the study was not powered to detect a difference due to the rarity of IgE-mediated reactions. Despite a trend towards an increased risk of reactions in patients with a history of a BLA, the majority of the few reactions that occurred were non-severe in nature. The benefits of challenging a BLA outweigh the risks in this setting.All Authors: No reported disclosures"}
{"text": "The use of cannabidiol (CBD) has received growing attention, and cannabis-based medicines are being explored as analgesics. In 2021, a task force, initiated by the International Association for the Study on Pain (IASP), published a series of narrative and systematic reviews and meta-analyses covering multiple aspects of pre-clinical and clinical pain research examining the efficacy and safety of cannabinoids as analgesics. It was concluded that the available evidence does not support the use of cannabinoids as analgesics on either safety or efficacy grounds.The Lancet Regional Health\u2014Europe, Pramhas et\u00a0al.,In the current issue of The primary result from the study by Pramhas et\u00a0al.,,An important exploratory outcome from the study by Pramhas et\u00a0al.,The strength of the study by Pramhas et\u00a0al.,Chronic musculoskeletal pain is complex and multiple factors are generally associated with high levels of clinical pain, such as poor quality of sleep, inflammation, psychological factors and sensitization of the nervous system.Kristian K-S Petersen received the invitation to write this commentary and wrote the first draft of the manuscript. Lars Arendt-Nielsen and Andrew SC Rice have completed a series of systematic reviews, meta-analyses and recommendations within the area of cannabis-based medicine and provide critical feedback to the manuscript. All authors agreed to submit the final manuscript.Kristian K-S Petersen chairs the Special Interest Group for Musculoskeletal Pain under the International Association for the study of Pain (IASP). Lars Arendt-Nielsen was the president for the IASP and initiated the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia and Andrew SC Rice chaired the Task Force."}
{"text": "Suicide represents one of the most discussed mental health issues in the world today and health challenges for the future. The burden of suicide is calculated in very high numbers (800 thousand people per year) by the WHO (2014), ranking it among the other most frequent causes of death. The key criteria to determine suicidal or non-suicidal behavior is the presence of intentional self-injurious behavior, in which the individual intentionally attempts to harm himself.Objectives: Aim of the study: was to make a presentation and evaluation of the demographic and clinical factors of suicidal self-injurious behavior in patients hospitalizedPatients\u2019 data were obtained from the archived clinical files of the Psychiatric Emergency Department and other wards at \u201cXhavit Gjata\u201d Tirana Psychiatric Hospital. The method used is a descriptive retrospective study of patients admitted during period of January-May 2019. About 75 archived clinical files were thoroughly studied and analyzed, on various demographic and clinical variables.Albanian women remain more at risk for suicide attempts, while male suicide mortality is higher, as in the world. Higher determination and the use of more lethal methods ranked among the factors contributing to the higher mortality of men. The 29-49 age group is the most affected in our study according to suicide attempts and self-harming behavior. The most pronounced accompanying diagnoses of suicide attempts are major depressive disorders, but not leaving behind psychotic disorders. The average length of stay in the hospital is 18.4 days.The deepening of knowledge on the etiology, on the factors influencing suicide and on the methods of treatment are only some of the issues facing public health today. Identification of self-injurious behaviors pave the way for treatment and assistance for anyone considering suicide.None Declared"}
{"text": "Cost Effectiveness and Resource Allocation (2023) 21:2110.1186/s12962-023-00430-2Following publication of the original article, the authors flagged the respective given and family names of the authors had been erroneously swapped. The author list has been corrected in the published article and the corrected names can be seen in the author list of this erratum.The publisher thanks you for reading this erratum and apologizes for any inconvenience caused."}
{"text": "Many artificial intelligence (AI) algorithms have been developed for medical practice, but few have led to clinically used products. The recent hype of ChatGPT shows us that simple, user-friendly interfaces are one major factor in the applications\u2019 popularity. The majority of AI-based applications in clinical practice are still far from simple-to-use applications with user-friendly interfaces. Therefore, simplifying operations is one key to AI-based medical applications\u2019 success. Many AI algorithms have been developed for medicine, but only a few have led to clinically used products and tools , 2. The The first drive of Karl Benz in his Motorwagen on Ring Street of Mannheim (Germany) in 1886 counts as the first drive of an engine-powered car on public roads after years of innovation . In the When the Xerox Palo Alto Research Center designed an experimental personal computer to investigate how small and cost-effective a personal computer could be, no one would have thought of the mass use of computers and other computer-related applications decades later . FurtherChatGPT  is an AI chatbot introduced recently . Almost History and the present show us that simplicity of operation is one major key to the success of new technological applications. Improving the simplicity of operation would help accelerate the broad implementation of AI-based applications in clinical practice."}
{"text": "In recent years, there has been a growing interest in the development of eco-friendly solutions to control pests and promote soil health. One promising approach is the use of microbe-pesticide interactions to achieve smart-soil bioremediation  and Hansschlegelia zhihuaiae S113 to remediate soils contaminated with the herbicide bensulfuron-methyl. The researchers found that the combined use of AMF and H. zhihuaiae S113 was more effective in reducing bensulfuron-methyl residues in soil compared to the use of either organism alone. The study also showed that the combination treatment improved soil nutrient availability and microbial activity, which may have contributed to the enhanced biodegradation of bensulfuron-methyl. In another study, Kumar et al. suggested that the use of environment-restoring microbes isolated from the rhizosphere of horticultural crops under subtropics may provide a promising approach for the bioremediation of chlorpyrifos-contaminated soils. Sharma et al. identified the rhizospheric bacteria for the removal of the carbendazim in soil. They showed the inhibitory effect of carbendazim in isolated bacterial strain. They showed carbendazim  decreases the concentration of indole acetic acid, ACC deaminase and siderophore production in bacterial cells.Li et al. suggest that the L1 microbial consortium has the potential to be used for the bioremediation of chlorimuron-ethyl-contaminated soils. However, further research is needed to optimize the conditions for the degradation process and to assess the long-term effectiveness and safety of this approach. The findings of this study may also have implications for the development of microbial consortia for the bioremediation of other herbicides and pollutants. The identification and characterization of the novel dmdA gene and its product may also have implications for the development of new herbicide-resistant crops and the biotechnological production of valuable compounds from dicamba. Zong et al. reported on the novel pyrethroid degrading enzyme SGNH esterase Est882, which can degrade diverse pyrethroids significantly.Singh and Saxena discussed the recent findings on the pesticide-microbe interaction and showed the relationship among environmental factors at various trophic levels. He et al. discovered the cypermethrin-degrading binary consortium of the genus Rhodococcus and Comamonas. The developed consortium was effective for the elimination of pyrethroids from the environment. Wahla et al. reported that biochar-immobilized bacteria enhanced metribuzin degradation in the environment. Similarly, Pan et al. observed that immobilized bacteria can accelerate atrazine degradation in soil. Zhao et al. suggested development of the solid agents can facilitate the soil microbial degradation of pesticides.Baazeem et al. reported Bacillus subtilis and other bacterial strains identified in their study can be used as an alternative to chemical pesticides for the control of Aphis punicae and Aphis illinoisensis. However, further research is needed to evaluate the efficacy of these bacterial strains under field conditions and to assess their long-term impact on the environment. Siddique et al. highlight the importance of insect gut microbiota in the degradation of pesticides. The gut microbiota of insects can play a critical role in detoxifying pesticides and reducing the accumulation of pesticide residues in the environment. The gut microbiota can also modify the physicochemical properties of pesticides, making them more susceptible to degradation. The composition of gut microbiota in insects can be influenced by several factors, including diet, host genetics, and environmental conditions. Therefore, the gut microbiota of insects can adapt to the presence of pesticides, leading to the development of pesticide-resistant gut microbiota. Astaykina et al. reported the impact of three pesticides on the gut microbiota of a earthworm Lumbricus terrestris. Pathak et al. discussed the negative impacts of pesticides on the environment, and living systems. They suggested the adoption of more sustainable and eco-friendly management strategies using microbial technology.Jaffer et al. described the the gut microbiota in insect physiology and the biodegradation of pesticides, and suggests that this knowledge could be leveraged for the development of more sustainable and eco-friendly approaches to pest management.The articles published on this Research Topic advanced our understanding of pesticide-microbe interactions in soil and other environments. The Research Topic focuses on the degradation of pesticides using various bacterial and fungal strains. In addition, the Research Topic gives insights into the impact of pesticides on the gut microbiota. Further work is needed to meet the major challenges in the field of microbe-pesticide interaction. Advances in 'omics technologies will promote discoveries of novel methods and future applications capable of cleaning large-scale polluted sites in an eco-friendly manner.The editorial draft was written by PB, SC, and CM. All authors contributed to the revision and improvements and approved the final version for submission. All the editors collaborated well for the successful completion of the Research Topic."}
{"text": "Mental disorders are increasingly recognized as leading contributors to the global disease burden, and of the years lived with disability . TF-CBT is the first line of treatment for patients with PTSD and uses stabilization techniques before the confrontation. The authors reported that in patients without concurrent somatoform disorders, integrating pranayama into TF-CBT might reduce their post-traumatic symptoms and increase their mental quality of life more efficiently than TF-CBT alone. However, the authors also emphasized the preliminary nature of the findings and the need to replicate the results by intention-to-treat analyses. These findings are relevant given the reported flare-up of post-traumatic stress symptoms (96.2%) as mental health consequences of COVID-19 . The article by Shidhaye et al., addressed maternal mental health outcomes  in pregnant women from rural settings of India, representing a marginalized sector of the population with enhanced vulnerability during the pandemic (Busch-Hallen et al., Another clinical trial of this Research Topic by Inbaraj et al., the authors presented the design and method of a randomized clinical trial, wherein they aimed to study the Impact of integrated yoga therapy on cognitive impairment and cardiac dysfunction regarding the quality of life in breast cancer patients undergoing chemotherapy. These subtle adverse effects, particularly changes in memory or cognition, remain unattended in many women, affecting their memory, and the ability to think clearly during and after chemotherapy (Vitali et al., In the study protocol by This research compendium also included an interesting state-of-the-art narrative review article on the coexisting condition of irritable bowel syndrome and fibromyalgia. These two health conditions share common pathophysiological mechanisms; sensitization of peripheral and central pain pathways and autonomic dysfunction. The conjuncture of these two conditions led to increased symptom severity, mental health comorbidities, and decreased quality of life. On an individual basis, mind-body interventions have been reported to benefit both the conditions and influence central pain syndromes and autonomic dysregulation. The authors evaluated the current evidence on the role of mind-body therapies in the coexisting state. They reported the limited availability of data in co-diagnosed patients. They also warranted the need for high-quality trials to tailor the programs individually.Given the wide diversity in psychological morbidities and scarcity of data, it becomes imperative to conduct studies to address the gaps in the area, ranging from epidemiology to intervention research.VM: manuscript writing. NM: review of manuscript. All authors contributed to the article and approved the submitted version."}
{"text": "Background\u2003Free tissue transfer is considered the gold standard option for the reconstruction of distal leg defects. Free tissue transfer using recipient vessels in the contralateral leg (cross-leg bridge) is a potential option to supply the flap if there are no suitable recipient vessels in the injured leg. Most studies have described this technique using end-to-end anastomosis which sacrifices the main vessel in the uninjured leg. This study evaluated the use of a cross-leg free latissimus dorsi muscle flap for the reconstruction of defects in single-vessel legs, using end-to-side anastomosis to recipient vessels in the contralateral leg without sacrificing any vessel in the uninjured leg.Methods\u2003This is a retrospective study that included 22 consecutive patients with soft tissue defects over the lower leg. All the reconstructed legs had a single artery as documented by CT angiography. All patients underwent cross-leg free latissimus dorsi muscle flap using end-to-side anastomosis to the posterior tibial vessels of the contralateral leg.Results\u2003The age at surgery ranged from 12 to 31 years and the mean defect size was 86\u2009cm2. Complete flap survival occurred in 20 cases (91%). One patient had total flap ischemia. Another patient had distal flap ischemia.Conclusion\u2003Cross-leg free latissimus dorsi muscle flap is a reliable and safe technique for the reconstruction and salvage of mutilating leg injuries, especially in cases of leg injuries with a single artery. As far as preservation of the donor limb circulation is concerned, end-to-side anastomosis is a reasonable option as it maintains the continuity of the donor leg vessels. Reconstruction of defects in the middle and lower thirds of the leg is challenging and requires innovative solutions. Microsurgical reconstruction with free tissue transfer has been considered the gold standard option for treating such defects, and this necessitates the presence of adequate recipient leg vessels.If there are no reliable recipient blood vessels, the use of the contralateral leg vasculature is a potential option to supply the transferred tissues. Using cross-leg bridge free tissue transfer was first described by Taylor et al in 1979, and the principal concept of this technique is to anastomose the flap to intact vessels in the contralateral noninjured leg. This temporary vascular anastomosis supports the flap until it forms sufficient vascular connections with its edges and bed in the injured leg, then separation is performed.A number of studies have reported successful reconstruction of leg defects with cross-leg free tissue transfer, utilizing muscle/musculocutaneous flaps such as latissimus dorsi, rectus abdominis, gracilis, and vastus lateralis musclesY- orT-shape fashion and suturing it to the recipient vessel in a flow-through anastomosis fashion.Most of these previous studies used end-to-end anastomoses to the recipient vessel in the contralateral uninjured leg. The major drawback of end-to-end anastomoses is scarifying one of the main blood vessels of the uninjured limb. Therefore, several new reconstructive techniques have been introduced in order to maintain and preserve the integrity of the recipient arterial system of the uninjured leg. These techniques include redirecting the artery of the flap to the distal end of the recipient vessel after pedicle divisionAlthough there are many studies which demonstrated the use of free tissue transfer with end-to-side anastomoses to recipient vessels in the same injured leg with the aim of preserving distal perfusion in patients with impaired vasculature,The purpose of this study is to present the outcomes of the use of cross-leg free latissimus dorsi muscle flap for reconstruction of defects in single-vessel legs, using end-to-side microvascular anastomosis to recipient vessels in the contralateral leg without sacrificing any of its vessels.We retrospectively reviewed 22 consecutive patients with traumatic soft tissue defects, in legs with a single artery as documented by CT angiography, who underwent cross-leg free latissimus dorsi muscle flap with end-to-side microvascular anastomosis to the posterior tibial artery of the contralateral leg. After the ethical approval of the study protocol, patients' data were collected from the patients' registry. The patients' demographic and clinical data included sex, age, type of injury, location of the injury, defect size, vascular status of injured legs, associated comorbidities, and time of flap separation, postoperative complications, and revision procedures.Under general anesthesia, sharp debridement is performed removing all necrotic or scarred tissues until reaching a healthy bleeding tissue bed. In the contralateral noninjured leg, the posterior tibial artery and one of its venae comitantes are dissected and prepared as recipient vessels. An inferiorly based skin flap, approximately 4\u2009cm in width and length, is elevated to form the base of the bridge and protect the vascular anastomosis.With the patient in the lateral position, latissimus dorsi muscle flap is harvested with the dominant thoracodorsal pedicle. A small skin island is included with the muscle to facilitate flap monitoring. The muscle is then sutured to the healthy edges of the defect in the injured leg allowing maximal interface between the flap and the recipient site. The inferiorly based skin flap previously raised on the uninjured limb is turned and sutured to the opposing edge of the muscle flap to form the bridge .The two legs are fixed together using an external fixator. End-to-side microvascular anastomosis is then performed between the thoracodorsal vessels and the posterior tibial artery and one of its venae comitantes on the contralateral uninjured leg. Patients are maintained on low-molecular weight heparin from the time of surgery till the patient is completely mobilized to protect against deep venous thrombosis. All patients stayed hospitalized until flap separation for monitoring of the flap and adequate wound care. The muscle is covered by a split-thickness skin graft either before the time of flap separation or during the flap separation procedure.After 3 weeks postoperatively, the free flap pedicle was occluded with noncrushing clamps at the bedside and the flap vascularity status was assessed clinically using a needle prick test. If there is bright red blood bleeding in the distal part of the flap and no signs of insufficient flap circulation noted, we then conduct the second stage of flap separation and divide it from the recipient extremity. If flap circulation seems insufficient, we wait further 4 or 5 days and repeat that. After the removal of the external fixator and separation of the two legs, physiotherapy is started immediately to prevent joint stiffness.2(mean 86\u2009cm2). Follow-up ranged from 12 to 18 months, with an average of 15 months. The patients' demographic, clinical data, and vascular status of each patient are summarized inThe mean age at surgery was 21 years with a range from 12 to 31 years. Of the 22 patients, 19 were males and 3 were females. All defects were located in the leg. The defect was on the right leg in 14 patients and the left leg in 8 patients. The defect size ranged from 35 to 280\u2009cmAll injured extremities were reconstructed with latissimus dorsi cross-leg free flaps as described in the surgical technique section. End-to-side anastomosis was performed to the contralateral posterior tibial artery in all cases to maintain distal blood flow. The second stage procedures were performed between 3 and 6 weeks.Complete flap survival was reported in 20 cases (91%). One patient had total flap ischemia which was managed by debridement and negative pressure wound therapy for 3 weeks until the wound was clean with healthy granulation tissue, then a split-thickness skin graft was applied. Another patient had distal marginal flap ischemia that was managed by debridement, antibiotics, and wound care until healing by secondary intention occurred. Infection in the recipient site occurred in three patients and was treated conservatively by antibiotics and repeated wound dressings. Mild seroma in the flap donor site occurred in two patients and was managed by syringe aspiration for one time with no recurrence. All wounds in the contralateral leg healed uneventfully without complications apart from the anticipated scarring. Five patients needed regrafting of residual small exposed parts of the muscle flap due to partial skin graft loss . AlthouTransposition of local tissue flaps (fasciocutaneous or muscle), if available, is the first choice to reconstruct defects of the leg. When there are no available local tissues for transposition, distant flaps and free flaps play a major role in these occasions.Pedicled cross-leg flaps have been widely used for the reconstruction of leg and foot defects since 1854.The continuous improvement of the outcomes of microsurgical interventions has made free flap reconstruction a routine option in lower extremity reconstructive surgery.Haddock et al described using the perforator-to-perforator anastomoses as another solution to avoid scarifying of the ipsilateral limb recipient vessel.Therefore, it is necessary to use alternative options when there are no adjacent vessels available near the soft tissue limb defect and to perform the microvascular anastomosis outside the zone of injury. These include the use of vein graftsThe use of cross-leg bridge free flaps is a relatively old surgical technique, firstly described by Taylor et al in 1979 to solve the problem of lack of vessels in the recipient leg using cross-leg free DCIA flap to reconstruct bony and soft tissue defect in the leg.Cross-leg free flaps allow the transfer of the needed tissues including skin and muscle with or without bone using microvascular anastomoses performed away from the zone of injury to reconstruct challenging tissue defects with healthy vascularized tissue.Yamada et al applied the same technique in six patients using free rectus abdominis muscle flap anastomosed to vessels of the contralateral noninjured leg with a good outcome.Latissimus dorsi flap has many advantages as a cross-leg free flap in the reconstruction of complex leg defects as it can provide a sizable flap with a long pedicle and good vessel caliber.The use of the posterior tibial vessels as cross-leg bridge recipient vessels has often been described in the literature as an end-to-end anastomosis as this allows easy positioning and safe anastomosis.This problem has led to design several innovative techniques to maintain the integrity of the recipient arterial system. Akyurek et al described a new technique to restore the continuity of the recipient artery in cross-leg free latissimus dorsi flap procedure after end-to-end anastomoses. They reestablished the continuity of the posterior tibial artery at the time of flap separation by dissecting the thoracodorsal artery till its bifurcation in the muscle flap, transecting it, and reanastomosed to the distal ligated end of the posterior tibial artery.Yu et al suggested an alternative option to preserve integrity of the recipient vessel which is an end-to-side anastomoses to the contralateral limb in order to maintain continuity of the distal blood flow, although they performed the microvascular anastomoses of their cross-leg bridge free flaps series in an end-to-end fashion.In the present study, we performed an end-to-side anastomosis of the thoracodorsal vascular pedicle of the free latissimus dorsi flap to the contralateral recipient posterior tibial artery while preserving the single vessel of the injured leg untouched and at the same time preserving the recipient vessels of the uninjured limb undisturbed after separation of the flap. This is the first case series which reported cross-leg free flap reconstruction using an end-to-side anastomosis to the posterior tibial vessels of the contralateral leg. We found that the use of this technique in 22 consecutive cases has resulted in an overall success rate of 91% which is comparable to the results of other previous studies describing cross-leg free flap using end-to-end or flow-through anastomosis. Furthermore, we believe that the end-to-side anastomosis technique, described in this study, have distinct advantages. The most obvious advantage is the prevention of reduction of the blood flow to the recipient extremity and protecting the continuity of the posterior tibial vessels of the noninjured leg while maintaining efficient free flap perfusion. This technique has also obviated the need to use long vein grafts or to prepare bifurcated thoracodorsal arterial pedicle that cannot be easily available for flow-through anastomosis. In addition, it seems that end-to-end anastomosis to a major artery causes problems such as temporary congestion or severe swelling of the free flaps which are induced by excessive inflow. These may be other advantages of using end-to-side anastomosis.These findings suggest that cross-leg free flap using end-to-side anastomosis is an efficient and safe alternative for reconstruction of mutilating leg injuries with compromised vasculature, without sacrificing any vessel in the donor leg.The limitation of this study is its retrospective design and being a case series without prospective data or a comparison control group using end-to-end or flow-through anastomosis which preserves the integrity of the contralateral recipient vessel. However, this series demonstrates that the end-to-side anastomosis to the contralateral recipient vessel is a viable option in cross-leg free flaps reconstruction supported by the high rate of flap survival and low complication rate.In conclusion, cross-leg free latissimus dorsi muscle flap is a reliable and safe technique for the reconstruction and salvage of complex leg defects in mutilating leg injuries. It can provide a good reconstructive solution, especially in cases of leg injuries with a single artery, without increasing the risk of complications. As far as preservation of the donor limb circulation is concerned, cross-leg end-to-side anastomoses are a reasonable alternative as it maintains the continuity of the donor leg vessels for any possible future need."}
{"text": "In an era of electronical medical records, rapidly expanding publication rates of medical knowledge, and large-scale registries, orthopaedics is in a dire need of innovative approaches to facilitate the adoption of the latest knowledge in clinical practice. While machine learning (ML) has been heralded as one solution to many research tasks hampered by previous technological limitations , there iText classification \u2013 Categorisation and clustering of scientific articles based on level of evidence and/or sub-topics, detected using abstract screening for relevant terms.Information extraction \u2013 Identification of information related to patients, interventions, comparisons, and outcome variables (PICO elements) [lements)  from eleQuestion answering \u2013 Automated responses to frequently asked questions with a custom medical knowledge base used to generate conversational layers.Sentiment analysis \u2013 Assessment of the emotions and opinions of patients about a medical service based on analysis of the affective qualities of written reviews [ reviews .Summarization \u2013 Abstraction of a large volume of medical evidence to generate a short summary with essential and easy to understand information for patients.Natural language processing is a ML-based tool that involves quantitative encoding of information derived from human language. Data generated from speech- and text-processing NLP algorithms can be used to solve a variety of tasks with broad applications in medical practice and research. Due to limited examples of NLP-based research in orthopaedics , 15, comF1 score  are key metrics used in the evaluation and interpretation of NLP models.Understanding of the inner workings and performance of ML models are key steps in identifying applications for NLP in orthopaedic research . AccuracWhile there is no shortage of available data for orthopaedic research, a major barrier to the accessibility of data is due to its storage as unstructured text. A previously published editorial outlined the discrepancy between the publication rate of primary research articles and the synthesis of up-to-date evidence in the form of systematic reviews and meta-analyses . ConsequThe use of standardized knowledge bases is essential for the design and implementation of NLP algorithms designed for specific research purposes. We believe the next step towards solving the challenges associated with information extraction is to establish comprehensive knowledge-base of annotated disease- or injury-specific medical text. This idea rests on the principle that an NLP model is more likely to perform well when trained on a body of domain-specific information, with expert-level annotation and abstraction of the key element in the text, even if it has been pre-trained for general language understanding. A recent study of biomedical image analysis determined that improvements in labelling instructions have an immense impact on the interrater variability in the quality and consistency of annotations, and consequently, on the performance of the final algorithm . SimilarOver the recent year, large language models (LLMs), such as GPT-4 , Med-PaLWe believe the adoption of NLP frameworks to be one of the key steps in the evolution of medical data extraction and evidence-synthesis. There is currently a need for innovative solutions to obtain meaningful information from the growing availability of structured and unstructured medical text, with the goal to improve the quality of patient care. Considering the immense potential in the clinical and research setting, there is a growing need for the dedicated training of healthcare professionals in the fundamental concepts and applications of AI. The annotation of condition-specific training data and design of efficient NLP pipelines are complex tasks, which require close collaboration between the healthcare and technology sectors to establish high-quality and scalable systems despite existing disparities across the global healthcare sector. Rather than solely being the end-users of AI systems, healthcare professionals should take a more active role in the development of frameworks for specific aspects of orthopaedic research and clinical care. Finally, expert consensus is required to integrated labelled and unlabelled orthopaedic datasets to train LLMs and GAI models to perform domain-specific tasks, such as clinical concept extraction, medical relation extraction, and medical question answering, with high efficiency, accuracy and reliability."}
{"text": "Digital technologies and advances in computational methods have become key drivers of innovation in many medical fields. In precision psychiatry, accurate and reliable measures of mental health are critical for informing patient care and clinical research. There has been growing concern over the limitations of traditional mental health assessments that are typically grounded in nosology defined by the DSM and are based on interviewer-led assessments or patient self-report questionnaires. Whereas such gold-standard clinical assessments can be cost-prohibitive, insensitive to change, and prone to subjective biases, the use of digital technologies provides an opportunity to improve the practical feasibility as well as the inter-rater and test-retest reliability of repeated mental health assessments. The key promise of this approach is to unlock the clinical potential of digital technologies in ways that foster research of high clinical relevance and impact on clinical care. I will discuss these promises and challenges for the future use of machine learning approaches for predicting and monitoring post-traumatic stress and resilience.None Declared"}
{"text": "The transannular patch repair of tetralogy of Fallot never seems to go out of style, despite the availability of other valve function-preserving techniques. I read with great interest the current article from the highly credible and experienced team at Fuwai Hospital  . As ackn"}
{"text": "Silicosis still represents a major occupational Research Topic worldwide. The enforcement of strict safety standards and worker protection measures have lowered the level of occupational exposure and decreased the incidence of related lung diseases, in some countries. However, this success is mainly limited to high-income countries and new occupational and/or environmental hazard may arise from new materials or emerging pollutants (EP), as well-illustrated by the cases of accelerated silicosis from artificial stone (AS) dusts or the risk posed by natural occurrences of asbestos and asbestos-like minerals (NOA) , mainly in the form of ls (NOA) . In factls (NOA) . Diseasels (NOA) . Fibrousls (NOA) . The patls (NOA) ; ii) thels (NOA) . The comTo design an integrated occupational and environmental strategy for hazard assessment and control, the toxicity paradigms for airborne toxic particles have to be extended to the whole realm of inorganic dusts also in non-conventional exposure scenarios. To tackle this challenge, we must advance our knowledge on the complex interplay established by inorganic particles and biological environments. In parallel, new exposure scenarios of well-known or still poorly-described inorganic dusts, e.g., quartz , asbestoTo cover promising, recent, and novel research trends in all the above mentioned aspects of toxic or potentially toxic inorganic particles and fibres, we challenged the scientific community to advance the development of mineral particle eco-exposome, which represents the Frontier for assessing the effects of multiple exposures to chemicals. This challenging task translates, for inorganic particles and fibres, in the design of integrated investigation strategies that will bridge minero-chemical properties to hazard assessment.The contributions collected spanned from the definition of the geological occurrence of a well-known carcinogenic fibre to the description of the molecular interactions taking place at the bio-inorganic interface of silica and silicates.Patel et al. reviewed almost 200 references to define the new state-of-the-art in the geolocalization of the occurrence of erionite worldwide. Erionite is a fibrous zeolite which has been recognized as the causal agent to lung cancer and malignant mesothelioma. The extensive analysis of the literature provides more than 100 global locations where erionite has been reported. In addition to reporting the geological setting of host rocks and the paragenetic sequence of erionite formation, the paper includes a description of the fiber morphological and mineralogical properties and an overview of the techniques to identify and characterize the mineral. With an analytical perspective, the work by Avataneo et al. dealt with the emerging concern of the presence of asbestos fibres in water. To compensate for the limited attention that has been dedicated to waterborne asbestos, this experimental work mimicked a Scanning Electron Microscopy analysis of waterborne chrysotile from stream water and tested the reliability of the method with a multi-instrument, multi-operator double check of samples. Good practices to perform reliable analyses on surface water samples containing asbestos were proposed. To investigate the overlooked presence of emerging contaminants such as naturally occurring fibre-like particles (FLP), Talbot et al. performed a re-examination of several particulate matter filters from three sites across Auckland (NZ) that were collected during a 20-year long air monitoring campaign. The analysis confirmed the occasional presence of erionite in the re-analysed filters. A micro-dispenser method to prepare depositions of asbestos fibres for toxicological tests in vitro is reported by Della Ventura et al. This novel approach deposit micro-sized droplets from a suspension of fibres and allows control of some key parameters including the deposition area, the deposition time, and the uniformity and volume of the deposited liquid. Advances on the description of the molecular interactions taking place between inorganic particles and model membranes are reported in the collective Research Topic. Moving from the interaction paradigm proved to occur between cellular membranes and a specific population of weakly interacting silanols exposed at quartz surfaces, the nearly free silanols , Pavan et al. expanded their interaction model to the other crystalline silica polymorphs and paved the way to a comprehensive understanding of the structure-activity relationship between nearly free silanols and membranolytic activity of crystalline silica. With a complementary approach focussed on membrane chemistry, Sydor et al. showed that an increase in the cholesterol content of membranes can attenuate the silica-induced membrane alterations, ultimately suggesting that the selective manipulation of lysosomal cholesterol may be a way of mitigating silica-induced lysosomal disruption and preventing chronic inflammatory disease progression.The work by Overall, this Research Topic has put together some novel and relevant research that can pave the way for a more integrated comprehension of how inorganic chemistry, analytical approaches and toxicological investigations can be integrated to develop an eco-exposome approach to particle and fibre hazard assessment."}
{"text": "We aimed to investigate partnership-working across sectors through the example of the Wales Physical Activity Partnership (WPAP). Three national organisations specialising in sport, environment and public health formed a strategic alliance under the Welsh Government\u2019s direction to support the long-term innovative legislation of the Wellbeing of Future Generations  Act 2015 (WBFGA).We completed in-depth semi-structured interviews with WPAP members  involved in the leadership, management and work-stream levels of the partnership. The leadership group members were interviewed twice, with 12 months between interviews, to follow-up progress of the partnership and changes in strategic direction. The interviews were transcribed and analysed in NVivo using Braun & Clarke\u2019s (2014) thematic analysis.The participants had experiences of operating in leadership, management and working group roles within the partnership, each representing their organisation. The major themes were related to the partners sudden change in short-term priorities and the efforts to maintain momentum in line with the long-term direction of their alliance. The Covid-19 pandemic was felt to accentuate underlying issues, by limiting capacity and halting momentum in the developing the partners\u2019 shared agenda. The leadership group remained confident of the added value to their organisations by connecting sport, environment and public health and recognised the shared responsibility of their organisation in supporting the Welsh Government to increase physical activity across Wales. The working group members felt that the governance structure and division of work-streams diluted the potential of the three partners, and often felt \u201ccompartmentalised\u201d and there was limited communication between work-streams.The impact from the Covid-19 pandemic was a barrier to building and maintaining momentum in this partnership between sport environment and public health. Wales is the first country to impose that public organisations bear a legislative duty to evidence their contribution towards the long-term strategy to improve physical activity, health and wellbeing via the WBFGA. Innovative legislation has provided a foundation for organisations in diverse sectors to shift their agendas to evidence long-term contributions but short-term pressures, such as the Covid-19 pandemic, may dilute the commitment and strategic intent."}
{"text": "Hfq is required by many Gram-negative bacteria to chaperone the interaction between small non-coding RNA (sRNA) and mRNA to facilitate annealing. Conversely and despite the presence of Hfq in many Gram-positive bacteria, sRNAs in Gram-positive bacteria bind the mRNA target independent of Hfq. Details provided by the Hfq structures from both Gram-negative and Gram-positive bacteria have demonstrated that despite a conserved global structure of the protein, variations of residues on the binding surfaces of Hfq results in the recognition of different RNA sequences as well as the ability of Hfq to facilitate the annealing of the sRNA to the mRNA target. Additionally, a subset of Gram-negative bacteria has an extended C-terminal Domain (CTD) that has been shown to affect the stability of the Hfq hexamer and increase the rate of release of the annealed sRNA-mRNA product. Here we review the structures of Hfq and biochemical data that have defined the interactions of the Gram-negative and Gram-positive homologues to highlight the similarities and differences in the interactions with RNA. These interactions provided a deeper understanding of the how Hfq functions to facilitate the annealing of sRNA-mRNA, the selectivity of the interactions with RNA, and the role of the CTD of Hfq in the interactions with sRNA. Small non-coding RNAs (sRNA) have been shown to regulate a variety of different responses in bacteria by acting as a posttranscriptional regulator of translation and are often associated with adaptive stress response, including antibiotic resistance . The mosEscherichia coli (Ec) as an essential Host factor for the replication of bacteriophage Q\u03b2 RNA (Takada99).Hfq was first identified in e Q\u03b2 RNA , and is e Q\u03b2 RNA . Hfq is e Q\u03b2 RNA . One funcis-encoded and trans-encoded sRNAs  and Bacillus subtilis (Bs) residue F42, Staphylococcus aureus (St) Y42). Hfq residues make a base specific contact through a conserved Q8 that recognizes an O2 of uridine or O6 of adenine, a conserved K56 residue and an amine group at position 41 . A conserved H57 (Ec and Sa numbering) interaction with O2\u2019 of the ribose likely ensures a preference for RNA over DNA binding. The proximal side binding site appears to be a general binding site of all Hfq homologues and binds to single strand A/U rich RNA sequences and may participate in the rearrangement of secondary structures of the RNA  to an (A-L) recognition not only alters the specificity of the sequence bound on the distal side, but also reduces the maximum number of bases bound from 18 nucleotides by Gram-negative Hfq to 12 by the Gram-positive Hfq.Similar to Gram-negative bacteria, Gram-positive bacteria have six binding sites, with each binding site located at the interface of two subunits of Hfq. However, an inserted amino acid in the loop between \u03b2-strands 3 and 4 and a small number of seemingly conservative variations, particularly I30 to an aromatic , in Gram-positive Hfq results in a slight shifting of the first A-site and a loss of the second A-site . These cThe difference in the electrostatic surface potential of the lateral rim of Hfq between Gram-negative and Gram-positive homologues plays a significant role in the difference in the annealing function of Hfq homologues . The surE. coli numbering) is also highly conserved but has been shown to pack against the lateral edge of the core (The CTD of Hfq varies greatly not just between the Gram-positive bacteria where it is largely absent or severely truncated, but also within different species of Gram-negative bacteria in which the length of the CTD varies greatly . While tthe core . The midthe core .Two models of the Hfq facilitated sRNA-mRNA annealing in Gram-negative bacteria have been proposed based on the differences observed in the sRNA that is involved in the interactions with Hfq. Two different classes of sRNA, Class I and Class II, have been identified based on these differences in the interaction with Hfq and the recognition sequence of the sRNA . Both clClass II sRNA binds with the same binding motif to the proximal side of Hfq as Class I but the second binding site of the sRNA is on the distal side of Hfq with an AAN motif, as opposed to the rim. The mRNA targets of Class II sRNAs are unable to bind to the distal side of Hfq even if they contain an AAN motif and must therefore bind to the rim of Hfq at the UU binding site. The formation of the sRNA-Hfq-mRNA complex again results in the annealing of the sRNA with the mRNA sequence. However, in the\u00a0case of Class II sRNA, the mRNA is degraded, but the sRNA often remains bound to Hfq for multiple rounds of mRNA binding . As a coAn additional consequence of the difference in the interaction between Class I and Class II sRNAs is the role of the CTD of the Hfq in the regulation of the process. Early work into the role function of the CTD appeared conflicting, with some work indicating that the CTD played no role in the Hfq interaction with sRNA, while other work indicates that the CTD is required for the proper binding and annealing of sRNA to the mRNA target . While dThe facilitation of annealing of Hfq for Class I and Class II sRNA in Ec is initiated by the sRNA and mRNA binding to Hfq. Both RNAs potentially undergo a rearrangement of stem regions exposing the seed sequence at the lateral rim region of Hfq. The exposure of the single strand seed sequence of the sRNA and mRNA following the rearrangement of the stem regions allows the annealing of the sRNA-mRNA at the rim of Hfq . Class IThe CTD also plays an important role in discriminating between Class I and Class II binding of Hfq. In the presence of the CTD, Class II sRNAs bind preferentially to Hfq over Class I. However, the removal of the CTD removes the preference for Class II sRNA . It has Recent studies examining the stability of the Hfq using mass spectroscopy combined with the observations described above has led to a more comprehensive model of the chaperone activity of Hfq . The CTDcis-encoded that are perfectly or highly complementary to the mRNA target. Gram-negative bacteria contain more trans-encoded sRNAs that have limited complementarity to the mRNA target (trans-encoded sRNAs (cis and trans-encoded sRNAs to support this hypothesis.There are multiple differences in the binding surfaces of Hfq between Gram-positive bacteria compared to Gram-negative bacteria. The difference in the requirement of Hfq between the two classes of bacteria likely results in the origins of the sRNA in the different bacteria. The sRNA identified in Gram-positive bacteria are predominantly A target . Therefoed sRNAs . The co-DA: Writing \u2013 review & editing. DW: Writing \u2013 original draft."}
{"text": "Coronary revascularization is one of the most studied treatment modalities in cardiology; however, there is no consensus among experts about its indications in patients with stable coronary artery disease (SCAD). Contemporary data regarding the role of revascularization in SCAD are in clear conflict with the current European guidelines. This article discusses the main statements of the most significant American and European Guidelines on myocardial revascularization of the last decade and also analyzes the appropriateness of revascularization to improve the prognosis and symptoms in SCAD in the light of new research data, primarily the ISCHEMIA study (NCT01471522) and the ACC/AHA 2021 Revascularization Guidelines based on them. Data on the revascularization in SCAD obtained after the completion of ISCHEMIA  and their potential significance are discussed. The results of ISCHEMIA sub-analyses in the most important \u201ccontroversial\u201d subgroups  are reviewed, as are the results of the ISCHEMIA-CKD substudy in patients with severe chronic kidney disease (CKD). A record number of studies have been conducted on myocardial revascularization in SCAD , but desIn this article, we analyze the appropriateness of myocardial revascularization to improve prognosis and symptoms in SCAD and compare the statements of the current Guidelines with the new research data.The most significant recommendations on which clinical decision-making in practice has been based in the last decade were the European Guidelines on Myocardial Revascularization , the ESCThe indications for revascularization available in the listed sources are summarized below  and textEuropean revascularization Guidelines  are veryHowever, the ESC Guidelines on CCS  state inAlthough these guidelines have been the basis of clinical decision-making for a long time, they are controversial. Also, statements on the prognostic benefit of coronary artery bypass grafting (CABG) in individuals with high-risk coronary lesions and reduced EF are based on observational data from the 1980s and 1990s, conducted before the era of modern optimal medical therapy (OMT) . Neverthn = 5179) comparing an invasive and conservative strategy in patients with SCAD receiving contemporary medical therapy and PCI/CABG performed by contemporary approaches ) . RevascuAn additional follow-up of ISCHEMIA participants (ISCHEMIA-EXTEND) up to 7 years confirmed the conclusion of the main study that there was no benefit of the invasive strategy in terms of overall mortality. This resulted from the opposite effects of a statistically significant decrease in cardiovascular mortality found in the invasive group (probably as a result of a decrease in the frequency of spontaneous AMI observed in the early period of follow-up) and a parallel unexpected increase in non-cardiac, apparently oncological, mortality. The significance of these data has yet to be assessed.Based on the results of ISCHEMIA, the American Cardiology Societies issued the new Clinical Guidelines , where oAt the same time, revascularization by CABG in patients with 3-vessel disease and preserved EF received a Class IIb recommendation. In this regard, the European Association for Cardio-Thoracic Surgery, the American Association for Thoracic Surgery, and the Society of Thoracic Surgeons issued statements disagreeing with this conclusion. As an argument, they indicate that this conclusion in the Guidelines is based on a subgroup analysis of the RCT, which itself is not randomized. Moreover, a separate analysis of the predictive value of revascularization depending on its type was not published at the time of publication of the Guidelines ,36. It cThe ISCHEMIA study generally demonstrated no prognostic benefit of a primary invasive strategy for individuals with SCAD and a moderate-to-high-risk stress test receiving current OMT on the cumulative cardiovascular endpoint. No advantage of revascularization regarding all-cause mortality was confirmed in the ISCHEMIA-EXTEND 7-year interim analysis. Also, revascularization was of no benefit in SCAD patients with advanced CKD. It can be concluded that a conservative strategy may be the primary choice for the majority of patients with SCAD who meet the ISCHEMIA eligibility criteria and do not have limiting symptoms. For other SCAD patients not meeting the ISCHEMIA eligibility criteria, the tailored strategy choice is advisable.The ISCHEMIA findings conflicted with the current European guidelines, and given the size of the study and the high quality of the data, a revision of the recommendations seemed inevitable. However, the new ACC/AHA guidelines for revascularization based on the results of ISCHEMIA were not supported by the cardiac surgery communities regarding the appropriateness of surgical treatment of multivessel lesions. Indeed, conclusions about the insufficient prognostic effect of revascularization in patients with high-risk coronary anatomy in the main trial are based on secondary analysis. On the other hand, while the cardiovascular mortality benefit of invasive strategy in MVD patients was shown in the secondary analysis of ISCHEMIA EXTEND, it was offset by the unexpected rise of non-cardiovascular mortality. In this regard, the appropriateness of an invasive approach for patients with MVD should be specifically addressed and the conduct of an RCT with a direct comparison of invasive and conservative strategies in this category of patients looks justified and substantiated by the results obtained in ISCHEMIA and ISCHEMIA EXTEND. The same applies to patients with reduced EF and LMCA lesions, which were underrepresented or not represented in ISCHEMIA. These much-needed data will be able to complete the most up-to-date SCAD treatment strategy algorithm."}
{"text": "The energy of sunlight is converted into chemical energy during photosynthesis in plants. The blue and red spectral regimens are absorbed in the chloroplasts, and their energy ensures the production of NADPH and ATP by the use of water. Subsequently, atmospheric carbon dioxide is incorporated into ribulose 1,5-bisphosphate using NADPH and ATP, from which further carbohydrates will be synthesized. These carbohydrates will be used as the precursors of further compounds or for the production of energy for various metabolic processes during respiration. Besides ensuring energy for the various biochemical and physiological processes, light is also involved in the modulation of these processes. Plants have specific photoreceptors to perceive light signals from the sun including red- and far-red light-absorbing phytochromes (Phy), the blue and green light-perceiving cryptochromes (Cry), the blue light-sensing phototropins (PHOT), and the UV-B-absorbing UVR8 photoreceptor. These photoreceptors, in interaction with specific transcription factors, adjust the metabolic processes to daily and seasonal fluctuations of light intensity and spectrum.Under high light intensity, the excess energy can lead to greater production of reactive oxygen species (ROS) in the chloroplasts, which results in oxidative stress. While a moderate increase in the ROS levels may activate various adaptive processes, their great production is toxic for the cells due to the damage of proteins, lipids, and nucleic acids. The amount of ROS is controlled by the redox system consisting of non-enzymatic  and enzymatic  compounds. ROS and antioxidants regulate the redox environment in the cells, tissues, and organs of plants, which affects the activity of various proteins.International Journal of Molecular Sciences entitled \u201cLight-Dependent Control of Metabolism in Plants\u201d consists of five original articles and one review. Although the influence of light conditions on metabolism has been studied earlier in several research groups, the valuable contributions of this issue give much new information in this field and indicate the unsolved problems worthy of future research.This Special Issue of the Light can control metabolism at transcriptional, post-transcriptional, and post-translational levels. Eprintsev et al.  investigThe light quality-dependent transcriptional control of basic metabolic processes such as nitrate, sulfate reduction, and maintenance of redox homeostasis was shown by Balogh et al.  in barleThe transcriptional control of the various biochemical processes by supplemental far-red light was also shown in Chinese kale in the work of Li et al. . Far-redBrassicaceae family, and some of them have antioxidant functions, which may contribute to their efficient use against cancer. UV-A also increased the total flavonoid content, which could further increase the antioxidant capacity of this species. In addition, it also improved the growth of kale through the increase in chlorophyll content and its quality due to the elevation of protein and sugar levels. These observations give further evidence for the importance of the determination of optimal spectral conditions for indoor farming.Supplemental UV-A light also modified the metabolism in kale grown under red and blue illumination as described by Jiang et al. . It induMicroalgae by Rani and Mar\u00f3ti [The modulation of metabolism by changing the light conditions could also be useful for the removal of pollutants from the environment as it was observed for nitrate in green d Mar\u00f3ti . CompariAll five research articles demonstrated the transcriptional regulation of the metabolism by light and two of them ,4 showedThis Special Issue encompassed a very broad range of the light-dependent control of metabolism from the DNA-methylation through the transcription until the enzyme activation. It included both basic research questions (gene regulation) and applied research (waste management). Although this issue introduced several new aspects of the regulation of plant metabolism by intensity and spectrum of light, these investigations were carried out in various organs or tissues. The study of the metabolic changes at subcellular levels would be an interesting future research direction and it could contribute to the understanding of the fine-tuning of metabolism by light intensity and spectrum."}
{"text": "This finding corroborates previous studies that have demonstrated low quality-of-life scores among patients with cataracts We read with interest the letter to the editor by Fazzi and colleagues who report a negative correlation between anxiety (measured with the IDATE) and quality of life (measured with the WHO-QOL-BREF) in 52 patients with cataracts.We would like to clarify that the cited paper did not assess quality of life in patients with cataracts and hence did not demonstrate low quality-of-life scores among patients with cataracts."}
{"text": "Functional magnetic resonance imaging (fMRI) has been used to identify the neural activity of both youth and adults diagnosed with major depressive disorder (MDD) in comparison to healthy age-matched controls. Previously reported abnormalities in depressed youth appear to mostly align with those found in depressed adults; however, some of the reported aberrant brain activity in youth has not been consistent with what is observed in adults, and to our knowledge there has not yet been a formal, quantitative comparison of these two groups. In addition, it is not known whether these observed differences between youth and adults with depression are attributable to developmental age or length-of-illness.The aim of this study is to elucidate the similarities and differences in patterns of abnormal neural activity between adults and youth diagnosed with MDD and to then determine whether these observed differences are due to either developmental age or length-of-illness.We used multilevel kernel density analysis (MKDA) with ensemble thresholding and triple subtraction to separately determine neural abnormalities throughout the whole brain in primary studies of depressed youth and depressed adults and then directly compare the observed abnormalities between each of those age groups. We then conducted further comparisons between multiple subgroups to control for age and length-of-illness and thereby determine the source of the observed differences between youth and adults with depression.Adults and youth diagnosed with MDD demonstrated reliable, differential patterns of abnormal activation in various brain regions throughout the cerebral cortex that are statistically significant . In addition, several of these brain regions that exhibited differential patterns of neural activation between the two age groups can be reliably attributed to either developmental age or length-of-illness.These findings indicate that there are common and disparate patterns of brain activity between youth and adults with MDD, several of which can be reliably attributed to developmental age or length-of-illness. These results expand our understanding of the neural basis of depression across development and course of illness and may be used to inform the development of new, age-specific clinical treatments as well as prevention strategies for this disorder.None Declared"}
{"text": "In the published article, there was an error. The stated number of protocols needed to be corrected. These errors were identified after an audit conducted by the CONIS  of Costa Rica.A correction has been made to the Ethics Statement. This statement previously stated:The studies involving human participants were reviewed and approved by Ethics Committee of Hospital San Juan de Dios, Caja Costarricense de Seguro Social (CLOBI-HSJD #014- 2015) and the University of Costa Rica (837-B5-304). The patients/participants provided their written informed consent to participate in this study.The corrected statement appears below:The studies involving human participants were reviewed and approved by the Ethics Committee of the University of Costa Rica . The patients/participants provided their written informed consent to participate in this study.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Although we agree that this statement potentially reflects the reality, it is only an inference; it cannot be proved because the studies used different databases and methodologies .As reported at the conclusion of our article, we believe that the short-term consequences of the pandemic are already apparent, and they could be greater in low- and middle-income countries. The potential long-term impact of the COVID-19 pandemic on disease staging at diagnosis will remain an important question for years to come; we take the opportunity to highlight the continued need for interventions aiming at promoting equity of access to health care in Brazil\u2014including screening tests and effective treatments."}
{"text": "High-flow nasal therapy (HFNT) was introduced into clinical practice in the early 2000s as a form of noninvasive respiratory support (NIRS). During the last 20 years, a growing body of evidence has shown the value of this intervention in the management of acute and chronic respiratory failure. Indeed, HFNT has transformed the landscape of research on and the clinical management of respiratory failure; according to a report released by NEJM in 2015 [2 from anatomical dead space, generating a slight positive end-expiratory pressure effect that provides alveolar recruitment, and determines a reduction in inspiratory effort as well as an improvement in oxygenation with the delivery of a stable fraction of inspired oxygen that lowers the metabolic cost of ventilation [HFNT provides the delivery of humidified gas flow that meets or overcomes a patient\u2019s peak inspiratory flow, assures a continuous washout of COtilation , in seleThe beneficial effects of HFNT have mainly been demonstrated in patients with acute hypoxemic respiratory failure (AHRF), and clinical practice guidelines ,5 recommDespite the lack of evidence supporting the use of NIRS in pandemic viral illnesses , HFNT ha2 reduction in mild-to-moderate AECOPD during a short-term follow-up [HFNT could also play a role in the management of hypercapnic respiratory failure in patients with acute exacerbation of COPD  (AECOPD)ollow-up ; howeverollow-up , highligollow-up  as an alThe evidence for HFNT use in chronic respiratory failure has largely been focused on patients with COPD and bronchiectasis, suggesting that its use may influence exacerbations. HFNT prolonged the time to first exacerbation in a mixed population of COPD and bronchiectasis . AnotherJournal of Clinical Medicine seeks to collect high-quality research to explore its further potential clinical applications and to strengthen the evidence of its current indications.In the current era of personalized care, there is an exciting and bright future ahead of HFNT in both acute and chronic settings. The current Special Issue of the"}
{"text": "Radiotherapy iss an important method of local-regional treatment of malignancies and has witnessed impressive advancements in recent years. The main aim of radiotherapy is to increase the outcome of patients while minimizing side effects. The emergence of a new cutting-edge hybrid technology - Magnetic Resonance Image-guided Linear Accelerators (MR-Linac) - is a revolutionary breakthrough technology in the field. This new technology combines real-time MR imaging of \u201cthe anatomy of the day\u201d, prediction of the dose distribution, online adaptive optimization of the plan if needed, and continuous automatic cine-MR tracking of the target. As this technology has a significantly different workflow compared to conventional radiotherapy, it is crucial to understand the fundamentals of utilizing MR-Linac to reach the goal to obtain optimal patient outcomes. The following topics we would like to emphasize are the major important components of MR-Linac technology;1One of the key influences of MR-Linac is the ability to integrate high-quality real-time MR imaging into the MR-guided radiotherapy workflow. Physicians must notice the implication of this feature to visualize the exact location of tumors and critical structures immediately before the treatment, recontouring or editing tumors and neighboring normal organs and structures if needed, and tracking the tumors continuously during beam-on and stop the treatment automatically if the target is out of the boundaries.2The successful implementation of a new MR-Linac workflow requires close teamwork between physicians, Radiotherapy Technologists (RTTs), and Medical Physicists. Each team member has a valuable role in the different steps of the workflow. This collaborative approach aims to synergistically exploit the capabilities of MR-Linac .3Members of the team should collaborate to develop optimal personalized treatment plans based on the \u201canatomy of the day\u201d imaging where needed. A recent analysis of 50 patients with localized prostate cancer who were treated with ultra-hypofractionation using MRgRT in a total of 250 fractions has shown that in 76% (190/250 fractions) of fractions, reoptimizisation is needed due to various reasons . Second manuscript reports the dosimetric benefits of daily adaptation of SMART and the first clinical results in pancreatic tumors in 30 patients . Third manuscript assesses the quality of a new diffusion-weighted imaging (DWI) sequence implemented on an MR-Linac MRIdian system, evaluating and optimizing the acquisition parameters to explore the possibility of clinically implementing a DWI acquisition protocol in a 0.35-T MR-Linac . The fourth manuscript reported the use of MRgRT for pediatric patients over four years and describes important considerations in the selection and application of this technology in children . The fifth manuscript quantitatively characterizes the dosimetric effects of long on-couch time in prostate cancer patients treatment . Sixth manuscript reports the workflow and initial clinical experience of high-grade glioma radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow.  The seventh manuscript documented the critical steps needed for the appropriate delivery of MRgART for lung tumors safely and effectively. . The eight manuscripts reported one of the largest cohorts of patients treated with online MRgRT of liver metastases focusing on oncological outcome, toxicity, patient-reported outcome measures (PROMs), and quality of life . The ninth manuscript analyzed the role of MRgRT as a potential to become a widely utilized treatment platform and transform the radiation oncology treatment process just as earlier disruptive radiation therapy technologies have done . Tenth manuscript, aimed to optimize patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy . The eleventh manuscript reported the outcome and toxicity of the first 200 patients with prostate cancer treated with MRI-Linac .The first manuscript of this Research Topic aimed to evaluate the geometrical differences and metabolic parameters  as a tool for an individualized definition of the volume in need of dose escalation for squamous cell esophageal cancer (This editorial highlights the implications of recent research findings in this breakthrough technology. This Research Topic of the journal guide Physicians and Medical Physicists who are starting their voyage with this new technology and speed up their learning curve time in their new journey.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "The citation has now been inserted in the Introduction and should read:In the published article, Clinical Chemistry and Laboratory Medicine - A panhaemocytometric approach to COVID-19: a retrospective study on the importance of monocyte and neutrophil population data on Sysmex XN-series analysers .\u201dThe References section has been updated and renumbered accordingly.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Pulmonary tuberculosis is associated with long-term complications that affect both the respiratory and cardiovascular systems. We present the case of a 65-year-old male patient who presented with chief complaints of productive cough and breathlessness for the last four years. Further radiological investigations revealed a left-sided destroyed lung with left lung collapse and deviation of the mediastinum towards the left side. The patient responded well to treatment with broad-spectrum antimicrobial drugs and mucolytics. Tuberculosis\u00a0of the lung is considered globally to be one of the most lethal and deadly communicable diseases, especially in developing countries\u00a0.Mycobacterium tuberculosis. Tuberculosis of the lung is associated with a wide spectrum of chronic complications and sequelae that can significantly increase the morbidity of the affected patient [Pulmonary tuberculosis is an infectious disease caused by  patient . One of  patient .Unilateral lung destruction is considered to be one of the late complications of pulmonary tuberculosis, which usually requires years to manifest clinically . This luA 65-year-old male patient was presented to the Respiratory Medicine outpatient department (OPD) with chief complaints of productive cough and dyspnea which was present intermittently for the last 3 years. The patient also complained of left-sided chest pain on deep inspiration and coughing. A detailed history taking of the patient revealed that the patient had a history of smear-positive pulmonary tuberculosis (TB) 2 years back for which he had taken the full course of anti-TB treatment for a period of 6 months consisting of four drugs, namely isoniazid, rifampicin, pyrazinamide, and ethambutol.For further evaluation of the patient, a chest X-ray posteroanterior (PA) view was done which revealed destruction of the left lung parenchyma with ipsilateral mediastinal shift and herniation of a part of the right lung into the left hemithorax Figure .A detailed clinical evaluation was done which revealed signs of volume loss visible in the left hemithorax, such as a positive Trail\u2019s sign on the left side (undue prominence of the clavicular head of the sternocleidomastoid on the affected side), drooping of the left shoulder as compared to the right, evidence of rib-crowding on the left hemithorax, and a reduction in the spino-scapular distance on the left side Figure .Routine blood investigations of the patient were done which revealed no significant abnormalities. Sputum samples were sent for acid-fast bacilli (AFB) staining which was found to be negative.The patient was started on broad-spectrum antimicrobial therapy with the addition of metronidazole for coverage against anaerobic microorganisms. The patient reported symptomatic improvement after a period of 7 days and was discharged with advice to review in the OPD after 15 days.The most commonly affected parts of the lungs that are involved in a patient with pulmonary tuberculosis have been found to be the upper lobes, particularly the apical and posterior segments, with an almost identical incidence bilaterally . VariousThis higher incidence of involvement of the left lung can be explained by the anatomical features of the left main bronchus, which is considerably smaller in diameter and longer in length as compared to the right main bronchus . Due to These various complications and sequelae associated with pulmonary tuberculosis as summarized above greatly contribute to the increased morbidity and mortality in such patients.Tuberculosis is a disease that affects the quality of the patient, in both the short- and the long-term, significantly increasing morbidity and mortality through the development of various thoracic complications and sequelae. Patients who develop complications such as unilateral lung parenchymal destruction post-tubercular infection usually experience frequent respiratory tract infections and persisting dyspnea due to derangement of the normal pulmonary parenchyma structures. Such patients need early identification by means of screening with chest radiographs and should be educated regarding various preventive measures such as seasonal pneumococcal and influenza vaccination as well as the institution of a pulmonary rehabilitation program to improve the quality of life and exercise capacity of the patient."}
{"text": "In the Ethics subsection of the Methods, there is an error in the paragraph. The correct paragraph is: All data were de-identified prior to analyses. Written informed consent was obtained from all participants included in the Inter99 study. The ethics committee of Region North Jutland (N-20140048) approved the project and that blood samples from COGEN may be used without written informed consent from patients. COGEN also has permission from the Data Protection Agency (00916 GEH-2010-001). The Inter99 study was approved by the Scientific Ethics Committee of the Capital Region of Denmark (KA98155) and registered as clinical trial . Both studies were performed in accordance with the principles of the Declaration of Helsinki."}
{"text": "The management of this difficult and complicate disease is still a big challenge, even in countries with advanced health care resources. China has a large patient population with SLE. It is estimated that at least 1 million patients with SLE in mainland China, this number is still increasing as the diagnostic level is significantly improved. China has the highest disease burden of SLE in the entire world.,3 Therefore, establishing concrete and applicable strategy is crucial to manage such a huge patient population with limited number of rheumatologists in China. Under the leadership of National Clinical Center for Dermatologic and Immunologic Center (NCRC-DID) of China, a series of strategies have been established to prompt standardized treatment and management of SLE across the country. Hereby we report one of the approaches, developing centers of excellence (COEs) for SLE and their management.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations and multi-organ involvement. In recent years, improving the quality of care for patients with rheumatic diseases has become a high priority of National Health Commission of the People\u2019s Republic of China. The Guidelines for the Construction and Management of Departments of Rheumatology in General Hospitals and the Guidelines for the Basic Standards of Department of Rheumatology in General Hospitals were released in 2019 by the National Health Commission of the People\u2019s Republic of China. Furthermore, the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus, and the Recommendations for the Diagnosis and Management of Lupus Nephritis in China were published. ,5 With the goal of promoting the implementation of standard-of-care for patients with SLE, was launched program of COEs in SLE in January 2030. The COEs that could demonstrate high standard in medical service, education and research will be certified. In order to be certified as COEs, the institutions must meet the following requirements.The specialty of Rheumatology was established in 1970s in China. The disparity in development among regions and proficiency level among healthcare providers is significant across the country. The COEs must provide high-quality medical service for patients with SLE, offer the state-of-the-art techniques in the diagnosis and treatment of SLE. Additionally, COEs should demonstrate high-level service skills that enabling them to be actively engaged in promoting medical care, teaching, and scientific research in SLE. The COEs should play leading roles and academic progression impact in their regions.The centers applying for COEs must be affiliated to a tertiary general hospital as a stand-alone department.The COEs must provide comprehensive medical services including diagnosis, evaluation, and treatment of SLE as well as the management of comorbidities and complications. The COEs must also have the capability to organize multi-disciplinary consultation if needed.(1) Team members: The medical team of COEs should be composed of rheumatologists with knowledge and experience in the standard-of-care for patients with SLE and led by a dedicated expert in SLE.etc.(2) Centers: COEs must have outstanding capability in organization and management of patients with SLE, and with a well-established process in triage and patient referral. In addition, each COE must establish a multi-disciplinary team (MDT) that coordinates with interdisciplinary management, consultation and referral. The MDT should include specialties such as nephrology, hematology, pulmonary and critical care, cardiology, neurology, dermatology, (1) In-hospital services: COEs must have the capacity to promptly admit and provide medical services to newly diagnosed and followed-up patients with SLE. They must have the capability to manage complicated and critical cases and timely admit patients with emergency conditions.(2) Patient registration: COEs should actively register patients with confirmed diagnosis of SLE using the on-line registry system of SLE.(3) Equipment and techniques requirement: COEs must have the equipment required for the diagnosis and evaluation of SLE, including imaging for organ involvement evaluation, and techniques such as renal biopsy.(4) Medications: COEs must have access to the conventional medications of SLE and biological agents.(5) Follow-up services: COEs must provide for patients with SLE regular and long-term follow-up service.(6) Patient education: COEs must take the responsibility for patient education, not only focusing on helping patients to better understand the disease, but focusing on improving patient compliance.(1) The pre-defined number of out-patient visits and in-patient admission must be met at each COE.(2) COEs should follow the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus for early diagnosis, early intervention and adherent to Treat-to-target (T2T) strategy in order to improve long-term outcomes of patients.(3) Comprehensive evaluation of disease activity and organ damage should be conducted at a regular base. Individualized treatment regimen should be developed and modified based on the evaluation. Treat-to-target strategy should be followed when prescribing anti-malarial drug, glucocorticoid and immunosuppressive agents.(4) COEs should focus on prevention and management of comorbidities and complications of SLE. Each COE should have the capability to manage the risk factors and monitor new organ involvement as well as managing severe complications.(5) COEs should evaluate disease progression, side-effects of medications at a regular base, and stratify patients into different risk groups. Patients at high-risk should be treated aggressively in order to slow organ damage, reduce disease relapse and improve outcomes.The COEs should provide training and education to the local rheumatologists as part of the specialists\u2019 training program and continuing medical education program. The purpose of training is to promote the implementation of standard-of-care to clinical practice and improve the overall quality of care. COEs should also demonstrate their academic impact by leading high standard services locally and in neighboring provinces, in order to improve the competency of the local care providers in the region.(1) Continuing medical education: COEs should have the capability to undertake national continuing medical education programs on standard-of-care for patients with SLE and organize academic conferences in the region.(2) Physician training: COEs should provide training to local rheumatologists and MDT physicians at a regular base to facilitate the delivery of high standard healthcare services and update the latest guidelines, expert consensus, recommendations and cutting-edge research findings.(3) Academic impact: COEs should have the capability to organize academic conferences and teaching rounds in city hospitals. They should also have the capability to provide training for visiting rheumatologists from affiliated city hospitals and guide the management for critical cases in the region.COEs must have high-standard research team and facility. They should also have ongoing research projects in SLE and have the ability in integrating basic science, clinical and translational research. They should at the leading position of research and have academic influence in the region.(1) Team and facility for research: COEs should have leading investigators in SLE and a high-standard research team to conduct clinical research.(2) Research program: COEs should actively apply for and participate in national research programs and clinical trials.(3) Resources for research: COEs should build standardized medical biobank with associated clinical information.(4) Research network: COEs should be part of the collaborative research network of SLE and have the ability to conduct multi-center and large cohort studies.(5) Research production: COEs should have high-quality publications of clinical studies in the domestic and international academic journals as the first or corresponding affiliations.(1) The COEs program is initiated by NCRC-DID and funded by the China Health and Medical Development Foundation (CHMDF).(2) The standing committee appointed by NCRC-DID is responsible for certifying COEs.(1) The certification is based on a grading system .a) The candidate centers should reach at least 60 points on basic items.b) Center of Demonstration can only be certified if the candidate centers are scored 60\u201379 points on basic items and more than 100 points on all items.c) COEs can only be certified if the candidate centers are scored for more than 80 points on basic items and more than 120 points on all items.(2). The title of COEs is valid for two years and re-application is needed for renewal.We believe that the construction of the COEs in the country could remarkably improve the quality of care for patients with SLE in China. We also hope that the developing of the COEs will greatly prompt the standard and level of basic, clinical and translational research for SLE in China. We expect that Chinese patients with SLE will benefit from this COEs development program."}
{"text": "Author name was incorrectly written as Marie-Paule Mingeot. The correct spelling is Marie-Paule Mingeot-Leclercq.In the published article, an The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "The article was published April 21, 2023 with an error in the name of one of the co-author.The full name of this co-author is: Georgios Foukarakis."}
{"text": "As illustrated by the present Research Topic, emotion that can either enhance or hinder various aspects of our cognition and behavior. For instance, the emotional charge of an event can increase attention to and memory for that event  and memory-related regions  in the formation and retrieval of emotional memories , which are specific to emotional distraction (Dolcos et al., hypervigilance in these patients (American Psychiatric Association, hypervigilance hypothesis that may explain enhanced response to and distracting effect of neutral stimuli (Figure The fact that information unrelated to the trauma may also be highly distracting in PTSD patients is consistent with the clinically observed symptom of i Figure . This nehyperarousal observed in these patients (Figure Overall, the evidence from separate lines of investigations discussed above, regarding the neural changes in PTSD linked to dysfunctions in the recollection of traumatic events and the response to emotional distraction, converge toward the idea that non-specific response to emotional and neutral distraction may reflect retrieval distortions linked to inefficient initial encoding of trauma-related information. Namely, it is possible that the non-specific disruption of the dlPFC activity by trauma-related and neutral distraction is linked to the retrieval of the traumatic memories triggered by non-specific cues, which may also contribute to the perpetuation of the state of s Figure . Moreoves Figure  also ides Figure . In othes Figure  and provs Figure .hypervigilance and non-specific responses to trauma-related distraction, which contributes to the maintenance of a hyperarousal state (Figure In summary, available evidence from investigations of PTSD patients points to general and specific emotional and cognitive disturbances that are linked to alterations in the neural circuitry underlying emotion-cognition interactions. This evidence suggests that reduction of AMY and HC signals for trauma-related cues may underlie non-specific encoding of gist-based representations instead of specific and detailed contextual details of the trauma-related memories. This, in turn, may be linked to symptoms of e Figure . This eve Figure ."}
{"text": "Answer to the Rhythm PuzzleAt first glance the ECG looks very abnormal. The P-wave morphology is not compatible with sinus rhythm, the conduction intervals are normal, and the QRS complexes are very abnormal in amplitude (micro-voltages in the extremity leads). In lead II there is almost no signal at all.Although micro-voltages in the extremity leads are a common feature in one of the most prevalent familial cardiomyopathies in the Netherlands , the abn"}
{"text": "Persistent localized activity in neural networks has been suggested to serve as the neural substrate of short-term memory . Neural-In general, neural-field models are formulated in terms of Volterra-equation systems or systems of integro-differential equations. The dynamics of bump (pulse) solutions is often studied in a simplified framework by means of ordinary differential equations describing the time evolution of the pulse widths .It has been proven that in the absence of external input this simplified pulse-width system gives the correct prediction with respect to the linear stability of stationary solutions, with one notable exception. It is often conjectured that the Amari approach might correctly predict also nonlinear aspects of the dynamics . Here, we show that the Amari approach fails in the presence of spatially localized external input: the criteria for linear-stability of bumps in the pulse-width system do not coincide with those obtained for the full system. Therefore, for localized external input the analysis must rely on the full system.We determine fixed-point solutions and their stability analytically and illustrate the results by means of numerical simulations. Further, we numerically show that persistent localized activity in a two-population neural-field model can be switched on and off by means of brief external-input pulses localized in space in and time see Fig ."}
{"text": "Bienzyme conjugate was obtained by the covalent connection of superoxide dismutase with catalase through endothelial glycocalyx glycosaminoglycan \u2013 chondroitin sulfate (SOD-CHS-CAT). This SOD-CHS-CAT conjugate has vasoprotective activity in respect to platelet interactions, tonus of the ring arterial fragment of a rat blood vessel, as well as normalization of hemodynamic parameters in rats and rabbits in conditions of oxidative stress caused by the administration of hydrogen peroxide. The SOD-CHS-CAT conjugate had antiplatelet potential due to its antiaggregation action manifested through the combination of enzyme activities and an acquired supramolecular structure. The influence on arterial fragment tonus was equivalent for SOD and CAT in native and conjugated form. Blood pressure and heart rate were significant and effectively normalized with SOD-CHS-CAT conjugate in rats and rabbits (after hydrogen peroxide administration as a perturbance stimulus). We have discovered the possibility of using the antioxidant bienzyme conjugate in chronic prophylaxis. It is important for a real development of the oral form of the SOD-CHS-CAT conjugate. These results indicate that the development of enzyme conjugates can be medically significant, as a promising approach for the creation of new drugs. Enzymes are widely used as medication in thrombolytic therapy , 2. The It is widely known today that the development of many pathologies is accompanied by oxidative stress , 8. Norm Current views hold that superoxide dismutase, catalase, and glutathione peroxidase are the main antioxidant enzymes of the body. The autonomous functioning of the first two makes them attractive in terms of the development of antioxidant medication to protect the cardiovascular system against oxidative stress. Based on the described advantages, we chose Cu,Zn-super\u00adoxide dismutase (SOD), and catalase for the development of an enzymatic antioxidant derivate. 2 O 2 ) is used as a substrate by CAT, which finally yields water and oxygen as products 2 O 2 . T in mice . The results of the present study indicate that supra-molecular enzymatic conjugates are potentially effective and safe and that they can be used in practical medicine. Covalent cross-linking of enzymatic subunits accounts for a mutual stabilization of biocatalyst activity. Augmented molecular weight and the inclusion of chondroitin sulphate  in the conjugate results in a vasoprotective activity of the SOD-CHS-CAT derivate on the inner surface of the vascular wall. The therapeutical effect of the SOD-CHS-CAT is determined by covalent coupling of SOD and CAT activities, which underlies their combined action and formation of harmless products of enzymatic conversion. The supra-molecular structure of the nanoconjugate accounts for its previously unknown quality \u2013 the capacity to prevent induced platelet aggregation. The activity of the components of the SOD-CHS-CAT conjugate is very pronounced, since the influence of the SOD and CAT activities of the conjugate on the tone of the vascular fragment is similar to that of native enzymes. The contribution of chondroitin sulphate to the antiaggregational effect is also very clear. The described qualities determine the higher antioxidant activity of the SOD-CHS-CAT conjugate, as compared to the other combinations of its individual components. The SOD-CHS-CAT conjugate is well-tolerated, it possesses satisfactorily acute toxicity, normalizing action in relation to hemodynamics under oxidative stress, and a pronounced therapeutical effect. All these factors make the conjugate a prospective drug candidate. This study represents a new approach to the development of therapeutically significant enzymatic conjugates."}
{"text": "DNA methylation normally leads to silencing of gene expression but Epstein\u2013Barr virus (EBV) provides an exception to the epigenetic paradigm. DNA methylation is absolutely required for the expression of many viral genes. Although the viral genome is initially un-methylated in newly infected cells, it becomes extensively methylated during the establishment of viral latency. One of the major regulators of EBV gene expression is a viral transcription factor called Zta  that resembles the cellular AP1 transcription factor. Zta recognizes at least 32 variants of a 7-nucleotide DNA sequence element, the Zta-response element (ZRE), some of which contain a CpG motif. Zta only binds to the latter class of ZREs in their DNA-methylated form, whether they occur in viral or cellular promoters and is functionally relevant for the activity of these promoters. The ability of Zta to interpret the differential DNA methylation of the viral genome is paramount for both the establishment of viral latency and the release from latency to initiate viral replication. In cellular genomes, the methylation of 5\u2032 cytosines in CpG-dinucleotides leads to recruitment of methyl-DNA binding proteins that co-operate with other epigenetic events to promote the repression of transcriptional activity .Following infection, the viral double strand DNA genome is established in the nucleus of the cell where it circularizes to form an episome and then replicates once per cell cycle in synchrony with the host genome. During this time, the majority of the viral promoters are silent, with just a few directing the expression of the latency-associated genes. Many studies of individual viral promoters have demonstrated an inverse correlation between promoter activity and the presence of DNA methylation at CpG-dinucleotides within the promoter  and polycomb-associated tri-methylation of histone 3 at lysine 27 (H3K27me3) marks have been identified on the EBV genome . Second,The surprising finding was that the EBV genome requires DNA methylation to reactivate it from latency , 2012. TEgr1, which is activated by Zta . This could explain the requirement for genome methylation during the EBV life cycle.Zta expression is restricted to two phases of the EBV life cycle; immediately after infection and during the EBV lytic replication cycle. Zta is not expressed during viral latency, indeed enforced expression of Zta promotes cells to initiate the lytic replication cycle. Following physiological stimulation of cells harboring latent EBV, Zta is the first viral lytic replication cycle gene to be expressed and then activates the expression of many viral genes. Zta is expressed initially when the viral genome is heavily methylated and remains expressed when the genome is largely non-methylated. Zta interacts with several hundred sites on the viral genome and at about half of these site binding is dependent on the DNA methylation status . Many ofFigure 1).It is puzzling to understand how these methylation-dependent promoters evolved. Why is it advantageous to encode a transcription factor with both methylation-dependent and -independent recognition sites if both classes of ZRE should be equally \u201cvisible\u201d to Zta in the methylated state? To understand the driving force behind the differential binding of Zta at ZREs, we need to consider the situation where the EBV genome is non-methylated and the CpG-ZREs become \u201cinvisible\u201d .There are two stages in the life cycle of EBV when the differential recognition of methylation sensitive and insensitive ZREs in promoters could occur; in both the viral genome is non-methylated and Zta is expressed ((i) During the late stage of the EBV lytic replication cycle, large numbers of non-methylated viral genomes and Zta protein accumulate within the nucleus. Whether the demethylation occurs via an active or passive process has not been determined. However, it is clear that Zta interacts with the non-methylated EBV genomes that are present during late lytic cycle . Indeed,(ii) Immediately following infection of cells, the non-methylated EBV genome enters the nucleus, accompanied by a transient burst of Zta expression . The shoThe EBV genome provides an exception to the epigenetic paradigm of DNA methylation correlating with a silencing of gene expression. The virus also exploits a unique transcription factor to activate genes embedded in methylated DNA. The ability of Zta to differentially recognize methylated sequence elements together with the biphasic methylation cycle of the viral genome suggest that the selection of these properties was driven by the need to differentially regulate binding to different sub-sets of ZREs. Indeed Zta expression during the pre-latency stage and the lytic cycle results in the expression of different sub-sets of target genes, these are related to the location of methylation-dependent or -independent ZREs in their promoters and the methylation status of the viral genome.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Among its several activities, Nef is essential for maintaining HIV-1 maximal infectivity. In cell culture, such activity can account for as much as 98% of the HIV-1 virion infectivity and requires Nef to be expressed in virus producing cells rather than in target cells. However, the cause of the defective infectivity of Nef-negative HIV-1 and the mechanism by which Nef is able to restore such a defect remain elusive. The purpose of this research is to establish whether Nef contributes to HIV-1 infectivity by counteracting a cellular inhibitor or by promoting a cellular activity required for optimal infectivity.Nef is an HIV-1 accessory protein with a fundamental role for virus replication Several human cell lines of different histological origin were used as HIV producer cells in order to study the variability of the requirement of Nef for infectivity. Single cycle infectivity was measured on a HeLa-based reporter cell line after normalization based on reverse transcriptase of the inocula. To determine the dominance of the Nef requirement for optimal infectivity, virus is produced from heterokaryons generated from cells responsive or not-responsive to Nef.We analyzed the ability of Nef to enhance HIV infectivity produced in more than 50 cell lines. We found that the requirement of Nef is highly variable. We identified a group of cell lines (Nef-responsive) in which the lentiviral protein is most required (10-50 fold) and a group of cell lines in which Nef is not at all or only weakly required . All Nef-responsive cell lines belong to the lymphoid lineage, in line with the lymphotropic nature of HIV, while most cell lines belonging to the Nef-unresponsive group include mostly non-lymphoid cells. However, we identified two Nef-unresponsive cell lines of lymphoid origin, providing useful tools for further investigation to study the dominance of the Nef requirement for infectivity. We have established a heterokaryon assay which allows HIV-1 production only upon fusion of producer cells expressing complementary parts of the virus. We are now in the process of coupling producer cell lines with opposite Nef-responsiveness in order to verify the possibility that Nef counteracts a dominant cellular inhibitor of retroviral infectivity predominantly expressed in lymphocytes.Our findings show that the Nef requirement for virus infectivity is extremely variable depending on the type of producer cells and is strongest in lymphoid cells. From the study of cell lines with marked differences for Nef-responsiveness, we aim to identify cellular factors which determine the Nef requirement for HIV infectivity."}
{"text": "Protein-nucleic acid (protein-DNA and protein-RNA) recognition is fundamental to the regulation of gene expression. Determination of the structures of the protein-nucleic acid recognition and insight into their interactions at molecular level are vital to understanding the regulation function. Recently, quantitative computational approach has been becoming an alternative of experimental technique for predicting the structures and interactions of biomolecular recognition. However, the progress of protein-nucleic acid structure prediction, especially protein-RNA, is far behind that of the protein-ligand and protein-protein structure predictions due to the lack of reliable and accurate scoring function for quantifying the protein-nucleic acid interactions. In this work, we developed an accurate scoring function  for protein-nucleic acid interactions by incorporating both the specificity and affinity into the optimization strategy. Specificity and affinity are two requirements of highly efficient and specific biomolecular recognition. Previous quantitative descriptions of the biomolecular interactions considered the affinity, but often ignored the specificity owing to the challenge of specificity quantification. We applied our concept of intrinsic specificity to connect the conventional specificity, which circumvents the challenge of specificity quantification. In addition to the affinity optimization, we incorporated the quantified intrinsic specificity into the optimization strategy of SPA-PN. The testing results and comparisons with other scoring functions validated that SPA-PN performs well on both the prediction of binding affinity and identification of native conformation. In terms of its performance, SPA-PN can be widely used to predict the protein-nucleic acid structures and quantify their interactions. Precise regulation of the biological activities within cells is accomplished by biomolecular recognition which mainly involves three major biological macromolecules, i.e. protein, DNA and RNA. The protein-nucleic acid (protein-DNA and protein-RNA) recognition is essential to the regulation of gene expression at every level of the central dogma of molecular biology, including replication, transcription and translation of genetic information Although the structures of individual biomolecules are increasingly well determined and structural studies of the biomolecular complexes have been very active in the last decade, three-dimensional atomic structures of many biomolecular complexes are still difficult to determine due to the technical challenges of the experimental approaches For biomolecular functions, highly efficient and specific biomolecular recognitions are required to satisfy both the stability and specificity. The stability is determined by the affinity of the complex while the specificity is controlled by the partner binding to other competitive biomolecules discriminatively. The current scoring functions of biomolecular recognition The reason that the specificity usually was not taken into account previously in the development of the scoring functions is that the description of binding specificity was challenging to quantify. The conventional definition  of speciTo overcome the challenge, we have proposed a novel concept named as intrinsic specificity  [19]\u2013[23According to the theory of energy landscape In this work, based on our practical quantification of binding specificity, we have designed an optimization strategy to maximize both the affinity and specificity of native binding mode simultaneously for developing the scoring function of protein-nucleic acid interactions. The optimization strategy is to adjust the statistical knowledge-based potentials of atom pairs by iteration until the scoring function can effectively discriminate the native binding pose against the decoys. The flow of developing procedures is shown in Figure S1 in The requirement of optimizing the knowledge-based statistical scoring function is to train a set of known structural data. The training dataset of protein-nucleic complexes for developing SPA-PN were extracted from the database NPIDB (Nucleic Acids-Protein Interaction DataBase) et al.et al.et alTo validate the performance of a novel scoring function, two kinds of tests are needed. First, to evaluate the ability of SPA-PN on predicting the binding affinity. SPA-PN was tested on a dataset of protein-DNA complexes with known experimental binding affinities. This dataset for binding affinity prediction was employed from the binding database which is a modified version of Zhang et alet alSecond, in order to evaluate the ability of SPA-PN on discriminating the native conformation from decoy conformations, SPA-PN was tested on our collected benchmark of protein-nucleic acid complexes. The collected benchmark for binding pose prediction was obtained from available benchmarks of protein-nucleic acid complexes. It combines two protein-DNA benchmarks and two protein-RNA docking benchmarks. The first protein-DNA benchmark obtained from the PDIdb (Protein-DNA Interface database) For the optimization of SPA-PN, an ensemble of decoys for each complex are needed to calculate the ISR for specificity and carry out the iteration algorithm. The RosettaDock v3.4 was taken as the structure optimization and docking tool The knowledge-based scoring function consists of a set of statistical distance-dependent atom-pair potentials to quantify the interactions. Normally, the observed atom-pair potentials were directly derived from the Boltzmann relation widely applied in the derivation of knowledge-based statistical potentials for the protein-ligand, protein-protein and protein-nucleic acid interactions The observed statistical potentials from the known structures has its limitations as the statistical potentials extracted from To circumvent the reference state issue and improve the statistical potentials, earlier efforts The expected statistical potentials are calculated similarly as the observed statistical potentials, which isThe iterative method To validate the effectiveness of the iterative procedure on the improvement of the statistical potentials, we show the evolution of the average interfacial RMSD  to predict and explain the experimentally determined affinities; and (2) to score and rank the binding poses generated by the docking programs. Thus, to validate the performance of SPA-PN, two kinds of tests related to corresponding applications are carried out and the testing results are shown in the sections below.The prediction accuracy of the binding affinity determines the performance of the scoring function on how well it can reproduce the experimentally measured affinity and predict the biomolecular interactions. Due to scaling, the scoring functions usually can not reproduce the absolute values of experimental binding affinity, the Pearson correlation coefficient  Two of most frequently occurred atom pairs. (C and D) Atom pairs related to hydrogen bond. (E and F) Atom pairs involving phosphorus atom. Table S1 Training dataset for the development of SPA-PN. Table S2 Experimental determined affinities and SPA-PN predicted affinities for 30 protein-DNA complexes of the testing dataset1, the calculated affinities were obtained by scaling the binding scores with linear fitting equations  based on the experimental affinities. Table S3 PDB codes of the testing dataset2. Table S4 15 Atom types used for calculating the atom pair potentials based on the SYBYL definition of atom type. The atom types can be converted from PDB files by the software OpenBabel. Table S5 95 effective types of atom pairs for the protein-nucleic acid interactions with the cutoff of total occurrences larger than 600 in the training dataset. Table S6 The high accuracy quality of CAPRI assessment criteria was taken to define the near-native conformation.Supporting figures and tables. (DOC)Click here for additional data file."}
{"text": "Molecules in neurons are in a state far from equilibrium. Therefore their transport properties are strongly affected by fluctuations. We present a model of stochastic molecular transport in neurons which have their synapses located in the spines of a dendrite. In this model we assume that the molecules perform a random walk between the spines that trap the walkers. If the molecules are assumed to interact with each other inside the spines, the trapping time in each spine depends on the number of molecules in the respective trap. The corresponding mathematical problem has non-trivial solutions even in the absence of external disorder due to self-organization phenomena. We obtain the stationary distributions of the number of walkers in the traps for different kinds of on-site interactions between the walkers and furthermore analyze how birth and death processes of the random walkers affect these distributions.We apply this model to describe the dynamics of the PSD-95 proteins in spiny dendrites. PSD-95 is the most abundant molecule in the post-synaptic density (PSD) located in the spines. It is observed that these molecules have high turnover rates and that neighboring spines are constantly exchanging individual molecules. Thus we predict the distribution of PSD-95 cluster sizes that determine the size of the synapse and thus the synaptic strength. Finally, we show that in the model non-equilibrium inter-spine dynamics of PSD-95 molecules can provide the basis for locally controlled synaptic plasticity through activity-dependent ubiquitinization of PSD-95 molecules."}
{"text": "We report a case of a 69-year-old male with non-ischemic cardiomyopathy, having drug- and antitachycardia pacing-refractory ventricular tachycardia resulted in multiple ICD shocks. The sustained and intractable ventricular arrhythmia was mapped and ablated with the aid of the three-dimensional electroanatomic mapping system, initially performed but unsuccessful from the endocardial site then performed successfully from the epicardial site via the coronary sinus. In some instances, catheter ablation from the epicardial aspect of the ventricles is needed although the majority of ventricular tachycardia (VT) is located and ablated in the right or left ventricular endocardium . EpicardA 69-year-old male patient with NICM was referred to our department for multiple antiarrhythmic drug- and antitachycardia pacing-refractory ventricular tachycardia (VT) episodes resulted in electrical storm and depletion of the battery of his VVI-ICD. No secondary abnormalities causing the tachycardia were detected. Surface electrocardiogram during VT revealed a possible focus of the basal posterolateral wall of the left ventricle . VoltageAlthough automaticity and triggered activity may responsible from the electrophysiological mechanisms of VT in NICM, the proven histopathological relation between cardiomyopathic changes including myocyte hypertrophy and fibrosis and, the inducibility of VT with extrastimuli may also suggest the susceptibility to reentrant arrhythmias. Most of the cases with VT can be successfully mapped and ablated from the endocardial site. When this is not possible, however, invasive percutaneous epicardial route may be required to map and ablate VT. Previously published several recent reports have demonstrated that the venous system of the heart seems to be alternative route for mapping and ablation of VTs originating from an epicardial region -6. Li et"}
{"text": "After the publication of this work, we notiWe also noticed in the first sentence of the second paragraph of the Materials and methods section we mistakenly stated that OGX-011 (ASO-CLU) was purchased from OncoGenex Technologies. As ASO-CLU is currently in the clinical testing phase, it is not available for sale from OncoGenex Technologies. The corrected sentence should read:ASO-CLU was acquired from OncoGenex Technologies.We apologise to the readers and OncoGenex Technologies for this oversight and any negative effects that may have resulted from it."}
{"text": "PP-plots for survival distributions are considered where one survival distribution is plotted against the other. This is seen as another way of visualizing the nature of the relationship between the two survival distributions along with typical Kaplan-Meier plots. For three survival distributions, the PPP-plot is introduced where the survival distributions are plotted against each other in three-dimensions. Two test statistics are defined, based on areas and lengths associated with the PP- and PPP-plots to test the null hypothesis of equivalent survival curves. A simulation exercise has shown that the new tests are worthy competitors to the logrank and Wilcoxon tests. Also illustrated is how the PP-plot can be used to estimate the hazard ratio and also to assess the ratio of hazard functions if proportional hazards are not appropriate. The methods introduced are illustrated on two cancer data sets."}
{"text": "Bioprostheses made of bovine and porcine tissue are widely used during surgery in the cardiovascular disease. However, the durability of bioprostheses is limited due to immune reaction-mediated cardiac valve destruction upon post-operative follow-up. The objective of this study is to analyze the tissue failure patterns by difference of species and their structural characteristics.The various xenogeneic tissues  were fixed in 0.5% glutaraldehyde solution and implanted into the subcutaneous tissue of the wild type-mouse and the KO mouse for 3 months. The implanted mice were harvested and studied for the histopathology, amounts of calcification and immune responses by serum ELISA.The titer of xenoreactive antibody  after the implantation with xenogeneic tissue in alpha-gal KO mouse tended to increase, with IgM level decreasing faster than IgG level thereafter. The calcification patterns and amounts were similar in both bovine and porcine tissue, but the level of calcification was more severe in KO mouse implantation model than the wild type mouse model. The xenoreactive antigeneicity was lowest in the valve leaflet and the calcification was most severe in aortic wall in both KO mouse & wild type mouse by histologic and quantitative calcium analysis.There was different antigenic response among the different xenogenic tissues. The removal of alpha-gal antigenecity is strongly advised and the choice of the xenogeneic tissue with low degree of antigenicity and calcification seems to be important to prevent the degenerative failure of bioprostheses."}
{"text": "Defining \u2018usual care' in studies of health services is challenging as it comprises a large variety of locally variable services. Building Blocks is trialling the Family Nurse Partnership Programme (FNP) in England. FNP is a complex intervention provided to first-time teenage mothers in the community setting. It was developed and previously trialled in the USA where support services are very different. To fully interpret trial results, particularly when making international comparisons, insight into the control condition is essential.We used a mixed methods approach to 'map' services provided to teenage mothers in our 18 trial sites. Initially, a variety of local professional stakeholders described characteristics of health and social services across five domains. This data informed the construction of a follow-up web-based survey filled in by a single local informant per site. Finally, in-depth telephone interviews with a sample of these informants sought to highlight changes in service provision over the course of the trial.The outcomes of the initial mapping exercise lacked consistency but were useful to inform both the construction of the follow-up survey and the main trial data collection questionnaires. The web-survey results provided snapshots of service provision per site and the interviews contextualised local changes.Variation of usual care needs to be acknowledged in the interpretation of results, particularly in the assessment of the study's generalisability. Our service mapping exercise provided global insight into within-site variations and changes over time. Practical limitations prevented exploring details of uptake and local criteria for entitlement."}
{"text": "Personalised medicine is replacing the one-drug-fits-all approach with many prognostic models incorporating biomarkers available for risk stratifying patients with breast cancer, such as the Nottingham Prognostic Index and Adjuvant! Online and more recently multiparameter assays, OncotypeDx and Mammaprint.Evidence of biomarkers having non-proportional effects have been emerging and therefore violating the assumption of proportional hazards when performing Cox regression. A classic example is the risk of recurrence after breast cancer depends on the duration of follow-up for estrogen receptor (ER) and progesterone receptor (PgR) expression status. The genet al.[A review of existing approaches for the analysis of non-proportional effects with respect to survival data found there to be a number of well-developed approaches for incorporating non-proportional effects but a lack of application of these approaches in practice. Two key approaches are the multivariable fractional polynomial time (MFPT) approach by Sauerbrei et al. and flexet al..There is a need for more widespread use of flexible modelling to move away from standard analysis using a Cox model when the assumption of proportional hazards is violated. Fully determining the effects of markers in prognostic studies will help develop novel models for the selection of patients for appropriate treatments."}
{"text": "The fifth sentence of the Abstract is incorrect. The sentence should read: \"Clustering analysis (using an unweighted pair-group method with arithmetic mean), revealed strong concordance between the strength of genetic relationships among populations and their geographic proximity.\"In addition, the second sentence of the first paragraph of the Introduction is incorrect. The sentence should read: Indeed, it is has been listed in the American Quarantine regulations [1]."}
{"text": "The development of stratified medicine depends on an understanding of treatment-effect mechanisms . Yet the evaluation of these mechanisms is often absent from the design and analysis of studies for stratified medicine, and even if present, is subject to unmeasured confounding.We review the problem of confounding (common causes) for the drawing of valid inferences concerning treatment-effect mechanisms, even when the data has been generated using a randomised controlled trial. We illustrate the potential of the predictive biomarker-stratified trial design, together with baseline measurement of all known prognostic markers, to enable us to evaluate both the utility of the predictive biomarker in such a stratification and to estimate how much of the treatment's effect is actually explained by changes in the putative mediator. We call this a biomarker-stratified efficacy and mechanisms evaluation (BS-EME) trial design.The analysis strategy involves the use of instrumental variable estimation methods, using the treatment by predictive biomarker interaction as an instrumental variable together with adjustments for all know prognostic markers; the latter contributing to increased precision  rather than bias reduction. The analysis approach provides unbiased estimates even in the presence of unmeasured confounding.We conclude that stratification without corresponding mechanisms evaluation lacks credibility and in the almost certain presence of mediator-outcome confounding, mechanisms evaluation is dependent on stratification for its validity. Our trial design and analysis approach evaluates both stratification and treatment-effect mediation."}
{"text": "The IVAN trial is a multi-centre factorial non-inferiority randomised controlled trial of 610 participants to compare treatments for neovascular Age-related Macular Degeneration . Many of the trial outcomes are longitudinal continuous outcomes measured at regular intervals over the two-year study period.The aim of the analyses was to obtain estimates of the drug and treatment regimen effects at two-years. For many of the outcomes, standard mixed-effects models fitted the data well. However, for some secondary outcomes, and in particular total lesion area, the distributions were highly skewed; 28% of 1536 measurements of lesion area were zero indicating a lesion was not present, which rendered standard regression modelling unsuitable.One approach taken to analyse this outcome was to dichotomise the variable into lesion present and lesion absent, and fit a logistic regression model with repeated measures. This analysis identified a statistically significant difference between the proportions of patients with no lesion present at two-years on the different treatment regimens. However the analysis did not make full use of the data available and information about the size of the lesion was not evaluated.An alternative approach that we have investigated is to use two-part modelling whereby the dichotomised data is analysed using logistic regression, and the non-zero values then analysed using mixed-effects models. We will present the results of this analysis and describe the methodological challenges faced when implementing it in the context of the IVAN trial."}
{"text": "Most species of bats making echolocation use the sound pressure level (SPL) and Doppler-shifted frequency of ultrasonic echo pulse to measure the size and velocity of target. The neural circuits for detecting these target features are specialized for amplitude and frequency analysis of the second harmonic constant frequency (CF2) component of Doppler-shifted echoes. The neuronal circuits involved in detecting these echo features have been well known . In natuThe model contains two hemispheres, in each of which, the network model consists of cochlea (Ch), inferior colliculus (IC), and Doppler-shifted constant frequency (DSCF) processing area. The Ch network has a frequency map by which sound frequency is encoded. The model for detecting frequency information of echo sound was based on the model previously presented by us .The SPL We showed that in IC, the amplitude information of echo sound is encoded by integrating the outputs of ipsi and contralateral Ch neurons and then combined with the Doppler-shifted frequency information encoded by tonotopical map of Ch neurons. The accuracy of the amplitude and frequency information was improved in the DSCF area. The model reproduced well several experimental results observed in IC and DSCF neurons. We also showed that AC and DC components of echo signal are discriminated in the two sub-networks of DSCF. The discrimination ability is due to the difference in time constant between DSCF neurons in the two sub-networks.We presented the neural mechanism for detecting SPL amplitude and Doppler-shifted frequency of echo sounds. The model offered the neural mechanism of how amplitude and frequency information of echo sound are processed and then combined in IC and DSCF area. We also presented that DSCF area discriminates between AC and DC components of echo sound."}
{"text": "We developed a neuromechanical computational model of cat locomotion that simulated the locomotor movements of cat hindlimbs controlled by spinal locomotor central pattern generators . In the closed-loop model, CPG operation was adjusted by afferent feedback from the hindlimbs. The CPG model was based on the previous two-level model  and inclThe hindlimbs with the pelvis and trunk were modeled as a 10 degree-of-freedom sagittal plane system of rigid segments interconnected by frictionless revolute joints. The hindlimb interactions with the ground and other body segments were modeled as linear springs and dampers . The twoThe developed neuromechanical model demonstrated stable locomotion and exhibited realistic patterns of muscle activation, limb kinematics, and ground reaction force dynamics. The model was used for investigation of the role of afferent feedback and the CPG in control of locomotion under different conditions."}
{"text": "The etiology of the far more prevalent late-onset AD is not primarily genetic in origin even though research over the last two decades has identified one or more genetic risk factors that predispose their bearers to development of the disease. Studies of late-onset AD have been strongly influenced by the amyloid cascade hypothesis. This influential hypothesis posits that plaques of \u03b2-amyloid  accumulate in the neuropil, where they eventually initiate a neuropathogenic process that engenders production of insoluble tangles of modified tau protein , the ultimate result of which is progressive cognitive dysfunction. Firm and final diagnosis of the disease remains dependent on postmortem quantitation of the density and character of NSP and NFT in specific regions  of the affected brain. In addition, inflammation in the late-onset AD brain has been well documented, but this potentially important aspect of pathogenesis has not found a major place in the suite of factors thought to play primary roles in the neuropathogenic process. For many years, it has been accepted that the etiology of early-onset Alzheimer's disease (AD) is genetic in nature, with the relevant mutations involving genes encoding products that function in pathways dealing with processing of Substantial evidence derived from clinical trials, animal model studies, and other sources indicates that late-onset AD cannot be explained solely or primarily by accumulating NSP and NFT despite the fact that these are the most obvious and consistent pathological features of this disease. Rather, the evidence strongly suggests that late-onset AD results from a complex interplay between genetic and environmental factors, most of which remain to be elucidated. In this special issue, we were interested particularly in papers that present alternative viewpoints concerning the complex etiology and pathogenic processes underlying late-onset AD. The solicitation targeted reports of primary research from different fields, including new genome sequence or structure data that shed light on the complex genetic background giving increased susceptibility to disease induction, new insights regarding relevant environmental influences that may contribute to that induction, and new studies focusing on the biochemistry and molecular genetics of AD. Further, we wanted review articles that summarized recent research developments that engender new views on the etiology and/or neuropathogenic mechanisms of AD as well as hypothesis-driven but evidence-based arguments regarding etiology and neuropathogenesis.The first paper included in this special issue presents an interesting, and we think cogent, argument for a reconsideration of the amyloid cascade hypothesis. The authors of this review conclude that current evidence indicates that the production of NFT and NSP is independent of one another and that these are probably the products, not the cause, of the neurodegeneration that characterizes late-onset AD. The article presents a modified version of the hypothesis that provides a reasonable explanation of the pathogenesis of the disease. postmortem examination of the brain of affected individuals, a pressing need exists for identification of markers that can reliably indicate the presence of AD in individuals at much earlier stages of the disease induction process. The second paper included in this special issue presents new research indicating that delineation of certain aspects of the IL-10 genotype and expression of one membrane-located adenosine receptor might prove useful in identifying individuals with the early signs of dementia who are at high risk of progressing to incipient late-onset AD. Since firm diagnosis of late-onset AD depends on \u03b2-amyloid at high levels might be initiated and maintained. The first of the three papers reviews the biochemical roles of the transglutaminase enzymes, the long-standing hypothesis that the activity of these enzymes contributes to oligomerization and accumulation of \u03b2-amyloid, and posits that specific inhibitors of the enzymes found in the CNS may prove to be effective therapeutic targets to ameliorate disease progression. The final three papers accept the amyloid cascade hypothesis as a mechanistic explanation for the characteristic neuropathogenesis of late-onset AD, but each develops an interesting new idea concerning how the accumulation of \u03b21-42 is infused into mice, the activity of a particular ABC transport system is impaired, leading to attenuated removal of \u03b2-amyloid from the brain. This intriguing observation suggests that the documented age-related decrease in the expression of that transporter may contribute to the accumulation of \u03b2-amyloid in the brain and thus of NSP formation. The final paper in this special issue is a study of the function(s) of a noncoding transcript from the BACE1-encoding gene, using a transgenic mouse model in which A\u03b2 production is excessive. Previous work from this group had demonstrated that these noncoding transcripts stabilize the mRNA specifying BACE1, thereby increasing the production of insoluble \u03b2-amyloid. In the present study, knockdown-based inhibition of either the noncoding or BACE1-encoding transcript engendered decreased \u03b2-amyloid production and attenuated neuronal degeneration. These last three papers point to new ways of reducing the burden of NSPs in the brains of transgenic mice. The challenge now is to determine if these approaches can be applied to the brains of aging primates, and if so, whether reducing the burden of NSPs will be sufficient to slow the rate of cognitive decline.The next paper reports that when AAD and stroke together account for the bulk of cognitive impairment and mortality worldwide. As the risk factors and causes of stroke are becoming better understood, interventions have started to decrease the incidence of stroke . By conAlan P. HudsonAlan P. HudsonBrian J. BalinBrian J. BalinKeith CrutcherKeith CrutcherStephen RobinsonStephen Robinson"}
{"text": "Modeling various neuronal functions in search of emergent properties may achieve success when the gold standard of replicating the models in physical systems starts exhibiting some of these properties. Since very large number of functions can be modeled and need testing, we suggest an alternate method of examining higher brain functions: seeing them as internal sensations formed from their hypothetical basic units. Here, we explain the need to replicate the natural mechanism using electronic circuits, discuss some of the technical aspects and introduce some concepts for searching for properties of internal sensations evolving from them. Understanding the nature of conscious internal sensations in the brain remains a challenge . The cenInternal sensations such as consciousness and memory can only be accessed by the owner of the nervous system. Even though the virtual nature of internal sensations has been of concern since the time of Descartes, philosophers have maintained the radical view that Cartesian sensations represent something real ,13. InteCurrently, internal sensations are assessed by observing behavioral activities either in the form of locomotion or speech or other motor activities. We are not directly examining the internal sensations; in fact, they remain completely unexplored. The depth of this issue can be seen in the following example. Let us imagine an individual with locked-in syndrome  who loses both the eyeballs and eyelids ). Given that an individual with locked-in syndrome is functionally capable of much, even of authoring a book , it can From the fact that the stimulation of different locations of the human brain induces hallucinations , it can Oscillatory neuronal activities at different neuronal orders induce sub-threshold activation of different neurons at their higher orders. Re-activation of the functional LINKs during memory retrieval can result in the activation of these sub-threshold activated neurons that are often reported as neuronal activities representing memories from a second-person perspective  embranes  and is iSpatial amplification of signals: Activation of a synapse induces excitatory postsynaptic potential (EPSP) at the postsynaptic terminal that propagates towards the cell body. Summation of nearly 40 EPSPs arriving from any 40 synapses (out of an average 2.4-8x104 dendritic spines [4). This indicates that the electronic equivalent of the axon hillock should have a function of a direct current step-up transformer. Since the output of the system is not an amplified input sensory signal, we may treat the sensory inputs as a source of electricity (similar to photo-electricity).b) c spines  can trigGradual decay of signals: It is known that excitatory postsynaptic potentials (EPSPs) from apical synapses of cortical pyramidal cells do not reach the cell body [c) ell body  and willIntroducing functional LINKs in an electronic circuit model: Inter-postsynaptic functional LINKs may be introduced using an AND logic gate that function when both postsynapses are activated simultaneously. If this can lead to the activation of a silicon-controlled rectifier (SCR) that leads to the opening of an OR gate between these postsynapses, then at a later time-point the activation of either one of the postsynapses may be able to open this OR gate . Artificial systems with these functions may be examined for semblance formation.d) Maintaining appropriate oscillating neuronal activities: The formation of semblances is seen as an emergent property of a system with oscillatory neuronal activity. Fine-tuning of systems properties to match the formed internal sensations of retrieved memories of an item to that of the actual properties of the item used in associative learning is the final step of the process. The knowledge that changes in the frequency of oscillations during sleep [e) ng sleep  and anesng sleep  changes Overlapping semblances determine the identity of the internal sensations: Inputs (EPSPs) summated at the axon hillock from nearly any 40 postsynaptic terminals give rise to an action potential, which in turn activates nearly 2.4-8x104 axonal (presynaptic) terminals and their corresponding postsynaptic terminals in the next layer. Therefore, an action potential generated is not input-specific . This information can be used while extrapolating for the semblions from a postsynapse activated through inter-postsynaptic functional LINK by lateral entry of activity from the cue stimulus  s Figure .Recapitulating ontogeny during AI development: It is important that the construction of the artificial systems should recapitulate the developmental stages of the nervous system. In this regard, discontinuity of the tracings in the electroencephalogram (EEG) among very premature infants [g)  infants  suggestsObtaining logic output to identify internal sensations: What methods will allow us to obtain a read-out for the nature of semblions? At the behavioral level, monkeys were conditioned to respond to electrical stimulation delivered to different layers within the visual cortex V1 [h) ortex V1 . By induortex V1 . Can we This letter has highlighted the technical aspects of engineering a feasible system in physical states based on the hypothesis of the formation of semblances, both to understand the intrinsic science behind the formation of internal sensations and to replicate the mechanism in artificial systems. The existence of diverse types of nervous systems in the animal kingdom organized in a wide range of sequences of the same expected operational units lends hope to the goal successfully transferring the mechanism to physical systems.BOLD: Blood Oxygenation Level Dependent; EEG: Electro-encephalogram; fMRI: Functional Magnetic Resonance Imaging; LISNE: Locked In Syndrome with No Eyeballs and Eyelids; TBI: Traumatic Brain Injury.The authors declare that they have no competing interests."}
{"text": "Dear Editor-in-Chief:I read with interest a recently published article in your esteemed journal by Lavasani et al., entitled \u201cStudy of the pharmacokinetic changes of Tramadol in diabetic rats\u201d. LavasanThe results of this investigation unequivocally confirmed that the exposure of tramadol increased substantially (approximately 4-fold) in diabetic rats with an identical 4-fold reduction in the oral clearance. Also, tThe intent of this note is to provide additional clues to further tease out the observed findings of tramadol disposition in diabetes rats. Although shift in volume of distribution can alter exposure, perhaps, the decreased total body clearance is the key driver to explain the exposure increase for both tramadol and the metabolite M1. The disposition of tramadol is governed by efficient hepatic clearance and renal excretion of both the parent and the major oxidative metabolites (inclusive of M1). HoweverIn conclusion, the interesting work of Lavasani et al., has thrown some new light on the importance of well-planned experiments to tease out the variables that account for pharmacokinetic disposition of tramadol in diabetes rats. The sug"}
{"text": "Grid cells in the medial entorhinal cortex (mEC) and place cells in the hippocampus are paradigms for population coding of spatial information . Both thIn order to understand the relative contributions of grid cells and non-spatial inputs in determining place field size and stability, we propose a computational model of the hippocampal-entorhinal network that includes a modular organization of grid cell inputs arranged in order of increasing spatial scale, as is seen experimentally in the mEC. Our underlying place cell model is a firing-rate based model inspired by previous work , in whicOur main findings suggest that:1.) For a wide range of parameters, the relative amounts of spatial and non-spatial inputs to place cells plays a more important role in determining place field size and stability than the spatial scale of grid cell inputs. This implies that the dorso-ventral gradient in place field size may reflect a dorso-ventral gradient in non-spatial inputs, rather than grid scale, and is agreement with prior suggestions of a functional distinction between the dorsal and ventral regions of the hippocampus .2.) In our model, place fields are sensitive to changes in the firing rates of the grid vertices of individual grid cells, emphasizing the potential implications of this grid field heterogeneity for place field formation and stability."}
{"text": "Prior research shows that work in agriculture and construction/extraction occupations increases the risk of environmental heat-associated death.To assess the risk of environmental heat-associated death by occupation.This was a case-control study. Cases were heat-caused and heat-related deaths occurring from May-October during the period 2002\u20132009 in Maricopa County, Arizona. Controls were selected at random from non-heat-associated deaths during the same period in Maricopa County. Information on occupation, age, sex, and race-ethnicity was obtained from death certificates. Logistic regression analysis was used to estimate odds ratios for heat-associated death.There were 444 cases of heat-associated deaths in adults (18+ years) and 925 adult controls. Of heat-associated deaths, 332 (75%) occurred in men; a construction/extraction or agriculture occupation was described on the death certificate in 115 (35%) of these men. In men, the age-adjusted odds ratios for heat-associated death were 2.32  in association with construction/extraction and 3.50  in association with agriculture occupations. The odds ratio for heat-associated death was 10.17  in men with unknown occupation. In women, the age-adjusted odds ratio for heat-associated death was 6.32  in association with unknown occupation. Men age 65 years and older in agriculture occupations were at especially high risk of heat-associated death.The occurrence of environmental heat-associated death in men in agriculture and construction/extraction occupations in a setting with predictable periods of high summer temperatures presents opportunities for prevention. Published reports suggest that agricultural workers are at elevated risk of death due to heat-related illness The Maricopa County Department of Public Health (MCDPH) attempts to systematically ascertain environmental heat-caused and heat-related deaths that occur in the county during the summer. Maricopa County, Arizona is a setting with predictable conditions of high heat in the summer, and deaths associated with high environmental heat continue to occur in spite of the predictability of high heat. Information from this surveillance effort provided a unique opportunity to estimate the magnitude of the increase in the risk of heat-associated death among people with occupations that often involve work outdoors.A study of farm workers in North Carolina showed that a high proportion (94%) of Hispanic farm workers reported working in extreme heat This was an epidemiologic case-control study. The source of data was death certificates. Cases were deaths occurring in May through October during the period January 1, 2002-December 31, 2009 in Maricopa County that were identified as heat-caused or heat-related by the MCDPH as part of its program of on-going surveillance of heat-associated deaths. Controls were deaths occurring in Maricopa County selected at random from among all non-heat associated deaths in Maricopa County during the same period with frequency matching of cases and controls by year of death using a case-control ratio of 1\u22362. Two controls were selected per case to increase statistical power and make estimates of odds ratios more precise.The study was reviewed and approved by both the Arizona State University Institutional Review Board and the Arizona Department of Health Services Human Subjects Review Board. The research used information recorded on death certificates for individuals identified by the MCDPHS and the Medical Examiner as heat-associated. Patient data from hospital records were used by MCDPH to identify heat-associated deaths. The use by the MCDPH of patient data from hospital records is a component of its routine public health activity in conducting surveillance to monitor heat-associated health events. Data from hospital records were used by the Maricopa County Medical examiner to certify deaths possibly due to heat as heat-associated for the purposes of completing the death certificate. The use of data from hospital records by the Medical Examiner without consent is permitted by law. In Arizona, hospitalized patients are not asked either to approve or disapprove the use of information from their hospital records for research. The Arizona Department of Health Services Human Subjects Review Board waived the requirement for consent based on a judgment that the research posed no more than minimal risk; that the rights and welfare of human subjects were not adversely affected by the waiver; and that obtaining consent from people who have died is impracticable. The Arizona State University Institutional Review Board did not require consent because it does not consider research using information about people who have died to be human subjects research.Since 2006 prospectively and retrospectively since 2000, environmental heat-associated deaths have been identified by the MCDPH in a formal surveillance system. The MCDPH begins its surveillance process by gathering information on suspected heat-associated deaths using a variety of sources. These include the Office of Medical Examiner case list, which identifies suspected heat-associated deaths referred to the Medical Examiner; the Arizona Department of Health Services, which identifies deaths with environmental heat mentioned on death certificates; local hospitals, which identify suspected heat-associated morbidity/mortality cases reported by emergency department staff and infection staff; Humans Remains Release Forms, which include death reports received from hospitals and other institutions within 24 hours of death; and media reports of heat deaths. To assure that the MCDPH list of heat-associated deaths is complete and that no deaths have been erroneously certified as heat-associated by community physicians rather than the Medical Examiner, a multiple-causes-of-death search is done daily using the electronic death certificate database. The search is done to identify both International Classification of Disease, Tenth Revision (ICD-10) codes associated with environmental heat  and key phrases in the text fields for causes and underlying causes of death .Suspected cases of heat-associated deaths identified by the MCDPH surveillance system that do not appear on the Medical Examiner's case list as suspected heat-associated deaths are referred to the Medical Examiner. The Medical Examiner either rules out or confirms the deaths as environmental heat-associated deaths based on information about the circumstances of death and his/her examination of the remains when indicated. Certification by the Maricopa County Medical Examiner is the basis for designation of death as being environmental heat-associated and the certified environmental heat-associated deaths include not only deaths caused by environmental heat exposure but also those in which environmental heat exposure precipitated a death technically caused by something else . The MCDPH heat-associated death surveillance system thus differs from most other heat mortality surveillance systems, which include only deaths for which the underlying cause of death appears as environmental heat exposure using the ICD-10 codes listed above.Suspected heat-associated deaths identified in the MCDPH surveillance system certified by the Maricopa County Medical Examiner are classified in one of two categories. Deaths in the first category are directly caused by environmental heat exposure. In these deaths, environmental heat is mentioned in Part I of the death certificate (diseases or conditions in the direct sequence causing death) whether or not environmental heat is described as the underlying cause of death on Part I of the death certificate. Deaths classified in the second category \u2013 heat-related deaths \u2013 mention environmental heat terms in Part II of the death certificate causes of death (diseases and conditions contributing but not directly resulting in the death) sequence but not in the Part I sequence. The current study includes both categories \u2013 heat-caused and heat-related \u2013 and labels them heat-associated deaths in keeping with the terminology used by the MCDPH in its surveillance operation. For the purposes of surveillance and in this study, a death is considered environmental heat-associated if it was related to heat generated by the climate  and excludes heat from man-made sources such as ovens or manufacturing equipment.Text information recorded in the industry and occupation fields of the standard death certificate was inspected and used to classify the occupation of cases and controls. A person was classified as having a construction/extraction occupation if the term \u201cconstruction\u201d or \u201cmining\u201d or \u201cminer\u201d appeared in either the industry or the occupation text field on the death certificate or if the description of the person's occupation or industry is included in the Standard Occupation Classification major group 47-0000 \u2013 Construction and Extraction Occupations Classification of occupation was completed by one investigator (Petitti) blind to whether the death was heat-associated. A formal assessment of the reliability of the classification of occupation was completed. In it, an investigator not involved in the initial classification (Harlan) classified occupation in a random sample of 150 deaths blinded to case-control status and to initial classification. Cohen's Kappa was used to assess reliability Information on race/ethnicity was obtained from the ethnicity and race fields of the death certificates. The coding of race and ethnicity on the Arizona death certificate uses categories and follows rules specified by the National Center for Health Statistics for the United States Standard death certificate. Over the period of this study, changes were made in the level of detail requested for the ethnicity field and the completeness of designation of individuals as Hispanic or non-Hispanic in the ethnicity field changed. In an attempt to make the data on race/ethnicity consistent across time, race/ethnicity was classified in a single category. A person was classified as Hispanic if the term \u201cHispanic\u201d appeared in the ethnicity field of the death certificate. People designated as non-Hispanic and those not designated as Hispanic were further sub-classified as non-Hispanic white, African-American, Native American, or Asian/Pacific Islander based on text information in the race field of the death certificate.Cases and controls were first described using percent distributions. Unconditional multiple logistic regression was used to estimate age-adjusted odds ratios for heat-associated death and 95% confidence intervals according to occupation. The percentage of deaths with an unknown occupation was substantially higher in cases than in controls. For this reason, the referent for the analysis of occupation was chosen to be other known occupation. Seventy-five percent of heat-associated deaths were in men and all but four of the subjects classified as having a construction/extraction or agriculture occupation were men. For this reason, the multiple logistic regression analyses to estimate the odds ratios for heat-associated death were done separately in men and women.To assess whether the association between occupation and heat-associated death was modified by race/ethnicity or age, odds ratios for heat-associated deaths were estimated according to occupation in strata of race-ethnicity and age. Because the number of heat-associated deaths in African-American and Native American men was small, these analyses were limited to non-Hispanic white and Hispanic men.\u00ae software version 9.2 The Hosmer Lemeshow chi-square statistic was used to assess model fit There were 463 cases of heat-associated death during the period 2002\u20132009; 925 controls age 18+ years of age were selected for these cases. Nineteen cases of heat-associated death with known age less than 18 years of age were excluded. Nine cases of heat-associated death with unknown age were included in the analysis after noting that all of them had an entry in the occupation and industry field whereas approximately 98% of deaths at ages less than 18 had blank entries for occupation and industry. There were 444 cases and 925 controls included in the analysis.In women, using all other known occupation as the reference category, the age-adjusted odds ratio for heat-associated death was 6.32  in association with an unknown occupation. Using non-Hispanic white women as the reference category, the age-adjusted odds ratios for heat-associated death were significantly increased in Hispanic women  and Native-American women  and increased, but not significantly, in African-American women .To assess whether race and age modified the associations of occupation with heat-associated death, we did stratified analyses. These analyses excluded Native Americans and African-Americans and those with unknown or Asian race/ethnicity because the numbers of cases and controls in these groups was small.The odds ratios for heat-associated death in association with agriculture occupations were increased in all age groups. However, the odds ratios in association with agriculture occupations in men age 65\u201384 years and 85+ years were somewhat higher than at younger ages: 4.05  and 16.45  respectively. Adjustment for race/ethnicity (Hispanic versus non-Hispanic white) in these age-strata attenuated the association between heat-associated death and occupation because of the strong correlation between being Hispanic and agriculture occupation.Our data show an association of heat-associated death with construction/extraction and agriculture occupations in men in Maricopa County, Arizona as expected given prior research. The increase in the risk of heat-associated death in association with agriculture occupations was not greater in Hispanic than in non-Hispanic white men. However, Hispanic men were more likely to work in agriculture and the difference in the distribution of occupation in Hispanic men contributed to, but does not fully explain, the overall higher risk of heat-associated death among Hispanic men in this study. Our study was not able to disentangle fully the independent effects on heat-associated death of race/ethnicity and occupation because of the small number of deaths in some categories. The study does not rule out the possibility that men who were African-American and Native Americans might be at especially high risk of heat-associated death.Our study suggests that the increase in the risk of heat-associated death in association with construction/extraction and agriculture occupations may be modified by age. In men age 18\u201349 years, the risk of heat-associated death was close to 1.00 and not statistically significantly increased in association with construction occupations. In men age 65 or more years, the magnitude of the increase in the risk of heat-associated death in association with agriculture occupations was large: about 4 in men age 65\u201384 years and about 7 in men age 85+ years. These findings were based on only a small number of cases of heat-associated deaths in older men and must be interpreted cautiously.Our findings are consistent with published reports from prior research that examined death certificate data for heat-associated deaths among workers in occupations classified as agriculture, construction, and mining (extraction) A 2008 report from the Centers for Disease Control and Prevention estimated that heat-related average annual death rate for agricultural workers was 0.39 per 100,000, compared with 0.02 for all United States civilian workers We found a very high risk of heat-associated death in associated with having an unknown occupation both in men and women. Unknown occupation is a marker for homelessness. Other investigations of heat-associated death conducted by the Arizona Department of Health Services and the MCDPH have identified homelessness as an important contributor to heat-associated death in Maricopa County Investigation of heat-associated death conducted by the Arizona Department of Health Services has identified attempts to cross the desert to enter the United States illegally as a factor in heat-associated death in Arizona Our study has several limitations. A first major concern is the use of death certificates as the source of information on occupation. The accuracy of this information is uncertain. More importantly, our study does not directly assess the effect of work related to occupation in construction and agriculture. In fact, only 12 of the heat-associated deaths were designated as being deaths due to injury at work. All of these deaths were in men; seven were in men with a construction/extraction or agriculture occupation and 2 were in men with unknown occupation. Guidelines to Medical Examiners and Coroners on how to complete the \u201cinjury at work\u201d section of the death certificate specify that a death should be designated as due to an injury at work if the injury occurred: while working or in vocational training on job premises, while on break or at lunch or in parking lot on job premises, while working for pay or compensation, including at home; while working as a volunteer law enforcement official, or while traveling on business, including to/from business contacts The fact that the highest risk of heat-associated death in association with agriculture occupations was observed in men age 65 years or more raises the possibility that occupation may be a marker for the risk of heat-associated death and not due directly to work in agriculture or work out of doors. Determining whether there was a direct link between work in construction/extraction or agriculture and death due to heat would require collection of information directly from observers. Further research based on more detailed information about the circumstances of death for heat-associated deaths in those with a construction or agriculture occupation might clarify the contribution of work in a hot environment to the death.Recognizing the problem of heat-related illness and death in workers, California and Washington have adopted stringent workplace safety standards designed to prevent heat-related illness Washington State has applied the standards to all employers with employees in outdoor settings In 2011, the Occupational Health and Safety Administration (OSHA) initiated a nationwide outreach campaign to raise awareness among workers and employers about the hazards of working outdoors in hot weather One of the challenges of better understanding heat-related illness and mortality is determining the threshold of human tolerance to excessive temperatures. The Centers for Disease Control and Prevention (CDC) defines sustained periods of hot weather as those with daytime temperatures of 105 or more degrees Fahrenheit (40.6 degrees Centigrade) and a nighttime minimum temperature of 80 or more degrees Fahrenheit (26.7 degrees Centigrade) persisting for at least 48 hours Our findings may have larger implications. Periods of high temperature are projected to become more common"}
{"text": "The posterior medial frontal cortex (pMFC) is known to be involved in adaptive goal-directed behavior, but its specific function is not yet clear. Most theories have proposed that the pMFC monitors performance in a reactive manner only, but it is possible that the pMFC also contributes to performance monitoring in a proactive manner. To date, the evidence for proactive pMFC activity is equivocal. Here, we investigated pMFC activity before, during and after the performance of a challenging motor task. Participants navigated a cursor through narrow and wide mazes in randomly intermixed trials. On each trial, participants saw previews of the actual maze display prior to gaining control of the cursor. Event-related potentials (ERPs) to the preview displays were compared to ERPs elicited by no-go signals and errors. Compared to the wider maze, the preview display for the more challenging narrow maze elicited a medial-frontal negativity (MFN) similar to the ERP components elicited by no-go signals and errors. Like these known ERP components, the preview-elicited MFN appeared to be generated from a source in pMFC. This is consistent with the hypothesis that the pMFC participates in adaptive behavior whenever there is a need for increased effort to maintain successful task performance. Converging lines of evidence suggest that the posterior medial frontal cortex (pMFC), an area that encompasses the anterior cingulate cortex (ACC) and the pre-supplementary motor area (pre-SMA), plays a critical role in adaptive, goal-directed behavior reactive manner only \u2013 that is, it monitors performance online or it contributes to learning after the task has been performed.The most prominent theories link activity within this cortical region to the monitoring of task performance. For example, the conflict-monitoring hypothesis proposes that pMFC detects response conflict occurring when two competing responses are co-activated and signals to pre-frontal cortex the need for increased cognitive control error-likelihood hypothesis suggests that increased pMFC activity can be triggered before, during, or after task performance \u2013 as long as the eliciting event signals a high likelihood of error. Empirical evidence for the error-likelihood hypothesis has been mixed, however: the original error-likelihood study reported fMRI results consistent with the hypothesis Researchers have begun to challenge the notion that the pMFC monitors performance exclusively in this kind of reactive manner, suggesting instead that the pMFC can act proactively to alter performance on an upcoming task effort-allocation hypothesis, pMFC is involved in representing and updating action-outcome contingencies based on the amount of effort required by the task and the potential benefit that these actions might generate. The pMFC might be further involved in allocating the necessary effort to select and produce actions that lead to favorable consequences An alternative hypothesis posits that the pMFC is sensitive to cues that signal situations that demand increases in cognitive or physical effort According to the effort-allocation hypothesis, pMFC is responsive only to information that can be used to alter behavior or action-outcome associations, and this defines an important distinction between the effort allocation hypothesis and the error-likelihood hypothesis. Cues indicating error-likelihood do not necessarily carry this type of information: a signal indicating increased error likelihood need not provide information about how to improve performance. The pMFC may become active only when circumstances are such that a strategic response to information about error likelihood is possible, suggesting a link with effort allocation rather than pure error likelihood, and this could underlie mixed results in tests of the error-likelihood hypothesis The present study used event-related potentials (ERPs) to determine whether the pMFC is active prior to, as well as during, performance of a challenging motor task. An important aspect of this motor task was that it provided information that could directly guide the selection of action and lead to preparatory adjustments before participants could begin to solve the task. We predicted that under these conditions the pMFC would contribute to behavioral adaptation proactively as well as reactively. To test this prediction, we developed a virtual-maze task in which observers previewed a maze prior to performing a maze-navigation task. This task required that the mouse cursor be kept on the maze path, and we varied the difficulty of the task by randomly intermixing narrow and wide mazes. The preview of the to-be-navigated mazes informed participants whether errors would be more or less likely and enabled participants to prepare for successful completion of the impending task.The high temporal resolution of ERPs allowed us to measure separate ERP components in response to the preview displays, subsequent Go and No-Go signals, and the eventual successful and unsuccessful maze navigations . Critically, this enabled direct comparisons of the proactive ERP activity elicited by narrow preview displays and the well-known reactive ERP activities associated with response conflict stemming from the No-Go signals Experimental procedures were approved by the Simon Fraser University research ethics board.Sixteen healthy university students participated in the study. Data from two participants were excluded from all analyses because of excessive noise in the electroencephalogram (EEG). The remaining 14 participants  provided written informed consent prior to the start of the experiment and received course credit for their participation.The experiment was conducted in a sound attenuated and electrically shielded chamber that contained a 19-in CRT monitor with the screen resolution set to 800\u00d7600 pixels. Participants sat in an adjustable chair and viewed the monitor from a distance of 65 cm. A computer running Presentation  controlled stimulus presentation and registered the participants' mouse movements. A second computer running custom software (Acquire) controlled EEG acquisition. The acquisition computer housed a 64-channel A-to-D board  that was connected to an EEG amplifier system with high input impedance .Participants navigated a cursor through a single-path maze using a standard computer mouse with the right hand . Each tr2. To increase motivation, participants were told that the experiment was in fact a game in which they earned points for each successfully completed task and lost points for time-outs and errors. At the end of each block participants received feedback about their accumulated score in point units, along with a 'scoreboard' that presented scores earned by earlier participants in the experiment. The results displayed in this scoreboard were fabricated and were included in the design only to motivate participant effort. Each block consisted of 16 trials. The full experimental session was composed of 30 blocks.On the first trial, participants had a limit of 13 seconds to complete the task, after which the maze turned red representing a timed-out trial and central feedback indicated the loss of one point. The time limit varied from trial to trial according to an adaptive procedure. After each unsuccessful trial, the time limit was increased by 250 ms and after each successful trial the time limit was decreased by 250 ms. All displays and colored stimuli were physically equiluminant at 6.00 cd/mcompletion time).As indirect measures of the effort needed to complete the task, we calculated the percentage of trials on which participants successfully navigated the maze (correct), went off the maze path (incorrect), or did not complete the maze in the allotted time (time-out), separated by effort condition. We further calculated the amount of time it took for participants to successfully complete the Low-Effort and High-Effort mazes (herein termed 14) permutations of the data.We were also interested in obtaining a measure of the behavioral adjustments made in response to increased recruitment of control. In performance-monitoring studies, a commonly used measure of monitoring is post-error or post-conflict slowing of reaction time RTs; . To inveWe recorded EEG from 63 tin electrodes attached to an elastic-fabric cap . All but 5 of these electrodes were positioned according to the 10-10 system . The remaining 5 electrodes were positioned inferior to the standard row of occipital electrodes. Horizontal electrooculographic (EOG) signals were recorded bipolarly using electrodes positioned at the external canthi. All EEG electrodes were referenced to an electrode placed on the right mastoid (M2). Electrode impedances were kept below 10 k\u03a9. EEG signals were amplified by a gain of 20,000 and a band pass of 0.1-100 Hz, digitized at 500 Hz and stored on a computer for offline averaging. Offline analysis was performed with EEGLAB After pre-processing the data, we extracted ERPs by averaging EEG epochs separately for 6 conditions of interest. In the first analysis we compared ERPs elicited by the initial presentation of the Low-Effort and High-Effort mazes (preview displays). We further looked at the correlation between the amplitude of the ERP component elicited in response to the preview displays and completion and reaction times. In the second analysis we compared ERPs elicited by the presentation of the Go and No-Go signals, and in the third analysis we compared ERPs elicited by the successful completion of the task and by errors. All ERPs were baseline corrected using the average amplitude of the 200-ms period preceding onset of the relevant event of interest . All statistical comparisons were performed on the mean amplitude of the waveforms for the FCz electrode during 80-ms time windows centered on the time of peak amplitude of the components of interest (see Results). The comparisons were performed through one-tailed paired permutation tests based on all possible permutations of the data (214).We used a two-step procedure for source analysis. First we used BESA 5.3 software (Megis software) to generate a distributed linear solution based on a Classical LORETA Analysis Recursively Applied (CLARA) model The behavioral results showed that the High-Effort maze was considerably more difficult to navigate than the Low-Effort maze . ParticiIn our main contrast of interest, we compared the ERPs elicited by the onset of the Low-Effort and High-Effort preview displays. In the second contrast of interest, we compared ERPs elicited by the onset of the Go and No-Go signals. In the third contrast of interest, we compared ERPs elicited by errors and correct task performance. We time-locked the ERPs to the moment the errors occurred  and the moment the task was successfully completed . These times were also marked by a change of maze color to indicate the end of a correct trial or an error. Neural sources were estimated using CLARA at the time of peak activation for each of the five contrasts of interest. Consistent with our predictions, the CLARA analysis showed increased activation in the pMFC in response to the presentation of the High-Effort preview display compared to the presentation of the Low-Effort preview display. This activity was estimated to be in the dorsal-rostral ACC and was accompanied by increased activation in bilateral fusiform gyrus . The dipWe followed similar procedures with the source analysis for the two ERP components identified for the No-Go minus Go contrast. Similar to what we found for the High-Effort minus Low-Effort contrast, the CLARA analysis estimated that the dorsal ACC and bilateral fusiform gyri were involved in the generation of the No-Go N2 . In addiThe CLARA analysis revealed three neural sources of the ERN/Ne . The firThe CLARA model for the Pe contained a single source, which was located in the ACC and extended into posterior cingulate cortex . The dipThe foci in ACC and posterior cingulate are consistent with previous studies performing source estimation for the ERN/Ne preparatory medial frontal negativity (MFN) that peaked at around 480 ms after the onset of the maze and had a pMFC source. This finding adds to the growing body of literature showing pMFC activity elicited proactively in anticipation of task performance In the present study we developed a new paradigm to investigate the proactive involvement of pMFC in effort-based behavioral adjustments. Our data showed that the presentation of the High-Effort maze elicited a The preparatory MFN observed here is consistent with both the effort-allocation and error-likelihood accounts of the pMFC: the High-Effort preview display predicted increased error-likelihood, which could also be seen as a negative prediction error if participants generated the expectation of a low-effort trial. Such an expectation would not have been based on a preponderance of low-effort trials because low- and high-effort trials were equally likely and randomly intermixed. However, participants likely preferred low-effort trials and thus may have come to anticipate them. The preview display also provided participants with information about the effort necessary to successfully navigate the maze. This latter feature of the design might be crucial. Extant studies that have failed to find increased pMFC activity in response to high error-likelihood cues provided no information that could be used proactively to improve performance e.g., . In contAlthough the goal of our study was not to test the error-likelihood hypothesis directly, or to pit the effort-allocation hypothesis against the error-likelihood hypothesis, we would like to suggest that the involvement of pMFC in performance monitoring indexed here reflects the need for increased effort and not the concomitant increase in error likelihood. Although the present data cannot conclusively distinguish between these two possibilities, this interpretation finds support in two recent studies. The first showed that cues informing participants about the presence or absence of conflict in a subsequent Stroop-like task activated the pMFC independent of conflict and error-likelihood A central goal of our study was to compare the ERP component elicited by the High-Effort maze to the ERP components elicited by conflict and errors. Early definitions of ERP components were based on common latency, polarity and scalp distribution, but more recent views suggest that a more appropriate definition is based on common computational operations and neuro-anatomical generators A potential problem with the idea that conflict, errors and effort-related cues elicited ERP components reflecting the same general neurocognitive processes is the fact that there were slight differences in the precise location of the pMFC activation foci for each component. Also, the additional foci that were activated in conjunction with the pMFC differed between the components. This subtle variation may reflect activation of physically distinct functional units in pMFC that contribute to a general cognitive function, but have dedicated anatomical connectivity with other brain areas Recent evidence has suggested that the role of the pMFC in allocating effort may be through a role in action selection involving effort-based cost-benefit analysis It is possible that in our experiment the increased pMFC activation in response to the High-Effort preview display at least partially reflects this role of the pMFC in integrating effort and reward to guide decisions about actions holding action-outcome contingencies that take into account the ratio of effort to reward, but is also involved in exploratory behavior building these relationships. Previous studies have shown that the pMFC is more strongly activated during early than late phases of learning The pMFC has also been associated with free choice during exploratory behavior The present results show that a preview display indicating the need for increased effort activates the pMFC prior to the execution of the task. Under the same experimental paradigm, we also observed pMFC activation related to response conflict and errors in performance. We suggest that a unifying role for the pMFC in response preparation and performance monitoring might be to build and utilize action-outcome contingencies. These would be created based on effort-benefit analysis with the goal of supporting behaviors that lead to positive outcomes"}
{"text": "We developed a model of the layered cortical network that integrates a major body of the available physiological and anatomical connectivity data on the cortical microcircuit . The modIn mono-layered balanced random network models the external input can be characterized by a single parameter, the external background firing rate. In contrast, the multi-layered network requires the specification of background inputs for every layer. We therefore distinguish the number of inputs a neuron of a given cell type receives and the background firing rate per external synapse. The experimentally observed cell-type specific firing rates are more accurately reproduced by a data-based estimate of the number of external inputs than by a layer-independent input parameterization. Still, it remains unclear how the overall contributions of background activity to the different layers shape the activity of the network.Here, we analyze the dependence of the activity in the full-scale local cortical network model on the external inputs. We apply large-scale parameter scans in NEST  to studyThe layered cortical network robustly reproduces the activity patterns observed in vivo for a wide range of external input configurations: the cortical microcircuit dynamically reconfigures its activity and preserves a default state. This robustness does not affect the ability of the network to process transients and changes in the balance of external inputs. This microcircuit mechanism may provide an explanation for the similarity of the spontaneous firing rates that have been observed, especially in layer 2/3, in various species and areas .Supported by the Helmholtz Alliance on Systems Biology, JUGENE Grant JINB33, the Next-Generation Supercomputer Project of MEXT, Japan, and EU Grant 269921 ."}
{"text": "Numerical methods in biomedical research belong to a rapidly developing field which provides a state-of-the-art tool for biomedical research and applications. Reliable predictions will lead to patient-specific simulations in the next decade to improve the diagnosis and treatment of diseases. The main focus of this special issue is on the interface between numerical methods and biomedical applications for the human body. It is also interesting to have quantitative analysis from the molecular up to the whole organ level. The goal of this special issue is to bring together experts in related fields of computational biomedical research, for example, multiscale flow modeling, blood flow propagation, fluid-solid coupling, inverse problems in biomechanics, high performance computing of multiphysics discretization schemes, cardiovascular biomechanics, and porous media, to both foster engagement across areas of numerical methods and to identify novel applications to challenging biomedical modeling problems. The special issue has 12 papers and the details of these papers are as follows.One paper presents the state-of-the-art parallelization technique taking advantage of the unique anatomical fiber architecture of skeletal muscles. The authors demonstrate the model's capability of simulating different aspects of nonisometric muscle contraction and the chemoelectromechanical behavior in complex skeletal muscles such as the tibialis anterior muscle.The construction of artificial muscles is one of the most challenging developments in recent biomedical science. Another paper discusses the theoretical Hill-type muscle and stability model in determining the force-velocity relations of different animal species, which are based on the literature data from biological experiments. It showed that an antagonistic muscle actuator can help in stabilising a single inverted pendulum model in favour of a control approach using a linear torque generator.One of the papers shows how the computational lower extremity model based on the inverse dynamic analysis and an optimization technique can be used to investigate different muscle activities and joint force patterns in knee osteoarthritis (OA) patients during walking. It provides insight into biomechanical changes in OA patients and evaluation of the postoperative functional outcomes of the OA treatments.Another paper describes the use of an indentation test in determination of in vivo mechanical characteristics of human skin. It proposes a triphasic in vivo model of intact skin based on a general phenomenological thermohydromechanical and physicochemical (THMPC) approach of heterogeneous media.One of the papers develops a computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH) to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Good agreement was observed between the 2D numerical model and the animal measurements. In the authors' simulated disease treatment, the model suggests that targeting proximal vascular remodeling, and in turn stiffness, may aid in recovery by further reducing RV afterload and power requirements.Another paper proposes the analytical solutions for the mathematical model in describing the formation of liver zones via Adomian decomposition method with a system of nonlinear integropartial differential equations. This paper may shed light on the mathematical aspects of the formation of liver zones and explaining the distribution of two types of the liver cells.One of the papers suggests creating a standardized nasal cavity model for adult Malaysian females. Computational fluid dynamic (CFD) analysis was performed to better understand the characteristics of the standardized model. The Malaysian female standardized model is larger in cross-sectional area when compared to the standardized Caucasian model, thus leading to lower average velocity magnitudes.The accuracy of the numerical result is closely related to mesh density as well as its distribution. The aim of an another paper is to evaluate the hybrid mesh with unstructured mesh and study its effect on the flow parameters inside the nasal cavity by considering the complexity of its anatomical architecture. The hybrid mesh reported lower grid convergence index (GCI) than the unstructured mesh and thus its usefulness in nasal airflow studies.The mathematical analysis for optimizing numerical performance based on different time integration schemes that pertain to both the fluid and solid accelerations is presented in one of the papers. The choice of time integration schemes has a significant influence on the stability of fluid-structure interaction coupling. This implies that in addition to material and its geometric properties, the choice of time integration schemes is critical in determining the stability of the numerical computation.Another paper studies an integrated myocyte-Isac-Fb electromechanical model to investigate the effect of fibroblasts (Fbs) and stretch activated ion channel current (Isac) on cardiac electrical excitation conduction and mechanical contraction. The numerical results indicated that Fbs and Isac coupling caused diverse effects on action potential morphology during repolarization, depolarized the resting membrane potential of the human atrial myocyte, slowed down wave propagation, and decreased strains in fibrotic tissue.Medical schools can benefit from a tool, system, or method that will help instructors train students and assess their tactile proficiency throughout their education. The robotic lumbar spine has the potential to satisfy these needs in palpatory diagnosis. One of the papers demonstrates the dynamic model and nonlinear control of a 15-degree-of-freedom, cable-actuated robotic lumbar spine (RLS) that enables the solution of positive and continuous cable tensions for cable-actuated robots. Another paper investigates the multiobjective optimization design of spinal pedicle screws using neural networks and genetic algorithm to achieve an ideal with high bending and pullout performances simultaneously. The optimal design has significantly higher fatigue life and comparable pullout strength as compared with commercial screws.In this special issue, we have provided examples of recent progress in computational and mathematical methods in biomedicine, for the benefit of students, researchers, healthcare professionals, and teachers."}
{"text": "The evolving nature of palliative care and its renewed role in people living with HIV/AIDS (PLWHA) in the post-HAART  era warrants an evaluation of the present curriculum in medical under graduates.The objectives are(1) to measure the existing knowledge regarding palliative care and its application to PLWHA among medical interns and (2) to measure the impact of a structured intervention on knowledge dimensions.Interventional repeated measures study.A convenience sample of 106 interns in the medical college completed a pre-test assessment and a post-test assessment following a structured intervention for evaluation and comparison of knowledge over three dimensions which were (1) knowledge of palliative care and its application in PLWHA, (2) medical symptoms in PLWHA requiring palliative care and (3) psychosocial needs in PLWHA requiring palliative care.t=9.12, P value <0.001), medical symptoms in PLWHA requiring palliative care  and psychosocial needs in PLWHA .The mean scores on knowledge showed a consistent increase after the structured intervention and Student\u2019s t-test was significant across three dimensions of knowledge of palliative care and its application (In spite of the unique challenges presented by the varying course of illness in PLWHA and the variety of needs on the medical, psychosocial and family dimensions, a structured approach and an integrated course curriculum involving principles of both primary and palliative care principles will improve the efficiency of the undergraduate medical education program and enable delivery of effective palliative care interventions and improve quality of life in PLWHA. Since the case series in 1981 of Kaposi sarcoma to the adoption of highly active anti-retroviral therapy (HAART) and the transition of HIV/AIDS to a chronic manageable disease, palliative care has played a varying and evolving role from end of life care in the pre-HAART era to palliation of symptoms and toxicities of HAART era currently.3 There iWHO  defines palliative care as \u201can approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.\u201d The specWith an estimated disease burden of 1.8 to 3.2 million people living with HIV/AIDS in India, these pa6Studies7 on pallThe current study aimed at measuring existing knowledge of palliative care and its application to PLWHA in medical interns, the effect of a structured intervention on improvement of knowledge and application to make recommendations for an integrated curriculum incorporating primary and palliative care targeted to PLWHA.An interventional repeated measures study was conducted and a convenience sample of 106 interns in the medical college completed a pre-test assessment and a post-test assessment following a structured intervention for evaluation and comparison of knowledge regarding palliative care needs in PLWHA.t-test was performed on the pre- and post-test scores in each dimension individually.Baseline characteristics regarding the intern\u2019s age and sex, exposure to terminal and non-terminal PLWHA, completion of medicine and allied postings and attendance of formal training courses in palliative care if any were obtained. Knowledge was evaluated by a self-administered, 32-item semi-structured questionnaire factored into three dimensions, namely (1) knowledge regarding palliative care and its application, (2) knowledge regarding medical symptoms requiring palliative care in PLWHA and (3) knowledge regarding psychosocial needs requiring palliative care in PLWHA. The palliative care and application knowledge dimension consisted of seven items factored into three domains , the medical symptoms dimension consisted of 11 items factored into three domains  and the psychosocial dimension of 14 items in five domains . The respondents completed the questionnaire both pre- and post-intervention and the mean score in each domain for the three dimensions was calculated. Student\u2019s The structured intervention consisted of multiple interactive didactic sessions conducted over a period of 3 days by a team of faculty in the Department of Internal Medicine and the Department of Community Medicine. The content of the workshop was developed after the review of the existing curriculum and an assessment of the needs of the interns after a focus group discussion. The categories covered broadly included an overview of palliative care and its application to PLWHA, the shift from the divergence of palliative and curative care to an integrated continuum, the most common medical symptoms in PLWHA requiring medical care including pain and its management, fatigue and sleep disturbance, initiation of HAART and its adverse effects, delivery of palliative care, end of life care, nutritional and spiritual needs of the patient, social support, special needs in children and psychological symptoms. Post-intervention, the questionnaire was re-administered.P-values (Student\u2019s t-test).Statistical analysis was performed using PASW software version 18 (SPSS) and measures obtained were percentages, descriptives , box plots for data presentation and paired tests of significance and th percentile, median, 75th quartile and maximum score are depicted in the box plot. The median, represented by a square block, shows a consistent rise across the three dimensions on the pre- versus post-test after intervention.t-test was performed on the test scores on the individual dimensions and the score and the t-values are depicted in Tables t-test  on comparison with cumulative scores across pre- and post-test. Similarly, cumulative scores for the domains in the medical symptoms in PLWHA requiring palliative care dimension and psycho-social needs of PLWHA requiring palliative care dimension were obtained and the t-test was significant in both . The domains on the dimension of the medical symptoms in PLWHA requiring palliative care  and psycho-social needs of PLWHA requiring palliative care  all showed a consistent increase across mean scores.A Palliative care training in the undergraduate medical curriculum is loosely structured and ill defined in countries like USA7 and Indet al[A similar study by Velayudhan et al introducet al,[Palliative care needs in PLWHA have been evaluated in a study by Uwimana et al, in a quaet al[Easterbrook et al describeet al,[et al,[et al,[Billings et al, conductel,[et al, and Blocl,[et al, provide et al.[The trajectory of AIDS illness and the benefits of application of palliative care intervention at an early onset in disease progression to reduce the burden of AIDS epidemic were the focus of the study by Grady et al. The manaIn culmination, applying the principles, knowledge and recommendations gleaned through these studies and application of the intervention, initiatives and evaluation methods helped develop a rounded approach to the introduction of palliative care principles in medical interns targeted to PLWHA and the significant test results after comparison of pre- and post-intervention scores in the present study provides a framework for further development of a palliative care curriculum which is both beneficial to the medical interns and patients receiving their care.In spite of the unique challenges presented by the varying course of illness in PLWHA and the variety of needs on the medical, psychosocial and family dimensions, a structured approach and an integrated course curriculum involving principles of both primary and palliative care principles will improve the efficiency of the undergraduate medical education program and enable delivery of effective palliative care interventions and improve quality of life in PLWHA.The intervention and knowledge examination relied largely upon classroom methods of teaching and evaluation which form the core of the examination-oriented approach in medical education in India. A skill-based competency approach with involvement of simulated or real PLWHA and case-based studies will further help orient the approach toward an effective development of curriculum in future evaluations."}
{"text": "There was an error in the accession number in the Data Availability section of the Discussion. The correct accession number is IM-15154."}
{"text": "A funding organization and grant for the fifth author were incorrectly omitted from the Funding Statement. The following sentence should be read as the second sentence of the Funding Statement: \"Neha Koonjoo was supported by TRAILDNP from the public grant of the French 'Agence Nationale de la Recherche' within the context of the Investments for the Future Program, referenced ANR-10-LABX-57 and named TRAIL.\""}
{"text": "Infection-related preterm birth is a leading cause of infant mortality and morbidity; knowledge of bacterial populations invading the amniotic cavity and the routes of invasion is required to make progress in the prevention of preterm birth. Significant advances have been made in understanding bacterial communities in the vagina, but much less studied are intra-uterine bacterial populations during pregnancy. A systematic review of data published on the intra-uterine microbiome was performed; molecular information and summaries of species found in healthy individuals and in women with diagnosed infections served to construct a database and to analyse results to date. Thirteen studies fulfilled the review's inclusion criteria. The data of various investigations were collated, organized, and re-analyzed to achieve a more comprehensive understanding of microbial populations in the intra-amniotic space. The most common intra-amniotic bacterial taxa were species that can colonies the vagina in health and disease; there were others associated with the habitats of the mouth, gastrointestinal tract, and respiratory tract. The results suggest a central role for the ascending route of infections during pregnancy, and point to a possible secondary contribution via haematogenous invasion of the intra-amniotic space. The complete census of the intra-uterine microbiome awaits completion. Excluded were publications: (a) in a language other than English; and (b) that did not specify the type of microbes involved in the invasion of the amniotic space.Perusal of the selected papers and references therein yielded 13 papers containing information required for this review  presented with an intra-uterine infection. The use of non-culture direct-detection techniques has increased by ~5-fold the number of taxa known to be present in intrauterine infections during pregnancy.Meta-analyses of randomized trials evaluating antibiotic treatments report statistically significant prolongation of pregnancy associated with the use of antibiotics in women with preterm labor and intact membranes . Recognized genital pathogenic species were found at high frequencies, e.g., Ureaplasma uralyticum (11%), Streptococcus agalactiae (11%), Mycoplasma hominis (9%) and Fusobacterium nucleatum (9%)  women, and bacteria of the genus %) Table . Meta-an%) Table . This woListeria monocytogenes crosses the mucosal barrier of the intestine to disseminate haematogenously to any site, with a unique tendency to infect the fetoplacental unit  of giving premature birth to a child for mothers with periodontitis , determining differences in individual susceptibility, and identifying specific early-stage biomarkers that will allow the development of novel and timely intervention strategies.\u201d (Hussein et al., In the last 15 years, the significant progress made in the knowledge of the diversity of bacterial communities in the female genital tract and the role of bacterial infections in PTB wrought by novel sequencing techniques and bioinformatics tools, have made reduction of PTB a goal achievable by research directed toward prevention of BIAC by pathogens.Considering the limitations of studies based on bacterial cultivation to reveal all the microflora present, new comprehensive investigations employing non-culture methods and state-of-the-art sequencing analyses are required to establish the intra-uterine microbiome in health and disease. A complete census of the intra-uterine microbiota during pregnancy conducted concurrently with a census of the vaginal microbiome will serve to outline the characteristics of the bacterial communities in the female genital tract; in particular, the elucidation of the microbial intra-uterine populations in healthy pregnant women, as well as the contribution of ascending infections to BIAC.Future investigations that establish with more accuracy the bacterial taxa found in association with PTB, as well as their routes of invasion of the intra-amniotic cavity will provide important knowledge to support the development of earlier and more specific diagnostic methods of maternal genital infections. This will result in better targeted and more effective treatments, including many infections that presently are clinically silent and can cause significant morbidity in fetuses and infants. A full understanding of the female urogenital microbiome will render these infections amenable to intervention and will have an impact in the prevention of PTB.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The statistics of spikes in a neuronal network is constrained on one hand by the stimulus and shared noise, and on the other hand by neuron interactions and collective dynamics. The join spike statistics and its spatio-temporal correlations can be explicitly computed in conductance-based Integrate-and-Fire models ,2. The pMoreover, the dependence of spike statistics in network parameters such as synaptic weights and stimulus is explicit.Here, we address the following reverse engineering problem. Given a conductance-based Integrate-and-Fire model as above where the spike statistics dependence on synaptic weights is known, can one reconstruct this network of synaptic weights from the observation of a raster plot generated by the network ? We have solved this inverse problem using an explicit expression of a maximum likelihood estimator based on the Newton-Raphson method. This estimator employs analytically computed gradients and Hessian of the likelihood function given by the product of conditional probabilities. The explicit form of these conditional probabilities can be found in . Our resThis estimator is based on a plausible probabilistic model of spiking activity, and not a Poisson likelihood processing. So, it offers a flexible framework that should allow better statistical analysis of real data."}
{"text": "Most species of bat making echolocation use Doppler-shifted frequency of ultrasonic echo pulse to measure the velocity of target . To perfWe propose a network model for detecting the Doppler-shifted frequency . The modOur model reproduced well the two types of BF shifts and could explain systematically the neural mechanism underlying these BF shifts. We also showed that the DSCF neurons followed rapidly the frequency change of the moving target. The detection ability of DSCF neurons is due to a fast synaptic change of top-down connections from DSCF to IC neurons.We have presented a network model of the Doppler shifted frequency. The model well reproduced the two types of BF shifts observed by Xiao and Suga . The syn"}
{"text": "The Editor-in-Chief and the Medical Editors at BioMed Central have retracted this article  because"}
{"text": "In Donald O. Hebb's oft quoted thesis on synaptic plasticity, the change in efficacy in proportion to the degree of correlation between pre- and post-synaptic activity is expressed explicitly. The Hebbian learning rule has been demonstrated in simulations to be reliable and effective and appears to have a solid foundation in biology on the basis of experimental results. However, beyond binary simulation models of the Spike Timing Dependent Plasticity (STDP) rule, it has not been demonstrated that the causal correlation property of synaptic plasticity is as valid and as effective as always has been assumed.To clarify the exact nature of learning by means of spike timing dependent plasticity, a dynamic model has been developed based on the cross-correlation between pre- and post-synaptic activity as expressed by a dynamic activity measure. The components that form the model are centered around the following guiding principles. Firstly, the cross-correlation between local synaptic pre- and post-synaptic activity, as induced by the synapse itself in the post-synaptic cell, determines the strength of the potential for synaptic depression. Even though this may appear to be counter-intuitive, it reflects the depression due to pre-synaptic activity if little or no subsequent post-synaptic activity is present. The second component is the post-synaptic activity induced by the synapse locally. This represents the local response to synaptic input. The third component is the cross-correlation of the post-synaptic activity induced by the synapse with other post-synaptic activity contributing factors such as an action potential and other synapses. These three components form the autonomous learning rule from which Spike Timing Dependent Plasticity learning emerges. Due to the dynamic nature of the autonomous learning rule, it responds in a simple feed-forward manner to the synaptic input in combination to the localised post-synaptic activity. This precludes the need to perform spike matching and post-processing of the simulation and is more biologically relevant.The relation between the local dynamics of a single synapse and the localised dynamics due to post-synaptic activity becomes apparent by different emerging learning rules. The presence of action potentials and synaptic inhibition can change the shape of the STDP learning rule even to the extent that a Hebbian learning rule may become anti-Hebbian and vice versa. The synapse can respond to external input as well as compete with other synapses and tune itself to the local dendritic activity and the global neuronal activity.Synaptic adaptation due to the presence of nearby synapses and global activity has previously not been extensively studied. This work shows that synapses are not mere slaves to the input but perform more complex computations by combining the input with the local post-synaptic activity as well as the global dynamics due to other synapses and action potentials."}
{"text": "Open Medical Informatics Journal showcases a number of innovative and unique research approaches that highlight the current scope of socio-technical perspectives in the health informatics discipline. In just three short decades the discipline of health informatics has evolved from a primary focus on the \u201capplication of computers to all fields of medicine \u2013 medical care, medical education and medical research\u201d [This special socio-technical supplement of the esearch\u201d   to an iesearch\u201d . The incesearch\u201d -5. Reseaesearch\u201d .The papers in this supplement highlight how many of today\u2019s researchers have adopted a socio-technical focus as an established and credible methodology, not just for critiquing past mistakes, but for developing an understanding of key success factors in the development and implementation of new systems. The papers also show how researchers are using the basic concepts and multi-method socio-technical approaches, and applying these to a range of research situations. Chhanabhai and Holt demonstrate the universal relevance of socio-technical perspectives in their analysis of information and communications technologies in developing countries . The autThe authors contributing to this special edition also highlight the multi-disciplinary, interrelated character of health informatics. The papers by Borycki and Kushniruk , and CumContributors to this supplement also expand the focus of socio-technical systems research from interaction between clinicians and their systems to explore ways in which other users interact with information management systems. Cummings and Turner note that users of socio-technical systems are no longer restricted to health professionals and highlight the role of patients (or consumers) as important users in their own right . The incThe contributions to this supplement also point to links between the micro-environment of socio-technical systems and the macro-environment of power, politics and ethics. This is flagged by Chhanabhai and Holt who incorporate concepts of equality and empowerment into their discussion , while BThe final paper by Whetton and Georgiou  consider"}
{"text": "In a recent paper in this journal  with ion channels (major ingredients of the spike code) particularly in the nervous system.In recent experiments, microRNAs have been shown to modulate the subunit structure and the function of ion channels. In cardiac tissue microRNA expression regulates ion channel genes at the post-transcriptional level  and epigenetically regulates the expression of several genes, including those for the microRNAs (miRNAs) miR-148a, miR-152 that target DNMT-1  expression  methyltransferases in diabetic cardiomyocytes  are lengths of DNA that migrate between individuals even of different species  and within single cells (retrotransposons). We suggest that the exosome system may provide a route for this type of intercellular genetic communication."}
{"text": "The synaptic cleft is an extracellular domain that is capable of relaying a presynaptically received electrical signal by diffusive neurotransmitters to the postsynaptic membrane. The cleft is trans-synaptically bridged by ring-like shaped clusters of pre- and postsynaptically localized calcium-dependent adhesion proteins of the N-Cadherin type and is possibly the smallest intercircuit in nervous systems . The str"}
{"text": "Clean Care is Safer Care - and the strong focus of the diagnostic and biomedical industry on HAI prevention and the control of antimicrobial resistance (AMR).With the many changes in healthcare, the occurrence of new and emerging infectious diseases, and pandemic of novel resistance mechanisms, the prevention of healthcare-associated infections (HAI) has become increasingly important. Borders are disappearing - not only between different healthcare settings locally or nationally - but also between developed and resource-limited countries, thereby transforming the fight against HAI into a truly global challenge. This change is reflected by the World Health Organization's (WHO) choice of an infection control topic for the First Global Patient Safety Challenge - According to WHO, hundreds of millions of patients develop HAI every year worldwide and as many as 1.4 million occur each day in hospitals alone , but it Staphylococcus aureus (MRSA), became community pathogens (CA-MRSA) and even zoonotic pathogens with the emergence of livestock-associated (LA)-MRSA, thereby totally changing the epidemiology of MRSA. CA- and LA-MRSA even pose a serious challenge to the long admired \"search and destroy\" strategy. Many see the local or national prevalence of MRSA as a surrogate marker for the quality of infection control, and the increasing efforts of nations to address the challenge of ever-increasing MRSA rates seem to produce the right effect  are just a few examples of what we hope to cover.We are convinced that ARIC's choice of \"open-access\" is a logical step towards its goal to be truly international and to allow the transfer of knowledge and best practices to even remote places that cannot afford printed journals. We realize that open access has financial consequence for some authors and that the standard BioMed Central rules to waive article-processing charges may not be enough. BioMed Central provides an automatic waiver to authors based in any country classified by the World Bank as low-income or lower-middle-income economies, but we the online forum for sharing best practices, knowledge, and latest research with colleagues from around the world.We look forward to welcoming many papers and to developing this journal with your support into ARICAndreas Voss - Editor-in-Chief, ARICJan Kluytmans- Deputy Editor, ARICDidier Pittet - Executive Editor,"}
{"text": "Scant information exists about the time-course of events during withdrawal of life-sustaining treatment. We investigated the time required for end-of-life decisions, subsequent withdrawal of life-sustaining treatment and the time to death.Prospective, observational study in the ICU of a tertiary paediatric hospital.Data on 38 cases of withdrawal of life-sustaining treatment were recorded over a 12-month period (75% of PICU deaths). The time from the first discussion between medical staff and parents of the subject of withdrawal of life-sustaining treatment to parents and medical staff making the decision varied widely from immediate to 457 hours (19 days) with a median time of 67.8 hours (2.8 days). Large variations were subsequently also observed from the time of decision to actual commencement of the process ranging from 30 minutes to 47.3 hrs (2 days) with a median requirement of 4.7 hours. Death was apparent to staff at a median time of 10 minutes following withdrawal of life support varying from immediate to a maximum of 6.4 hours. Twenty-one per cent of children died more than 1 hour after withdrawal of treatment. Medical confirmation of death occurred at 0 to 35 minutes thereafter with the physician having left the bedside during withdrawal in 18 cases (48%) to attend other patients or to allow privacy for the family.Wide case-by-case variation in timeframes occurs at every step of the process of withdrawal of life-sustaining treatment until death. This knowledge may facilitate medical management, clinical leadership, guidance of parents and inform organ procurement after cardiac death. Withdrawal of life-sustaining treatment has become the predominant end-of-life scenario in children's hospitals in the developed world. A variety of studies over the last two decades have highlighted the intensive care setting as the central, and in some instances nearly exclusive, place for making life and death decisions within a modern children's hospital -5. AlthoIn this paper, we present the results of a 12-month prospective, observational study aiming to elucidate the time required for end-of-life decisions and subsequent withdrawal of life-sustaining treatment in an Australian paediatric intensive care unit.A prospective, observational study of deaths occurring in the Paediatric Intensive Care Unit (PICU) was conducted at the Royal Children's Hospital (RCH) Melbourne, Australia. The RCH is a 250-bed tertiary teaching hospital, which serves a population of approximately 6 million. The PICU is an 18-bed comprehensive intensive care facility admitting approximately 1400 children per year. It is engaged in the full spectrum of paediatric critical care including cardiac and trauma care.Information was obtained for deaths occurring during a period of 12 months (2007). Data collection for each case commenced when the decision to withdraw life-sustaining treatment had been taken by medical staff and parents. While retrospective information about the discussions regarding withdrawal of life-sustaining treatment had to be obtained from the medical record, all other data from that point on was collected contemporaneously. This involved one of the two researchers being either present at the time of withdrawal of life-sustaining treatment or collecting the data immediately afterwards, i.e. at the beginning of the following shift in case the researcher was not present when death occurred. Data collected included diagnostic category, age at the time of death, time of first discussion between medical staff and parents about withdrawal of life-support, time of the decision made by medical staff and parents to proceed with withdrawal, the initiation of withdrawal followed by the times of apparent and confirmed death. The term apparent death denotes the appearance of death to bedside personnel (physician or nurse) before confirmation by clinical examination. In addition, information was collected about presence of monitoring and staff during withdrawal of life-sustaining treatment. The data analysis excluded cases of withholding of life-sustaining treatment as varying levels and modes of life-support may continue to be provided to patients in this category in our unit. In contrast, withdrawal of life-support in our unit invariably entailed the discontinuation of all life-support .Numerical data was assumed to be non-parametric with calculation of median values and statement of minimum and maximum values. Data regarding the reasons for withdrawal of life-support, pharmacological management as well as number, occupation and seniority of staff present at the bedside was also obtained but is the subject of a separate paper. The research was approved by the RCH Ethics in Human Research Committee and written informed consent was not required for this observational study.Fifty-one deaths occurred in the PICU during the 12 months of the study. Forty children (78%) died following the decision to withdraw life-sustaining treatment while 5 (10%) died with some intensive care treatment being withheld. Six children (12%) died during resuscitation efforts. There was no case of confirmed brain death considered for organ donation. Complete datasets of 38 cases of withdrawal of life-sustaining treatment were recorded . Three cases involved the withdrawal of extracorporeal life-support  in addition to withdrawal of ventilation and inotropic infusions. Data of two cases were incomplete/unavailable. Distribution of age and diagnostic categories are displayed in table The timeframes for addressing the issue of a withdrawal of life-sustaining treatment varied widely Table . SimilarIn the vast majority of cases  all monitoring had been discontinued for withdrawal of life-sustaining treatment. Full monitoring  had been continued in 2 cases and one case was managed with ongoing pulse oximetry only.The proportion of cases of withdrawal of life-sustaining treatment among all unit deaths in our study is, at 78%, considerably larger than the percentages reported from other institutions. Studies from North America and the United Kingdom have described the percentage of withdrawal of treatment among the overall unit death rate between 60% and 65% ,12 whileThe nature of withdrawal of life-sustaining treatment prevents its study in randomised, controlled trials. Being observational and, as a study in a field with low mortality, inevitably being limited in the number of cases, our data must not be overinterpreted. The data is descriptive and merely depicts current clinical practice. Timeframes therefore should not be interpreted as benchmarks but instead observed as variables warranting examination and subject to a multitude of confounders, which are beyond control in this setting. The design of our study therefore strongly cautions against aiming to find correlations between the data. Its purpose was rather to facilitate understanding of a complex area of clinical practice by assembling a comprehensive picture of what until now has existed as fragmented pieces of data, records and subjective experience.Nonetheless, having been conducted in a predominantly prospective, contemporaneous fashion, the study accurately describes current time-courses and clinical practice in a large, tertiary PICU. The data show extreme case-by-case variations in time at every step of the withdrawal process until death. Time-related information regarding the decision-making process is currently not available in the literature. Garros and colleagues, in a prospective survey, reported slightly less than half of end-of-life discussions requiring two or more meetings between the family and medical staff . Our datWith regards to the dying process, other reports had previously described approximate timeframes for the end of life based on retrospective studies. McCallum and colleagues recorded a timeframe from making a Do-Not-Resuscitate order to death of less than 24 hours  while GaThis notwithstanding, our prospective data confirm Zawistowski's finding that most children die within the first hour after withdrawal of life-sustaining treatment. Our data do, however, also show that this broad conclusion needs to be further qualified as some children die instantly following the withdrawal of treatment while, importantly, there also exists a great variation in the time to death. With a median time of 0.28 hours from withdrawal of treatment to confirmed death, the dying process occurred within less than 20 minutes in most children but took longer in just under half the cases. Most importantly, our data again provide evidence of considerable variations in timeframes from withdrawal of life-sustaining treatment to death. The relatively small number of cases and the variety of confounders in a non-controlled study setting prohibit correlating diagnosis or level of intensive care support with a time-course following withdrawal. Clinical acumen and intuition, on the other hand, have in the past been proven inaccurate in similar circumstances for more homogenous patient populations . It is rFor the doctor and nurse at the bedside, knowledge of this fact will be essential for planning the withdrawal process and the care for the child at the end of life. This will not only pertain to logistics and a pharmacological management plan but also to defining roles, duties and boundaries during what will be a process of unknown duration. Preparing the family for the dying process that is unpredictable in time may then help to guide parents and relatives during agonizing moments for which few will have points of reference. This may indeed offer an opportunity to prevent increasing anguish if the end of life is drawn out and give the family a better chance to cherish the last moments with their dying child.Another layer of complexity is added to the end of life if organ donation after cardiac death (DCD) is considered. Current guidelines in Australia and New Zealand acknowledge the fact that time to death is unpredictable yet fail to address the practicalities of this circumstance . In the There is a wide case-by-case variation in timeframes at every step of the process of withdrawal of life-sustaining treatment. Understanding the time-course of events in this important area of paediatric intensive care is essential for providing high-quality medical management, clinical leadership and guidance to parents at a most challenging time. The unpredictability and considerable variation in time to death may constitute a noteworthy challenge for accomplishing organ procurement after cardiac death.DCD: Donation after Cardiac Death; ECMO: Extracorporeal Membrane Oxygenation; LVAD: Left Ventricular Assist Device; PICU: Paediatric Intensive Care Unit; RCH: The Royal Children's Hospital.JT declares that he has no competing interests. FO is affiliated with DonateLife Victoria.JT and FO jointly designed and conducted the study which had been conceived by JT. FO created the database, analysed as well as interpreted the data and drafted the article. JT and FO jointly revised the article. Both authors provided intellectual content of critical importance to this project and gave their final approval of this version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/11/39/prepub"}
{"text": "Gene-environment interactions have long been recognized as a fundamental concept in evolutionary, quantitative, and medical genetics. In the genomics era, study of how environment and genome interact to shape gene expression variation is relevant to understanding the genetic architecture of complex phenotypes. While genetic analysis of gene expression variation focused on main effects, little is known about the extent of interaction effects implicating regulatory variants and their consequences on transcriptional variation. Here we survey the current state of the concept of transcriptional gene-environment interactions and discuss its utility for mapping disease phenotypes in light of the insights gained from genome-wide association studies of gene expression. The presence and magnitude of quantitative interaction depends on several factors including the scale on which the phenotype is measured, how the \u201cgenotypic effect\u201d is considered and the statistical approach adopted (Thompson, Here we refer to gene-environment interactions as the differential effect of a given genotype exposed to different environmental conditions Figure . These iVarious statistical approaches including linear regression (to test for a linear trend, where heterozygotes are intermediate in phenotype owing to additive allelic effects, see Figure Caenorhabditis elegans recombinant inbred strains derived from parental lines collected in the UK and Hawaii. This work documented that no less than 59% of 308 trans-acting and 8% of an estimated 188 cis-acting genes showed a significant eQTL-by-environment interaction. Landry et al. (cis-eQTLs shown to be more stable across conditions while trans-eQTLs were predominantly condition-dependent. On the other hand, a study investigating olfactory behavior in Drosophila melanogaster showed that 50% of variation in this trait was attributable to gene-environment interactions and reported 20 transcriptional gene-environment interactions albeit in whole flies and using a relaxed statistical significance threshold (Sambandan et al., Transcript abundance, like any other quantitative trait, is the product of genotype, environment, and interaction effects. In contrast to the tremendous progress made in documenting main environmental and genotypic effects, systematic genome-wide surveys of transcriptional genotype-environment effects are scarce with the first notable findings reported for model organisms (Li et al., y et al.  investigy et al. . Furthera priori expectation for the number of transcriptional gene-environment interactions under the scenario of large gene-environment interaction effect on a given phenotype but this would depend largely on the genetic architecture of the phenotype in question. In an extreme example, if the trait depends heavily on expression of a single gene a gene-environment interaction at a single regulatory polymorphism with large effect on that gene could explain most of the gene-environment interaction effects on the trait. The notable success in detecting transcriptional gene-environment interactions in microorganisms is primarily a consequence of the tight link in time and space between transcript abundance and the environmental factors investigated. The contrasting findings on the extent of transcriptional gene-environment interactions that have been reported can be due to several reasons including the complexity of architecture of the genetic basis of the expression traits, species-specific patterns of gene expression regulation, and differences in the exposure under investigation.There is no trans-acting factors to be responsible for widespread transcriptional response to irradiation. Others reported dozens of interaction effects in response to pro-inflammatory oxidized phospholipids (Romanoski et al., Mycobacterium tuberculosis infection (Barreiro et al., in vitro experiments where homogenous cell populations are investigated and transcriptional response deliberately altered provide increased power to detect interaction effects as effect sizes become more pronounced and readily detectable using modest sample sizes. Nonetheless these experiments rely heavily on prior knowledge about the cell type relevant to the treatment in question.The literature on the topic of transcriptional gene-environment interactions in humans is slim with most of the comprehensive studies documenting genotype-treatment interactions Table . The firin vivo. However the system is made up of over a dozen cell types and overall profile differences are due to the joint contributions of variable cell fractions, and variable expression within cells. For instance, Fairfax et al. (in vivo in human transcriptomes have also been conducted. A study investigated differences in the pattern and strength of genotype-expression association in fresh human transcriptomes across groups sampled from different geographic locations suggested the presence of several interaction effects beneath genome-wide significance but no genome-wide significant interactions were reported likely due to lack of power (Idaghdour et al., Plasmodium falciparum infection (Idaghdour et al., Interaction effects can also be investigated in tissues with a heterogeneous cell composition but robust statistical analysis is required to tease apart true effects from those reflecting differential cell proportions between the groups contrasted (Emilsson et al., x et al.  characteIt is worth noting that studies mapping interaction effects vary widely in their methodologies, statistical approach, and the significance threshold applied to call interactions and there is a pressing need for a clear formulation of the concept of \u201ctranscriptional gene-environment interaction\u201d so that published findings can be reliably contrasted. The issue of dependence of the definition of interaction on the scale at which the trait is measured is of particular importance here, given that the first phase of the analysis of gene expression datasets involves normalization that can influence biological inference as evidenced by a systematic evaluation of the effect of nine different normalization strategies on various aspects of statistical inference including eSNP analysis (Qin et al., A major challenge for GWAS in general is that of power and the problem of multiple testing. This caveat is more pronounced for the discovery of interaction effects particularly when testing interactions with multiple environmental factors and given the high dimensionality of the data and the fact that in general detecting an interaction requires at least a fourfold larger sample size than does a main effect of comparable magnitude (Smith and Day, We argue that efforts to detect genuine gene-environment interactions in humans are more likely to be fruitful when using integrative approaches that capitalize on the advantages and power gained from the use of endophenotypes. These efforts will certainly be enhanced as more cohort studies and population-based biobanks turn their attention to deep endophenotyping (Awadalla et al., Knowledge of gene-environment interactions in humans holds the promise to enhance our understanding of the etiology of disease but also highlights the need to address several issues and questions related to this phenomenon. For example, the relationship between gene-environment interactions at the transcriptional level and at the disease level is a subject that warrants investigation. Unraveling these relationships in humans will be challenging given the extent of biological complexity of the black box between genotype and phenotype. Presumably transcriptional changes might be silent and do not result in phenotypic change. Distinct transcription profiles might also converge and yield similar phenotypes as well as the possibility that mechanisms of post-transcriptional regulation may account for buffering transcriptional variation and therefore break the otherwise statistically significant associations between gene expression levels and higher-level phenotypes. Furthermore, the generality of transcriptional genotype-environment interactions across multiple loci, particularly those involved in the etiology of disease, would cause a major hurdle for the identification of disease variants and might account for some of the failures of replication of associations where main genotype effects are estimated over a constellation of conditions represented in a study as is the case in GWAS.In conclusion, the insight that is coming out of the fields of quantitative genetics and epidemiology is the appreciation of the role gene-environmental interactions play in shaping disease phenotypes. However, robust demonstrations of these effects in humans are scarce. Genome-wide association studies of gene expression in various tissues and populations have opened up the opportunity to track and discover these effects in the transcriptome and to shift from focusing solely on main genotypic effects. The evidence in the literature of the prevalence of such effects in the human transcriptome is increasing, but these studies are still in their infancy and need to be extended to scenarios where regulatory variation is expected to depend on environmental triggers. It will also be interesting to explore and expand on these studies to see if the epigenome is subject to interaction effects (Cortessis et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The potential for unintended consequences of the spread of foreign genes  and of pleiotropic effects following transgene expression may be enhanced in long-lived forest trees. The COST Action FP0905 will focus on four key aspects related to the biosafety of genetically modified trees (GMTs): (a) analyses of the efficiency of existing gene containment strategies to avoid or if not possible to minimize gene flow; (b) facilitate efforts to develop site-specific integration of transgenes in tree genomes to minimize variability of transgene expression and pleiotropic effects, (c) evaluate possible methods to monitor GMTs in the whole production chain, and (d) conduct socio-economic and cost/benefit analyses in relation to the use of GMTs in plantations.Populus spp., Pinus spp., Eucalyptus spp., Betula spp., Castanea spp., Picea spp., etc.) as well as extensive expertise in correlated topics. The information gained should contribute to strengthen the scientific basis for the execution of the EU policy directives related to transgenic trees intended for cultivation in Europe. The main objective of the COST Action is to evaluate and substantiate the scientific knowledge relevant for GMT biosafety protocols by putting together already existing information generated in various European and Non-EU countries as basis for future EU policy and regulation for the environmental impact assessment and the safe development and practical use of GMTs.This Action combines multidisciplinary knowledge generated with transgenic lines of different forest genera  to implement collaboration of scientists.WG 1 - Biological characterization of GMTs: to characterize the GMTs in respect to their genetic and phenotypic features relevant for gene flow, gene containment and gene targeting.WG 2 - Environmental impact assessment and monitoring of GMTs in the whole production chain from plantation to final products: to study environmental risk assessment strategies and monitoring the GMTs along the whole production chain.WG 3 - Socio-economic implications of and recommendations for the use of GMTs: to make socio-economics analyses of the use of GMTs considering the concerns and acceptance by the public, the economic potential for GMTs and R&D efforts to be invested, as well as cost/benefit analyses, and propose recommendations for the use of GMTs.WG 4 - Management of intranet - internet websites and dissemination: through a website (www.cost-action-fp0905.eu), provide science-based information and increase public awareness in the utilization of GMTs in forest plantation and at the same time safeguarding the environmentThe knowledge gained will be summarised in a book as a final output of this Action which will report the state of art of knowledge and research on GMTs with suggestion on how to effectively implement present EU directives on GMO considering the problematic of forest trees and their environmental impacts.The Action started the 12th of April 2010 and it will end the 11th of April 2014. Actually, 23 COST countries  have signed the Memorandum of Understanding (MoU). Seven NON-COST countries  are participating to the Action.With integration of all the countries listed above, the EU COST Action FP0905 is expected to generate important benefits as it also foresees a strong collaboration among R&D bodies and legislative directives. This kind of collaboration will be fundamental, on the one hand, to address policy-making efforts and, on the other hand, to allow the scientific community to discuss to public concerns in a responsible way, particularly concerning socio-economic implications and biosafety issues of transgenic tree plantations."}
{"text": "How the visual system combines information from the two eyes to form a unitary binocular representation of the external world is a fundamental question in vision science that has been the focus of many psychophysical and physiological investigations. Ding & Sperling (2006) measured perceived phase of the cyclopean image, and developed a binocular combination model in which each eye exerts gain control on the other eye's signal and over the other eye's gain control. Critically, the relative phase of the monocular sine-waves plays a central role.We used the Ding-Sperling paradigm but measured both the perceived contrast and phase of cyclopean images in three hundred and eighty combinations of base contrast, interocular contrast ratio, eye origin of the probe, and interocular phase difference. We found that the perceived contrast of the cyclopean image was independent of the relative phase of the two monocular gratings, although the perceived phase depended on the relative phase and contrast ratio of the monocular images. We developed a new multi-pathway contrast-gain control model (MCM) that elaborates the Ding-Sperling binocular combination model in two ways: (1) phase and contrast of the cyclopean images are computed in separate pathways, although with shared cross-eye contrast-gain control; and (2) phase-independent local energy from the two monocular images are used in binocular contrast combination. With three free parameters, the model yielded an excellent account of data from all the experimental conditions.Binocular phase combination depends on the relative phase and contrast ratio of the monocular images but binocular contrast combination is phase-invariant. Our findings suggest the involvement of at least two separate pathways in binocular combination. We see the world with two eyes. It is remarkable that, most of the time, we perceive a single image of the world despite each eye having its own unique retinal image both phase and contrast from different monocular spatial patterns. We found that, surprisingly, the perceived contrast of cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. We propose a new multi-pathway contrast-gain control model (MCM) of binocular combination.Ding and Sperling We elaborated the Ding-Sperling binocular combination paradigm to measure both the perceived phase and contrast of the cyclopean percept. A stereoscope was used to present three sine-wave gratings to the observer in each trial : two tesThe perceived phase In To better illustrate the phase-independent property of perceived contrast in binocular contrast combination, we re-plotted the average perceived contrast of the four observers as functions of the phase-shift between the two monocular test gratings . Indeed,re equal .We can also evaluate whether two eyes are \u201cbetter\u201d than one. The average  normalized perceived contrast, defined as the contrast of the matched probe grating divided by the base contrast of each condition, is plotted in To control for potential contamination of high spatial frequencies presented in the edges of the sine-wave gratings In summary, we found that the perceived contrast of the cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. The findings of contrast-dependent phase combination and phase-independent contrast combination suggest that at least two separate pathways are involved in binocular combination. The new results require a reconsideration of existing binocular combination models.We elaborated the Ding-Sperling model, originally developed and successfully applied to model binocular phase combination, to develop a new multi-pathway contrast-gain control model MCM, . In the The MCM model successfully accounted for 99.4% and 98.7% of the variance in perceived phase and contrast of the cyclopean images for the average observer, with goodness of fit ranging from 98.9% to 99.6% for binocular phase combination and 96.5% to 99.3% for contrast combination for individual observers . The MCMIn this study, we elaborated the Ding-Sperling paradigm to measure both the perceived phase and contrast of the cyclopean images generated by binocular combination of two monocular sine-wave gratings. We found that the perceived contrast of cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. The findings of contrast-dependent phase combination and phase-independent contrast combination suggest the involvement of at least two separate pathways in binocular combination. We developed a multi-pathway contrast-gain control model (MCM) of binocular combination to account for our empirical results.Most previous studies on binocular combination have investigated how two identical monocular images combine The idea of multiple pathways for binocular combination is also consistent with physiological findings. There are both simple and complex cells in primary visual cortex In this study, we investigated the appearance of the cyclopean images from supra-threshold binocular contrast combination of monocular sine-wave gratings with relative phase-shifts up to 90 deg. We didn't study larger phase difference because of binocular rivalry in those conditions. It would be necessary to further test if the MCM can be used to model phenomena in near threshold conditions because appearance and contrast detection/discrimination may be computed in separate pathways Our results support at least two separate pathways, phase and contrast combination, in the MCM. The MCM has already provided an important theoretical framework in elucidating binocular deficits in amblyopia Four adult observers (22-28 yrs old), with normal or corrected-to-normal vision and na\u00efve to the purpose of the experiment, participated in the study with written informed consent. The research protocol was approved by the Ethics Committee of the University of Science and Technology of China.http://lobes.usc.edu/videoswitcher.html) was used to combine two 8-bit output channels of the video card to yield 14-bit gray-scale levels All stimuli were generated by a PC computer running Matlab  with PsychToolBox 2.54 extensions 2  was applied to the left and right edges of the gratings to blend the stimuli into the background. All other settings and procedures are stayed the same.2) and high-contrast frames  with diagonal bars  in both eyes. The high-contrast frames remained on the screen during the entire experiment to assist observers to fuse the images from the two eyes. After achieving correct fusion, the observer pressed the space bar on the computer keyboard to initiate the presentation of the three sine-wave gratings: two test gratings on the left side of fixation, and a probe grating on the right side of fixation, with the initial contrast and phase of the probe grating set randomly. Observers were required to adjust the contrast and phase of the probe grating to match those of the cyclopean image on the left. They were free to select which dimension to adjust first and to go back and forth on them, and pressed the \u2018Enter\u2019 key twice to report the results after they were satisfied with the match in both dimensions. Inter-trial interval of 1 second was provided. A typical trial lasted about 10 seconds.Each trial began with a fixation display consisting of fixation crosses Click here for additional data file."}
{"text": "Health educators need rigorously developed instruments to evaluate cognitive skills relating to evidence based practice (EBP). Previous EBP evaluation instruments have focused on the acquisition and appraisal of the evidence and are largely based in the medical profession. The aim of this study was to develop and validate an EBP evaluation instrument to assess EBP cognitive skills for entry-level health professional disciplines.The Fresno test of competence in evidence based medicine was considered in the development of the 'Knowledge of Research Evidence Competencies' instrument (K-REC). The K-REC was reviewed for content validity. Two cohorts of entry-level students were recruited for the pilot study, those who had been exposed to EBP training , and who had not been exposed to EBP training . The K-REC was administered to one cohort of students (n = 24) on two testing occasions to evaluate test-retest reliability. Two raters independently scored the first test occasion (n = 24) to evaluate the inter-rater reliability of the marking guidelines. Construct validity was assessed by comparison of the two groups, 'exposed' and 'non-exposed', and the percentage of students achieving a 'pass' score in each of these groups. Item difficulty was established.p < 0.0001) difference in the total K-REC scores. The test-retest and inter-rater reliability of the individual items and total scores ranged from moderate to excellent .Among the 100 participants , there was a statistically significant (The K-REC instrument is a valid and reliable evaluation instrument of cognitive skills of EBP in entry-level student health professionals. The instrument is quick to disseminate and easy to score, making it a suitable instrument for health educators to employ to evaluate students' knowledge of EBP or in the evaluation of entry-level EBP training. The most widely accepted definition of evidence based practice (EBP) involves three components: the integration of the best research evidence with patient values and clinical expertise . EvidencIt has been proposed that EBP consists of a five step process ,5,6. PreA previous systematic review  identifiA further 10 instruments evaluating cognitive EBP skills have been published since the 2006  systematp < 0.0001) [At the time of the current study 2008), the instrument developed in this study, the 'Knowledge of Research Evidence Competencies' instrument (K-REC) was the first known tool prospectively designed to collect data on cognitive EBP skills of entry-level allied health students. Since the initial literature search and development of the K-REC, two further instruments have been published that evaluated cognitive skills of EBP in the allied health disciplines 08, the i. The 'Ad 0.0001) .While the Fresno test has been recognised as the current best available instrument to comprehensively assess cognitive skills of EBP , the insDue to the focus of this study on the assessment of entry-level education (novice rather than postgraduate learners or clinicians), the instrument was intended to evaluate the first three fundamental steps of the EBP process model , rather than assessment of the fourth step involving the application of knowledge and skills in clinical practice. The aim of this study was to develop an instrument to evaluate entry-level respondents' cognitive skills regarding the research evidence component of EBP that:\u2022 could be used across the health professions;\u2022 was quick to complete and easy to score; and\u2022 was underpinned by a transparent and defensible psychometric testing process.The development of the instrument was completed in two stages. The first stage involved the development of the instrument and the second stage comprised the processes used to psychometrically evaluate the instrument.Ethical approval for the study was obtained from the University of South Australia Human Research Ethics Committee (protocol number P067/08).Firstly, the research team considered the content of the Fresno test in the drafting of the instrument. The first seven items of the Fresno test were relevant for application to health professions external to medicine and were considered in the development of the K-REC instrument. The remaining Fresno items (8-12) involved advanced statistical calculations , and questions about diagnosis and prognosis. While these skills are pertinent to all health professions, the instrument was intended for use with entry-level health professional students with varying degrees of exposure to EBP education (novice learners rather than graduates of professions). Therefore, a choice to focus on what might reasonably be expected to be taught generically across a range of degrees/stages of programs and across disciplines was required. In both forms of the modified Fresno test ,21, the One clinical scenario template was designed for the K-REC, with specific inclusion of each of the PICO components. The clinical scenario needed to be relevant to a variety of health professional disciplines and was therefore deliberately designed around the topic of a chronic condition (cystic fibrosis) and two possible types of intervention for this condition. The interventions included in the scenario (exercise and breathing exercises) were intentionally chosen to be understood by a number of health professional disciplines .Given the time and scoring related limitations of the Fresno test, the K-REC was designed to be relatively quick for respondents to complete and easy to score. The K-REC therefore consisted of a combination of short answer, multiple choice and true/false type questions rather than conforming to the open ended short essay answer style of the Fresno test. The final draft of the K-REC instrument was distributed to three senior academics with expertise in research methods and EBP and two entry-level physiotherapy students at the University of South Australia to review the clarity and formatting of the items and instructions. The instrument underwent three rounds of review and minor revision to the wording, instructions and layout of the instrument.entry-level respondents' cognitive skills regarding the research evidence component of EBP. The instrument therefore covered the first three steps of the five step EBP process model relevant to cognitive skill , but did not consider the last two steps involving the application of evidence into practice (APPLY and ASSESS) [The K-REC instrument was designed to evaluate cognitive skills of EBP, with a combination of items evaluating either knowledge, or skills in the application of knowledge . The K-REC instrument was intended to assess  ASSESS) . The finThe 'correct' answers for each item of the K-REC were determined through review of the Fresno test, and consultation and consensus of the research team and senior academics during the development procedure. The two open-ended items (1 and 7) were scored according to the presence or absence of set criteria. For item one, respondents were allocated half a mark for each of the PICO  components provided in their question. In item seven, respondents were required to list four characteristics of randomised controlled trials that would increase their confidence that the research was methodologically sound. Half a mark was awarded for any characteristic that was consistent with the Physiotherapy Evidence Database (PEDro) scale  which isThe aims of Stage 2 of the instrument development process were to explore the practicalities of the survey process , establish test-retest and inter-rater reliability, investigate the validity of the K-REC, and seek informal feedback from the participants about the appearance, layout and general user friendliness of the instrument.The recruitment strategy aimed to enlist two main types of participants:Exposed': participants who were representative of the target population for the K-REC and who could be reasonably expected to have a good understanding of EBP through exposure to formal EBP training, and,\u2022 'Non-exposed': participants who could be reasonably expected to have minimal understanding of EBP through minimal or no exposure to formal EBP training.\u2022 'Third year physiotherapy students (n = 24) were invited to participate as the 'exposed' group. At the time of the study (2008), these students had completed either a mandatory stand-alone EBP course (13 weeks) or an Honours research preparation course (2 weeks and ongoing supervision within a research team) where they were taught and assessed on the different components of EBP. Therefore, these students had prior exposure to formal training and were expected to have a foundation knowledge and understanding of EBP.Human movement students (n = 89) were invited to participate as the 'non-exposed group'. Rather than compare first and third year students from the same professional discipline (physiotherapy), human movement students were selected as they would have been exposed to similar information technology literacy  and were at the same time point in their entry-level programs as the physiotherapy students (third year). The human movement students were expected to have minimal knowledge of EBP, as at the time of the study these students were not required to enroll or be assessed in any EBP or research training course and were therefore not exposed to any formal standardised EBP or research instruction.The entire group of 24 physiotherapy students was invited to complete the K-REC instrument at a face to face class. Students were requested to write their student identification number on the survey to be used to match the second round of surveys (test-retest). A second administration to the participating physiotherapy students (n = 24) was completed three days after the first testing occasion. The completed surveys from the first testing occasion (n = 24) were independently scored by two raters to establish the inter-rater reliability of the instrument. In order to establish the discriminative validity of the K-REC, the 'non-exposed' cohort of human movement (n = 89) students were invited to participate at a face to face class. The mean item and total K-REC scores of each of the student groups ('exposed' and 'non-exposed') were compared to establish discriminant validity.Test-retest and inter-rater reliability was assessed by using the intraclass correlation coefficient (ICC) for items with interval data or those with ordinal data where the intervals between measurements were assumed as equivalent . The reliability of the remaining items was assessed using Cohen's Kappa coefficient (un-weighted) for categorical data  and percentage agreement (items 1 and 3). Agreement of less than 0.50 was classified as poor, between 0.50 and 0.75 as moderate, and greater than 0.75 was classified as a good level of reliability .Discriminative validity was assessed by comparison of the individual item and total scores from the two student groups (human movement and physiotherapy) with calculation of unpaired t tests, and the z-test for comparing proportions (two-tailed) for the differences between the percentage of students achieving a pass (\u2265 50% score) mark for each of the survey items in both student groups . ProbabiThe K-REC achieved an overall response rate of 88 per cent . The average completion time for the K-REC was approximately 10 minutes.All K-REC items and the total score achieved a moderate level of test-retest reliability or above Table . All parp < 0.0001) in the mean total K-REC scores between the 'exposed' and 'non-exposed' students.Discriminative validity of the K-REC was determined by the comparison of two student groups, one group with prior exposure to EBP training (expected to have an understanding of EBP process), and one group with no prior exposure to formal EBP training . The results of the total and individual survey item scores of the K-REC for both groups are shown in Table Considering the mean scores of each group of students for each K-REC item, for nine out of 10 (item eight has two sections which were considered separately) instrument items a higher proportion of 'exposed' than 'non-exposed' students passed. A z-test for comparing proportions (two-tailed) was performed to investigate the differences between the groups resulting in a statistically significant difference between groups for seven of the 10 instrument items Table .The values presented in Table The K-REC met the basic psychometric requirements for reliability, validity and usability of a standard instrument for collecting data on respondents' cognitive skills of EBP. The information gained through testing the instrument on two health professional discipline areas at one institution suggests that if the instrument is disseminated in a similar fashion, a reasonable response rate should be achieved.There are a variety of instruments available to assess EBP cognitive skills, some of which have been demonstrated to discriminate between novice and expert learners. The issue with pre-existing tools is that for novice learners, the relevance of the scenario questions and a floor effect is likely to be the issue especially with entry-level students in the early years of their programs. The K-REC instrument was designed to assess the cognitive EBP skills of novice learners (entry-level students) irrespective of their professional discipline. That is, the anticipated target audience of this instrument was predominantly entry-level health professional students, who could range from pre-novice , novice and intermediate EBP learners. While the K-REC could be used for expert learners, we suspect that a ceiling effect is likely to occur which may make it a useful tool for comparison between participants of varying EBP exposure but it is likely to be insensitive to change in EBP experts .The K-REC differed from existing instruments in terms of design, length, content and psychometric properties. The K-REC contains a clinical scenario template that may be relevant to a variety of health professional disciplines and individual items relating to the scenario. The K-REC therefore has the potential to be applicable to a variety of health disciplines, rather than being specific to one discipline. In contrast to the original Fresno test , and twop < 0.001, effect size 1.13). When comparing the psychometric properties of the K-REC to the other two instruments developed for allied health  or professional discipline versus optional, advanced or profession specific knowledge. This might explain why there is such a profusion of derivative instruments from the original Fresno test which modify, exclude or add items concerning statistical concepts, scenarios relevant to various professional groups, or focus upon questions of intervention rather than giving equal weight to questions of prognosis or diagnosis. Where instruments have been developed to assess the learning outcomes of specific EBP training courses, it is likely that the key items included within the assessment are reflected within the specific EBP education program. For example, the content of the Fresno test [Developers of instruments assessing EBP knowledge face a number of philosophical and practical issues. While the Sicily Statement clearly conveys the five fundamental steps of EBP, no similar consensus statements exist to guide which specific knowledge and skills might be considered essential to sno test  was desisno test  was devep value, effect size and confidence intervals) and questions relating to intervention (rather than prognosis/diagnosis).While it is clear that entry-level students should be able to critically analyse and evaluate the usefulness of research in disciplines such as physiotherapy and occupational therapy ,27, therAn additional issue concerning development of EBP evaluation instruments is whether the instrument is intended for repeated use with the same group of participants (eg pre and post EBP training). Where the identical instrument is used on repeated occasions with the same group, concerns arise over respondent familiarity with the items and expected answers. In a number of instruments, provision has been made for alternate items to be used on repeated occasions . The clinical scenario for a question of intervention developed for the K-REC was intended to comprise a template where the specific condition, intervention, comparator and outcome could be modified without altering the intent of the questions relating to the scenario . For example, the PICO components relevant in the scenario included within this tested version of the K-REC were:16 year old girl who has cystic fibrosis (POPULATION) and she has recently been admitted to hospital with a chest infection. Jane normally self treats at home with breathing exercises (INTERVENTION) taught to her by a physiotherapist. One of her friends also has cystic fibrosis (POPULATION) but she treats herself with exercise (COMPARATOR), not breathing exercises. Jane wants to know whether her lung condition (OUTCOME) would be more effectively managed with an exercise program. You have no experience of either breathing exercises or exercise programs for cystic fibrosis and are not sure what to recommend.\"\"Jane is a This scenario could be modified to be relevant to any health professional discipline by altering the PICO components, for example, based on one of the clinical scenarios within the AFT , the sce16 year old girl who has a traumatic brain injury (POPULATION), currently completing her final year exams and referred to you for memory rehabilitation. Jane has a number of usual strategies (INTERVENTION) but one of her friends also has had a traumatic brain injury (POPULATION) but she manages her memory issues with a diary (COMPARATOR). Jane wants to know whether she would function better at school (OUTCOME) with a diary. You have no experience of the usual strategies or diaries for memory problems in traumatic brain injury and are not sure what to recommend.\"\"Jane is a When the K-REC instrument with the above alternate clinical scenario was completed by a sample of entry-level physiotherapy students (n = 15), the inter-rater reliability of the marking guidelines remained high . The K-REC currently consists of a clinical scenario template, with two 'tested' scenarios. If the instrument were to be applied longitudinally, it would be necessary to develop and test a 'bank' of alternate clinical scenarios. While the option is there for users of the K-REC instrument to modify the clinical scenario template to suit various health professional disciplines, it is important to note that any modified scenario would need to be tested appropriately. It is also worth considering that the clinical scenarios contained in the original Fresno test, two modified versions and the instrument developed in the current study were all based on intervention style questions. The Centre of Evidence Based Medicine Levels of Evidence  currentlIt is possible that the three days between test occasions resulted in a degree of respondent familiarity with the items in the K-REC instrument for the test-retest reliability testing. The choice of how long to wait before retesting knowledge items requires a trade-off between the likelihood of participant recall and learning. In test-retest situations where the intent is to determine stability of respondent's answers, a longer duration is likely to reduce the potential for participants to simply recall the answers they provided during the first test occasion but increases the possibility of ongoing learning of the specific knowledge concepts included in the original test. In the current study, participants were university students currently engaged in courses where it was likely that there would be ongoing exposure to EBP principles and knowledge. The choice of a shorter period between test occasions was selected as a compromise between recall and learning.The predominant multiple choice question design of the K-REC has both advantages and disadvantages. By providing a list of possible answers, it may encourage respondents to complete the question (rather than omit the question) due to the fact that the 'correct' answer is somewhere in the list of options. The answers in the list may also act to prompt respondents if they are unsure or having difficulty remembering the answer to a particular question. It is possible that if the same items were designed as 'fill in the blank' type questions, respondents may be less likely to guess the answer. It is not possible to know from the data collected in this study whether respondents were influenced by the provision of answers in the multiple choice items in the K-REC.The items in the K-REC that related to the second step of the EBP process (ACQUIRE) did not discriminate between the groups with differing exposures to formal EBP training . The ability to effectively search the literature is an essential step in the EBP process . IdentifThe K-REC instrument was designed to evaluate the EBP cognitive skills of novice learners . It was therefore appropriate that the testing of the instrument compared the two extremes that could be present in entry-level training of health professionals, that is, those with no exposure to formal EBP training versus those with exposure to formal EBP training. While comparisons between novice, intermediate and expert learners would be useful to undertake with the K-REC instrument, it is unknown whether a ceiling effect might exist for the expert group, rendering this instrument inappropriate for this group.The Sicily Consensus Statement on EBP  highlighPrevious EBP instruments have most commonly contained items evaluating the 'ACQUIRE' and 'APPRAISE' steps of EBP . The tenThe K-REC instrument captures cognitive EBP skills relating to the first three steps of the five step EBP process model . The instrument has demonstrated very good reliability, and the validity findings show promise in the application of the instrument for evaluating change at an undergraduate health professional level.The authors declare that they have no competing interests.LKL, MTW and TSO all instigated and conceived of the study, and participated in the drafting and editing of the manuscript. All authors read and approved the final version of the manuscript. All authors contributed equally to this workLKL is a Lecturer in the School of Health Sciences at the University of South Australia. She has recently completed a PhD in the area of EBP and entry-level physiotherapy education. Her research interests are in health professional education, and the teaching of EBP process and best research evidence to undergraduate students.MTW is an Associate Professor in the School of Health Sciences at the University of South Australia. Her research interests included EBP education, with particular reference to educational processes for best research evidence, and the sensation of breathlessness in people with chronic pulmonary conditions.TSO is a Professor in the School of Health Sciences at the University of South Australia. His research interests include the links between time use and health outcomes, mathematical modelling of sports performance, anthropometry and historical trends in fitness, fatness, food intake and sleep of children.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/11/77/prepubK-REC instrument.Click here for fileK-REC marking guidelines.Click here for file"}
{"text": "The techniques of structural biology currently play an important role in the development of novel therapeutic agents including cancer chemotherapies. X-ray crystallography has proved to be a particularly powerful tool for both the discovery of novel compounds and their subsequent development. In this review of the literature, the steps involved in the determination of a crystal structure will be described, including how to obtain good quality crystals, how to perform the X-ray diffraction experiment itself and how to solve the phase problem and refine the final structure. Emphasis will be placed on how the end-user should be aware of the limitations of the techniques involved and the potential errors present in proteins structure deposited in the Protein Data Base. Fragment-based ligand discovery and theoretical docking offer alternative approaches for focusing the structural biologist\u2019s weaponry onto drug design problems. Of the many applications described in the literature inhibitors of HSP90 and Protein Kinase B will be used as examples of the ways in which improving specific protein-ligand interactions can be used to improve binding and pharmacokinetic properties. On the other hand, a complex structure involving a migrastatin analogue will exemplify the risks of over-interpretation of crystallographic data.There are no competing interests in this presentation."}
{"text": "Our results, based on demographic and osteometric data, indicate that full domestication of both cattle and suids occurred at the site during the 8th millennium. Importantly, domestication was preceded in both taxa by demographic and metric population parameters indicating severe overhunting. The possible role of overhunting in shaping the characteristics of domesticated animals and the social infrastructure to ownership of herds is then explored.The faunal assemblage from the 9 In this respect we part with older approaches seeking clear cut-off points between domesticated livestock species and their wild progenitors in the region, approaches which are being replaced by more nuanced documentation of the selective pressures introduced in the process of domestication Understanding of the role of humans as constant modifiers of their ecological niches is reshaping at present our understanding on the beginning of agriculture th millennium BP onwards. Age-at-death and sex ratio analyses of early livestock taxa show increasing departure from the prime-adult pattern that typified Palaeolithic and Epipalaeolithic hunting to selective culling of younger male animals. This pattern can be seen in a wide region stretching from the Taurus-Zagros arc to the Upper Euphrates th millennium BP Cyprus, brought there by Neolithic colonists, is a striking demonstration of such human involvement This documentation involves the decoding of genetic, metric and demographic markers that can be directly linked to an evolving human-animal relationship Genetic studies further revealed the occurrence of multiple domestication events for suids th to 8th millennium BP . This region, here defined as extending from the confluence of the Rivers Yarmuk and Jordan in the south to the Hula Valley in the North  evidence for the fully-domesticated status of cattle th millennium BP. This is evidenced by both demographic and metric data th millennium In the late 9th millennium BP, it is reasonable to search for evidence of intensified human exploitation of these animals in the preceding millennium. The zooarchaeological assemblages from the key site of Sha'ar Hagolan fill this gap. Located in the Jordan Valley, south of the Sea of Galilee (th millennium BP (Pre-Pottery Neolithic C), reaching its impressive florescence in the early 8th millennium BP (Early Pottery Neolithic Yarmukian culture), under the ameliorated climate of the early Holocene. The excavation of the PN strata at the site revealed a street system, a water well, courtyard houses and large assemblage of portable art, flint and pottery. Faunal and floral investigations conducted at Sha'ar Hagolan show an economy dominated by domesticated caprine herding and founder crop agriculture in the PPN If cattle and pigs are fully-domesticated in the northern Jordan Valley by the early 7The alluvial habitats modified by human agricultural activities around Sha'ar Hagolan facilitated encounters between humans and wild cattle and boar. That interaction is important for understanding the observed demographic and biometric changes associated with the domestication of cattle and pigs The faunal assemblage of Sha'ar Hagolan consists of two chronostratigraphical phases. The PN phase was radiocarbon dated to 6400\u20135800 cal. BCE All necessary permits were obtained for the described studies. Permission to analyze and published the animal bone assemblage from Sha'ar Hagolan was granted to us by Prof. Yosef Garfinkel, who headed the expedition of the Hebrew University of Jerusalem to that site. Permission to use data from Mishmar Ha'Emeq was granted by Dr. Omry Barzilai and N. Getzov, who directed the excavations at the site on behalf of the Israel Antiquity Authority.The animal bones from Sha'ar Hagolan presented in this study were recovered using a 2 mm mesh during eleven excavation seasons . Identification to taxon was carried out using the comparative collection of the Laboratory of Archaeozoology at the University of Haifa. The faunal assemblage from Sha'ar Hagolan is now curated in the Israeli Antiquity Authority storage facilities in Bet-Shemesh, Israel.Both fused and unfused specimens were measured using Vernier calipers to the nearest 0.1 mm following von den Driesch th millennium BP (Pre Pottery Neolithic B) site of Mishmar Ha'Emeq in the Jezreel Valley, excavated by Omry Barzilai and Nimrod Getzov of the Israel Antiquity Authority The log-transformed measurements were used to compare body-sizes between the PPN and PN suid and cattle bones from Sha'ar Hagolan. We used as a control a sample of wild cattle and boar from the 10Age-at-death was determined by epiphyseal fusion The interpretation of survivorship curves called for monitoring density-mediated attrition that could differentially delete juvenile bones from the assemblage The taxonomic composition of the faunal samples from the PPN and the PN of Sha'ar Hagolan are presented in th millennium , cattle measurements are positively skewed (Pearson's skewness\u200a=\u200a0.66), indicating that most values cluster at the lower half of the range and that, therefore, we likely observe a female-dominated sample . In contThe survivorship curve of PPN cattle is far steeper than the PN, to such an extent that very few mature animals appear to be present . The PN th millennium BP population . Survival to later adulthood appears to have been a rare occurrence in PPN populations. This is apparently not the result of a conservative herding strategy for either cattle or pigs, if we also take into account the female-dominated sex ratio, since it means very early culling of the reproductive core of the herd In the PN, the steep cattle mortality curve changes drastically in the direction of delayed culling: nearly half the population survives to older age. Also notable is the change in male-dominated sex ratio. This observation is in line with the measurements of unfused specimens, which are not large in relation to the cattle population average and preclude selective culling of young males. The small population of animals that were retained to an older age\u2014in marked contrast with that reflected in the PPN sample\u2014speaks for the presence of fully-domesticated cattle. Pig demography in the PN also demonstrates a sharp break with the previous millennium's culling practices. For pigs, the transition to the PN meant a younger age-at-death, with a sharp culling peak at the first and second years of life. The sharp positive skew in the PPN metric data, interpreted in terms of female dominance, disappears. In ordinal terms, more males are present. This very young age-at-death for pigs and the larger number of males present in the assemblage argues in favor of the presence of domesticated suids in the PN.th millennium followed a few centuries later by similar events further to the west in the Carmel region When combined with the evidence from the two sites where documentation of demography exists for the time period in the study region th millennium of the southern Levant is a solidly-based hypothesis th millennium Sha'ar Hagolan are in accord with the south Levantine context. It is also apparent that the transition to the PN at the site saw a sharp change in the mortality profiles of both taxa towards well-documented patterns for fully-domesticated animals, which do not match the steep mortality curves of the PPN at the site.The existence of domesticated cattle during the 8Whereas the conclusions on the domesticated state of cattle and suids in the PN settlement of Sha'ar Hagolan accord well with the expectations and data of previous research, which relied on shifts in taxonomic frequencies and metric data One of the consequences of overhunting is a reduction in mean body-size that can be observed in faunal assemblages Overhunted ungulate populations will also display steep mortality profiles, with high juvenile attrition\u2014the result of high recruitment rate brought about by reduced intra-taxon competition and lower chances of survival to maturity. Such populations are expected to show higher female frequency due to the general human preference to hunt the larger male animals th and 9th millennia BP, intensive hunting of wild cattle and wild boar was practiced in the northern Jordan Valley, departing from the emphasis on gazelles and deer observed in the preceding hunting cultures of the region During the 10From an optimal-foraging perspective, if the body-size of the hunted cattle and pigs was reduced to the point where the adult female body-size was incorporated in the diet \u2013 i.e., when preferential hunting of males ceases, adult females will become more dominant in the diet. This preference is especially true if very few territorial adult males remained and the majority of the population is aggregated in nursery herds composed of adult females and young males and females. Since the measurements from PPN Sha'ar Hagolan do not include young individuals, an observed pattern of female domination emerges. This pattern was first noted and interpreted by Grigson [15: 98]: \u201cHowever although the cattle of the seventh millennium bc sites were of wild size, there is a suggestion that in the western part of the area there was a stress on females; this could be interpreted as predation upon nursery herds and possibly as a first step towards domestication\u201d.Both overhunting and domestication manifest in the metric data in a similar way, by population mean body-size reduction and by a low proportion of adult males. Therefore, it is pertinent to explore the consequences of overhunting as possible candidates for shaping the archaeozoological signature of domestication. Further, overhunting may have caused domestication, as both motivation and an unconscious selective mechanism that pre-adapted prospective domesticates to full-fledged husbandry. Reduced body-size, sexual dimorphism, and enhanced fertility, when combined with selection against aggressively territorial individuals  are pre-adaptations to domestication caused by a simple, non-conscious process Alvard and Kuznar Under this scenario , the shiThe possibility of an \u2018overhunting\u2019 trajectory to domestication affects the interpretation of demographic and metric data as markers for domestication. It would suggest that in some cases body-size reduction could precede intentional demographic management of herd animals, and may be the result of a non-intentional process that was pre-adaptive to it\u2014as suggested some years ago by Tchernov and Kolska-Horwitz"}
{"text": "Stat5a gene of MLV integration has been already reported by us [There have been a few reports that the HIV-1 genome can be selectively integrated into the genomic DNA of host cell. However, actual target sequence of integration has not been reported. The target sequence within the second intron of ed by us 6(ACTGGGAAGGGAC)6-3\u2019 and a set of modified sequence DNAs by deletion of CAGT in the repeat unit. This CAGT and ACTG  in the repeat units originated from the HIV-1 proviral genome ends. We devised in vitro integration by using these sequence DNAs, HIV-1 provirus DNA, and recombinant HIV-1 integrase.On basis of the CA-rich sequence motif that was observed in MLV integration target sequence, we prepared a substrate repeat sequence DNA for In vitro integration occurred at the target sequence DNA at significant higher frequency and selectivity in comparison to random-sequence DNAs. Although the target sequence consisted of repeat segments, in vitro integration selectively occurred in the middle segment of the repeat sequence. On the other hand, both frequency and selectivity decreased markedly when using sequences with deletion of CAGT in the middle segment of the target sequence. Moreover, on incubation with the CAGT-deleted DNAs and target sequence, the integration efficiency and selectivity for the target sequence were significantly reduced. This interesting data indicated interference effects by the mixed sequence CAGT-deleted DNAs. Besides, efficiency and selectivity of integration into the target repeat sequence was found to vary discontinuously with changes in manganese dichloride concentration in the reaction buffer for in vitro integration. Because the structure transition at the critical concentration was exclusively observed in the target sequence DNA by electrophoresis, these discontinuous changes in in vitro integration were probably due to fluctuation in the secondary structure of the target DNA segment. Such structural isomers may be favorable for selective integration into the target sequence DNA.in vitro HIV-integration into the specified sequence. Similar DNA sequences can interfere with the process of selective integration. Dependency of in vitro integration upon the secondary structure of the target DNA is one of the models of in vivo integration that is promoted by open chromatin structure that is induced by transcriptional factor bound to the neighboring DNA segment. In addition, the present in vitro integration system can be useful for monitoring the integration activity or test of integrase inhibitor [There is a considerable selectivity in nhibitor ."}
{"text": "The aim of many microarray experiments is to build discriminatory diagnosis and prognosis models. Given the huge number of features and the small number of examples, model validity which refers to the precision of error estimation is a critical issue. Previous studies have addressed this issue via the deviation distribution (estimated error minus true error), in particular, the deterioration of cross-validation precision in high-dimensional settings where feature selection is used to mitigate the peaking phenomenon (overfitting). Because classifier design is based upon random samples, both the true and estimated errors are sample-dependent random variables, and one would expect a loss of precision if the estimated and true errors are not well correlated, so that natural questions arise as to the degree of correlation and the manner in which lack of correlation impacts error estimation. We demonstrate the effect of correlation on error precision via a decomposition of the variance of the deviation distribution, observe that the correlation is often severely decreased in high-dimensional settings, and show that the effect of high dimensionality on error estimation tends to result more from its decorrelating effects than from its impact on the variance of the estimated error. We consider the correlation between the true and estimated errors under different experimental conditions using both synthetic and real data, several feature-selection methods, different classification rules, and three error estimators commonly used (leave-one-out cross-validation,"}
{"text": "Soluble guanylate cyclase (sGC), the receptor for nitric oxide (NO), is one component of the nitric oxide (NO)-sGC-cGMP signaling pathway, which plays a key role in the cardiovascular system regulating smooth muscle relaxation and vasodilation and has been implicated in remodeling events in the heart and vasculature. Triggered by the binding endothelial-derived NO to the prosthetic heme group, sGC in smooth muscle cells converts GTP to the secondary messenger cGMP. Small molecule activators of sGC have been identified that either have the ability to activate the native heme-containing form of the enzyme (Heme-Dependent activators) or have the ability to activate to heme-free or oxidized form of the enzyme (Heme-Independent activators). The therapeutic potential of activators of sGC is illustrated by the successful clinical evaluation by Bayer of a Heme-dependent activator riociguat in pulmonary arterial hypertension . The cha"}
{"text": "This study compared the benefit of the novel one- step procedure for the managment of calculous biliary disease.A retrospective review of 25 geriatric patients was conducted one-step procedure with positionament of loop in digiuno for reductions a little bowel distenction. In 24 of the patients, the one-step technique was successful (96 %); in the remaining 1 patient (4%), conversion open technique was necessary; in this case not positionament of loop in jejunum. We define the one-step procedure to be a laparoscopic cholecystectomy whit IOC to confirm the presence of stone, to be a gold standard; intraoperative ERCP whit stone extraction was conected if necessary as part of the one-step procedure.This technique evidence a statistically significant difference of the hospital cost, such us the length of the stay and pre operative day and reduce the high conversion rate with alternatively technique in two-step. The incidence of overall complications was lower in the one-step technique. The findings showed that one-step technique was associated with less clinical pancreatitis respect at the two-stage technique.A laparoscopic cholecystectomy after ES is lengthier and more difficult then in uncomplicated cholelithiasis and should therefore be performed by an experienced surgeon. This new technique appears to be a significant conversion reduction versus two step procedure, and reduce the cost of hospitality and length of stay and preoperative days. Further research with a larger study population is necessary to determine the additional benefits of this procedure."}
{"text": "Anemia some of the most cutting-edge research outcomes pertaining to the latest complications and the novel treatment strategies in iron-chelation therapy. We also study the effects of these interventions on the quality of life of patients. It is studies like these that serve as the basis of evidence-based medicine and guide clinicians through their process of decision making. Beta-thalassemia is considered one of the most common genetic disorders which mass migration is introducing to countries worldwide and challenging them with its management. Advanced and improved medical care has allowed us to prolong the lives of thalassemia patients, simultaneously uncovering novel complications and outlining new challenges. We herein present in this special issue of One article of this special issue addresses the new method of using transactional Doppler ultrasonography for measuring intracranial blood flow velocity in patients with beta-thalassemia intermedia. This study shows higher blood flow velocity in these patients compared to the control group, which may point to a higher risk of ischemic events in the future. Another paper discusses that thalassemic DNA-containing red blood cells are under oxidative stress, which induces externalization of phosphatidylserine. This mechanism is involved in the removal of these cells from the circulation by the spleen, similar to that of the removal of senescent red blood cells.This special issue also includes a paper explaining the pathophysiology of bone modifications in beta-thalassemia. Imbalance in mineral turnover resulting in abnormal regulation of bone metabolism may be related to hormonal and genetic factors, iron overload, and iron chelation therapy. These factors and their contribution are addressed.\u03b2-thalassemia major is presented. It is the result of oxidative stress from free radical production, altered antioxidant enzymes, and its interaction with other essential trace element levels.Moreover, a review article that addresses the mechanism of tissue damage arising from iron overload in patients with \u03b2-thalassemia major and myelodysplastic syndrome with iron-overload treated either with deferasirox or deferoxamine injections. The results show that deferasirox can improve health-related quality of life treatment satisfaction and adherence compared to subcutaneous deferoxamine injection. This issue is crucial and often neglected in the long-term treatment of patients with iron overload.The last paper presented is a study comparing the quality of life in patients with Mehran KarimiSezaneh HaghpanahAli T. TaherMaria Domenica Cappellini"}
{"text": "P. falciparum malaria is close to licensure, having shown moderate levels of protection in clinical trials. Several analyses have shown the vaccine to be likely to be an effective and cost-effective addition to currently used control strategies. We previously used individual-based computer simulations  to analyze uncertainties in the predicted cost-effectiveness of introducing a malaria vaccine into the expanded programme on immunization in sub-Saharan Africa. We now extend these studies to include insecticide treated nets, a currently existing intervention. In addition, we also address model uncertainty in the current analysis.The first vaccine against We used techniques of probabilistic sensitivity analysis, involving randomly sampling the parameter vectors, to analyze the contributions of the different sources of uncertainty to the predicted cost-effectiveness. One specific aspect of these analyses of uncertainty is quantification of the value of acquiring additional information on these parameters by computation of expected value of perfect information (EVPI).Among the most important predictors of the cost-effectiveness of a control program are the cost of the intervention program and the transmission intensity at the time of the start of the program. EVPI is shown to be substantial, and in particular the accrual of up-to-date information on local endemicity would seem an efficient way to inform decisions about local deployment.Probabilistic sensitivity analysis and value of information analysis using computer simulation models provide a powerful way to identify data gaps hindering rational resource allocation in malaria control."}
{"text": "The arterial Switch operation (ASO) is now performed routinely for the repair of transposition of the great arteries (TGA). Neo-aortic root dilatation and reduced elasticity of the ascending aorta have been shown to impact the long-term outcomes of these patients.The aim of this study was to assess the effect of the ASO with the Lecompte maneuver on the dynamic behavior and dimensions of the aortic root, and the shape and curvature of the ascending aorta and aortic arch.Data was reviewed from nineteen TGA subjects  and twenty matched control subjects , who had undergone cardiovascular magnetic resonance (CMR) imaging for clinical indications at our Institution. Aortic flows at the root level and 3D Whole-Heart bSSFP were obtained using standard CMR sequences. Both groups had non-invasive brachial blood pressure cuff measurements. 3D Whole-Heart bSSFP images were used to create 3D models for each patient using commercial software  and the volume 3D centerline from ventricular apex to the descending aorta was calculated in order to better describe aortic geometry. Aortic flows and area changes were then analyzed from magnitude and phase-contrast images with an in-house written plugin  using an automatic propagation algorithm based on non-rigid registration.ASO subjects showed an abnormal aorta from the root to the arch with dilated aortic root and a more fragmented curvature of the ascending aorta with acute angulation of the aortic arch Figure . DilatatChanges in morphology, dimensions and dynamics observed in the ASO group suggest overall increased impedance, which is likely to be the mechanistic explanation for the long-term outcomes of this procedure.Carnegie Foundation, Fondation Leducq, UK National Institute of Health Research (NIHR), Royal Academy of Engineering and EPSRC."}
{"text": "Tuberculosis control in sub-Saharan Africa has long been hampered by poor diagnostics and weak health systems. New molecular diagnostics, such as the Xpert\u00ae MTB/RIF assay, have the potential to improve patient outcomes. We present a cluster randomised trial designed to evaluate whether the positioning of this diagnostic system within the health system has an impact on important patient-level outcomes.This pragmatic cluster randomised clinical trial compared two positioning strategies for the Xpert MTB/RIF system: centralised laboratory versus primary health care clinic. The cluster (unit of randomisation) is a 2-week time block at the trial clinic. Adult pulmonary tuberculosis suspects with confirmed human immunodeficiency virus infection and/or at high risk of multidrug-resistant tuberculosis are enrolled from the primary health care clinic. The primary outcome measure is the proportion of culture-confirmed pulmonary tuberculosis cases initiated on appropriate treatment within 30 days of initial clinic visit. Univariate logistic regression will be performed as the primary analysis using generalised estimating equations with a binomial distribution function and a logit link.Diagnostic research tends to focus only on performance of diagnostic tests rather than on patient-important outcomes. This trial has been designed to improve the quality of evidence around diagnostic strategies and to inform the scale-up of new tuberculosis diagnostics within public health systems in high-burden settings.ISRCTN18642314; South African National Clinical Trials Registry DOH-27-0711-3568.Current Controlled Trials  Mycobacterium tuberculosis strains leading to high mortality rates . Th. Th27]. misation . Hazard M. tuberculosis against the reference standard of single MGIT culture will be based on complete case analysis  and will only include individuals not on TB treatment at the time of enrolment. Estimation of sensitivity and specificity of Xpert MTB/RIF for the detection of rifampicin resistance against the reference standard of genotypic \u00b1 phenotypic DST on the culture isolate will be based on participants with M. tuberculosis detected by Xpert MTB/RIF and with a positive MGIT culture and valid drug susceptibility test (LPA \u00b1 phenotypic DST) results. This will include individuals on TB treatment at the time of enrolment (e.g. participants with AFB smear non-conversion or treatment failure).The diagnostic performance of Xpert MTB/RIF will be compared between the two arms. Estimation of sensitivity and specificity of Xpert MTB/RIF for the detection of In addition to evaluating the effectiveness of point-of-care positioning of Xpert MTB/RIF, data from the trial will be combined with those from a costing analysis to explore the cost-effectiveness of point-of-care placement. Health system costs will be obtained through monitoring of study expenditure and interviews with health service management. Collection of data relating to patient and household costs will be nested within the trial\u2014this will involve additional data collected from a subset of patients at baseline and at the 2-month follow-up to determine direct and indirect costs incurred during the diagnostic process. The framework for costing analysis is presented in Table\u2009The study will also compare the operational feasibility of Xpert MTB/RIF implementation at the hospital laboratory and at the primary health care clinic. This encompasses an assessment of the performance and robustness of the system, as well as evaluation of the practicality of operating the system at the laboratory and at the clinic. The key indicators to be assessed are displayed in Table\u2009The study has been approved by the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (BF033/11), the Ethics Committee of the London School of Hygiene and Tropical Medicine (5926), and the Health Research Committee of the KwaZulu-Natal Department of Health (HRKM084/11). Permission for the study was granted by Hlabisa Hospital and by the Community Advisory Board of the Africa Centre for Health and Population Studies.Given that the units of randomisation are time blocks, it is not possible for individuals to consent to randomisation. Individual consent for participation remains important given that the intervention is delivered to individuals and that individual-level data are collected at enrolment and at follow-up.There are TB suspects who are not eligible for this study and therefore will not have access to Xpert MTB/RIF testing within the study (suspects who are neither HIV-infected nor at high risk for MDR-TB). The justification for this is that these groups were a lower priority for this intervention given the much lower mortality rates and these suspects continue to receive diagnostic evaluation including sputum microscopy \u00b1 culture/LPA/DST according to national guidelines. At the time of study design it was predicted that, were Xpert MTB/RIF to be implemented in South Africa, the WHO recommendations would be followed (use in HIV-infected and those at high risk of MDR-TB). Although the national roll-out plan went beyond this in incorporating its use for all TB suspects, Xpert MTB/RIF has not yet been installed in Hlabisa sub-district and is therefore not yet available in the sub-district outside the trial.Evaluation of diagnostic tools provides different challenges than those of therapeutic interventions. Diagnostic accuracy studies are usually the starting point for evaluation of new technologies, yet to inform public health policies and implementation it is crucial to evaluate patient-important outcomes . The ultBlinding of patients or of health care workers is not feasible in this pragmatic diagnostic trial because allocation to trial arms involves different actions by the patient and the clinical staff. As a result of this, the outcomes are as objective as possible to limit potential bias from differential ascertainment of outcomes in the two arms. The possibility of differential recruitment into the trial arms exists but will be minimised by standardised referral criteria for the clinic health care workers; recruitment will be monitored by reviewing the clinic records to ascertain what proportion of patients with cough were referred to the study during each 2-week block. This will be reported if there is a major imbalance in recruitment to the two trial arms. There is a further risk of selection bias if there is differential non-participation. The proportions of eligible subjects consenting by trial arm will be monitored and will be reported accurately at the conclusion of the trial. There is some risk of contamination between the arms if, over time with point-of-care testing, the health workers see the importance and the effect of receiving the test result in a timely fashion and this then improves their ability to encourage all suspects to return and receive their result. This would tend to bias the findings towards the null hypothesis. We will explore this by assessment of the variability in the proportion returning for their test result by cluster and by time period.The evaluation of diagnostic accuracy is not the primary focus of the trial and the reference standard of a single culture could be considered an imperfect gold standard. In the initial Xpert MTB/RIF clinical validity studies, the reference standard used results of liquid and solid culture on two specimens  . ConversThere are a number of trials evaluating the impact of Xpert MTB/RIF in different settings and with different research hypotheses. Information about research projects is collated by the TREAT TB Xpert Research Mapping Project . SeveralThe study received final ethical approval in June 2011. Enrolment commenced on 22 August 2011. Enrolment is scheduled to complete in March 2013 and follow-up will be complete in May 2013.ART: Antiretroviral therapy; DST: Drug susceptibility testing; GEE: Generalised estimating equation; HIV: Human immunodeficiency virus; MDR-TB: Multidrug-resistant TB; MGIT: Mycobacterial growth indicator tube; NHLS: National Health Laboratory Service; PCR: Polymerase chain reaction; PHC: Primary health care; TB: Tuberculosis; WHO: World Health Organization; XDR-TB: Extensively drug-resistant TB.The authors declare that they have no competing interests.RJL and PGF conceived and designed the trial, with additional input from GSC, NM, MPN and MLN. NM helped with the statistical design and analysis plan. RJL wrote the first draft of the manuscript. All authors contributed to revision of the manuscript and approved the final version."}
{"text": "An isocentric superconducting rotating-gantry for heavy-ion therapy is being developed . This roAll of the superconducting magnets were designed, and their magnetic fields were calculated using the Opera-3d code . With thThe design study as well as major tests of the superconducting magnets was completed, and the construction of the superconducting rotating-gantry is in progress. The construction of the superconducting rotating-gantry will be completed at the end of FY2014, and be commissioned within FY2015."}
{"text": "Trypanosoma cruzi. This accounts for the absence of RNA interference phenomena in these parasites. In the present work we have cloned and characterized the small RNA population from T. cruzi, in two of its life cycle forms: epimastigotes and metacyclic stages. Our results showed a highly represented population of small RNAs derived from de cleavage of mature tRNAs representing about 30% in epimastigotes and 40% in trypomastigotes of small RNA fraction which we dubbed mini-tRNAs. Surprisingly, more than 98% of mini-tRNAs derived from the 5' half of tRNA for Asp and Glu and localize to particular granular structures in the cytoplasm of T.cruzi at all stages of its life cycle. These tRNA halves seem to be related with an Argonaute protein distinctive of trypanosomatids which was recently cloned and sequenced in our laboratory. This Argonaute protein was differentially expressed through the life cycle of T. cruzi and its expression was accentuated by starvation. Whereas their biological significance is currently unknown this mini-tRNAs population it has been described in the last year in other organisms as Giardia lamblia, Aspergillus fumigatus and many mammalian cancer cells. These mini-tRNAs have also been found in the supernatant of culture of T. cruzi as forming part of the secretome of these organisms, which led us to speculate about a putative role of these molecules in intercellular communication. This could represent a new family of small RNAs with relevance in gene expression regulation in particular for these unicellular parasites where gene regulation is achieved principally by post-transcriptional mechanisms. The complete knowledge of gene expression regulatory pathways in this kind of parasites that concern human health could be a source of study for development of vaccines or anti-parasitic treatment in base new tools as the RNA vaccines or biotechnological drugs.In the last decade a new family of small regulatory RNAs (sRNAs) of 20-30 nt in length, were recognized as key players in the regulation of gene expression at the transcriptional and post-transcriptional levels. The enzymatic machinery associated with the biogenesis and effector functions of these \"sRNAs\" has been found in the majority of the organisms studied. The exceptions for this are some species of trypanosomatids including"}
{"text": "With the advent of ChIP-seq multiplexing technologies and the subsequent increase in ChIP-seq throughput, the development of working standards for the quality assessment of ChIP-seq studies has received significant attention. The ENCODE consortium's large scale analysis of transcription factor binding and epigenetic marks as well as concordant work on ChIP-seq by other laboratories has established a new generation of ChIP-seq quality control measures. The use of these metrics alongside common processing steps has however not been evaluated. In this study, we investigate the effects of blacklisting and removal of duplicated reads on established metrics of ChIP-seq quality and show that the interpretation of these metrics is highly dependent on the ChIP-seq preprocessing steps applied. Further to this we perform the first investigation of the use of these metrics for ChIP-exo data and make recommendations for the adaptation of the NSC statistic to allow for the assessment of ChIP-exo efficiency. ChIP-seq couples chromatin immunoprecipitation with high throughput sequencing technologies to allow for the genome wide identification of transcription factor (TF) binding sites and epigenetic marks. The use of high throughput sequencing circumvents many of the limitations seen previously with ChIP-chip array based methods including probe specific biases and the physical limitations on the proportions of genomes which may be represented . Polymerase data was omitted from this study due to differential pattern of binding across transcriptional start sites and genes. ENA and SRA accession numbers for ENCODE/SYDH, CRUK ChIP-seq, and CRUK ChIP-exo datasets used in this study are included in the Supplementary Materials.TF and histone ChIP-seq was selected from the ENCODE/SYDH  . Analysis of overlaps and read counts within blacklisted regions was performed using the GenomicRanges Bioconductor package version 1.8.13 with R 2.15.1 .ChIP-seq and ChIP-exo reads were aligned to UCSC GRCh37 genome (February 2009 build) using BWA version 0.5.9   regions derived from a subset of the ENCODE open chromatin and input sequence data  were counted within all blacklists' regions for the ENCODE, CRUK, and ChIP-exo data sets. All data sets showed an enrichment of reads within blacklisted regions Figure , with ~1Across all datasets and blacklists there is enrichment for reads mapping to more than one location in keeping with repeat classes constituting large portions of the blacklists  is calculated from the weighted mean of the standard deviation of the depth of coverage across chromosomes normalized to the total number of reads sequenced  which may supersede that of the fragment length when assessing shift with maximum correlation for ChIP-seq as well as result in paired peaks on the Watson and Crick stand separated by the read length, thus leading to the incorrect prediction of the fragment length as the read length.The use of cross-correlation to predict fragment length provides further information about the overall quality of a ChIP-sample  typically achieve higher SSD and lower NSC or RSC scores than those with sharper signal enrichment over narrow regions .The cross-correlation profile for c-Myc (SRR568130; Figure In order to investigate the effects of differing filtering steps on cross-correlation profiles and hence NSC/RSC scores, reads were separated into those overlapping peaks, overlapping blacklists and duplicated reads. Whereas cross-correlation profiles derived from reads in peaks show the expected hump around the fragment length, the cross-correlation profile obtained by considering solely the DAC blacklist shows only the read-length spike illustrating the presence of the artifact signal within blacklisted regions and its influence in the read-length cross-correlation spikes for ChIP and input samples Figure . InteresTo systematically evaluate the effect of filtering steps on ChIP and background signal, cross-correlation profiles and their fragment-length and relative strand cross-correlation scores were assessed after blacklisting, duplicate removal and both simultaneously.The effect of blacklisting and/or duplicate removal on FSC scores is shown in Figure In keeping with the observations of DAC blacklisted reads contributing to the read-length cross-correlation peak, an increase in RSC scores across both ENCODE Figure  and CRUKThe use of cross-correlation analysis and NSC/RSC metrics for ChIP-exo data has not been previously investigated. Due to the enzymatic digestion of DNA fragments around binding sites cross-correlation profiles are expected to have a very different shape to that of successful ChIP. Neither the ER Figure  or FoxA1Cross-correlation profiles for ChIP-exo can be seen to be distinct between ER and FoxA1 ChIP. ER shows a broad enrichment over the read-length cross-correlation peak Figure  shows a Assessment of the effects of filtering on ChIP-exo shows that duplicate filtering has a dramatic effect on the overall cross-correlation profile whereas blacklisting has a specific effect in FoxA1 at the 28 bp cross-correlation peak and little effect at the 12 bp peak Figure . In thisFollowing the removal of aberrant signal and the contribution of this to the read-length cross-correlation peak, the ratio between the highest and minimum values of cross-correlation may replace the use of typical NSC scoring for ChIP-exo quality and so provide an equivalent measure of ChIP efficiency. The use of a metric equivalent to RSC's evaluation of signal to noise in ChIP-seq however is confounded by the overlap between read-length and fragment-length cross-correlation peaks. Nonetheless, in ChIP-exo data the observation of loss of a defined read-length cross-correlation peak after removal of artifact signal can act as an indication of successful removal of artifact signal.The processing of ChIP-seq data and the evaluation of ChIP quality remains an area of continued research. Following recent publications of ChIP quality metrics and analysis standards, we have performed the first systematic evaluation of the effects of ChIP-seq pre-processing steps on such metrics and an assessment of their application to the emerging technology of ChIP-exo sequencing.The assessment of ChIP-quality by the visualization of ChIP signal within genome browsers can be subjective to the investigator and is prohibitive of large scale evaluation of quality. The use of metrics of ChIP-quality therefore provides more objective methods to evaluate ChIP success as well as allows for high throughput classification of ChIP data. These metrics are however dependent on processing and filtering steps applied and therefore their interpretation must be made in their context.The removal of artifact signal can improve fragment length estimation and between sample normalization (Kharchenko et al., The SSD metric of signal inequality is highly sensitive to high signal artifact regions and so to evaluate ChIP enrichment masking of such regions is required prior to assessment of SSD. Furthermore, due its sensitivity to artifact regions, the SSD metric can be used as a flag for the persistence of artifact regions in input samples where higher scores for the input sample when compared to the ChIPed sample highlights the requirements for further artifact removal.The RSC metric provides a measure of ChIP to artifact signal, however the removal of blacklisted regions has been shown to eliminate the presence of the artifact peak and so the interpretation of RSC after blacklisting is obscured. In contrast to SSD, the assessment of RSC should be performed prior to blacklisting and the inspection of cross-correlation profiles be made after blacklisting to confirm the loss of the read-length peak within the cross-correlation profile.The treatment of duplicated reads in ChIP-seq varies between applications and the inclusion of duplicated reads is often performed in the context of differential affinity analysis (Ross-Innes et al., From these finding, we show the importance of the iterative assessment of quality over the masking of blacklisted regions and removal of duplicated reads. We recommend the assessment of RSC and NSC prior to blacklisting or duplicate removal and SSD before and after these steps to capture the extent and success of blacklisting.ChIP-exo sequencing presents a new methodology for genome wide ChIP analysis and provides a higher resolution and greater efficiency than seen for conventional ChIP (Serandour et al., The presence of artifact signal from blacklisted regions may be seen in ChIP-exo data but the degree of blacklisted signal was found to be consistently lower for this technology Figure . The sigThe use of standard cross-correlation analysis in the evaluation of ChIP-exo quality is confounded by the co-occurrence of both the read-length and the fragment-length cross-correlation peaks. Although this prohibits the use of the RSC metric, by identifying the expected cross-correlation profile of enriched regions, an adapted NSC metric may be generated as the extent of maximum cross-correlation within this profile over the background cross-correlation following the blacklisting of aberrant signal.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In aerobically grown cells, iron homeostasis and oxidative stress are tightly linked processes implicated in a growing number of diseases. The deregulation of iron homeostasis due to gene defects or environmental stresses leads to a wide range of diseases with consequences for cellular metabolism that remain poorly understood. The modelling of iron homeostasis in relation to the main features of metabolism, energy production and oxidative stress may provide new clues to the ways in which changes in biological processes in a normal cell lead to disease.in silico mutants. The simulations of the different mutants gave rise to a remarkably accurate qualitative description of most of the experimental phenotype . A second validation involved analysing the anaerobiosis to aerobiosis transition. Therefore, we compared the simulations of our model with different levels of oxygen to experimental metabolic flux data. The simulations reproducted accurately ten out of the eleven metabolic fluxes. We show here that our probabilistic Boolean modelling strategy provides a useful description of the dynamics of a complex biological system. A clustering analysis of the simulations of all in silico mutations led to the identification of clear phenotypic profiles, thus providing new insights into some metabolic response to stress conditions. Finally, the model was also used to explore several new hypothesis in order to better understand some unexpected phenotypes in given mutants.Using a methodology based on probabilistic Boolean modelling, we constructed the first model of yeast iron homeostasis including oxygen-related reactions in the frame of central metabolism. The resulting model of 642 elements and 1007 reactions was validated by comparing simulations with a large body of experimental results (147 phenotypes and 11 metabolic flux experiments). We removed every gene, thus generating All these results show that this model, and the underlying modelling strategy, are powerful tools for improving our understanding of complex biological problems. A large body of data suggests that mitochondrial abnormalities may link gene defects and/or environmental challenges to many pathologies including several neurodegenerative processes . MitoDue to its unique redox properties and chemical reactivity, iron appears to be a key player in abnormal ROS generation, principally as a catalyst of the Fenton and Haber-Weiss reactions . This esIn the growing field of systems biology, several attempts have been made to model cellular processes. For complex systems, these models can be classified into static ,17 and dOur understanding of the relations between oxidative metabolism and iron homeostasis is based on a large body of qualitative knowledge from heterogeneous sources, often lacking numerical data. It is therefore not possible to derive mathematical relationships based on biological knowledge for the entire system, and the model has to include uncertain knowledge. As a consequence, despite several attempts to construct models accurately describing certain aspects of iron homeostasis  similar to those of mammalian cells. We first validated the model by simulating 198 in silico mutations resulting from the deletion of individual genes from the model . An independent validation was provided by analysing the key transition from anaerobic to aerobic metabolism, by comparing in silico reactions frequencies with experimental fluxomic data  = > B  3) A = > (A is degraded) 4) A < = > B (reversible reaction).Click here for fileSensitivity analysis of the outputs of the model (PoP at steady state) when the weights of the reactions are modified.Click here for filePoP of elements in simulated mutants versus phenotypes manually curated by SGD in the corresponding mutants. The spreadsheet le is composed of 6 sheets (one for each type of phenotype). Each sheet contains the simulated PoP on the left and the SGD phenotypes on the right panel . One phenotype can be represented by multiple lines when multiple articles reproduced it. ND = no difference between the WT and the mutant were observed. Red cells mean that the differences observed in the in silico mutant is not in agreement with the experimental observations. Yellow cells mean that the differences observed in the in silico mutant is not in agreement with the experimental observations as referenced by SGD but that a more recent publication is in agreement with our simulations . Columns in the \"SGD Reference\" section: - Reference  -PMID: #### SGD REF: #### (separated by pipe)(one reference per row) - Experiment Type (Mandatory) -The method used to detect and analyze the phenotype - Mutant Type (Mandatory) -Description of the impact of the mutation on activity of the gene product - Allele  -Allele name and description, if applicable - Strain Background  -Genetic background in which the phenotype was analyzed - Phenotype (Mandatory) -The feature observed and the direction of change relative to wild type - Chemical  -Any chemicals relevant to the phenotype - Condition  -Condition under which the phenotype was observed - Details  -Details about the phenotype - Reporter  -The protein(s) or RNA(s) used in an experiment to track a processClick here for fileList of the elements of the model that are always \"ON\" during the simulations.Click here for fileThe WT model implementing the first hypothesis. The WT model implementing the first hypothesis explored in \"Results/Exploration of alternative hypothesis: an example of a use of the model\".Click here for fileClustering presented in Figure Click here for file"}
{"text": "Over the past years the ongoing human brain activity at rest came into focus, emphasizing the role of the rest-state activity for brain functions such as planning and perception in both healthy and diseased brains. For instance, it has been shown that the alpha rhythm during rest can be affected  using stimulations such as sensory or Transcranial Magnetic Stimulations (TMS). However, the origin and the mechanisms underlying the rest-state activity are not yet well understood.In this study, we focus on the propagation of large-scale brain responses to stimulations such as TMS to identify sub-networks involved in the rest-state.2 of the cortical surface. A sub-threshold Hopf oscillator with a Van der Pol term describes the temporal behavior of each NM and a Gaussian kernel defines the spatial interactions among the NMs. We also consider the connections through the white matter extracted from a combination of diffusion spectrum MRI tractography and the CoCoMac database. We systematically stimulate different brain areas and analyze the spatiotemporal responses of the model, using Principal Component Analysis.Using The Virtual Brain  we modelThe results provide evidence for the existence of a low dimensional set of networks during rest. Stimulations of brain areas involved in resting-state networks produce stronger and longer lasting responses than stimulations of other areas. We found overlapping of the networks with the dominant connectivity structures as well as with experimentally known resting-state networks (see Figure"}
{"text": "To describe a novel hardware MR-perfusion phantom to model first-pass of a bolus of contrast in the cardiac cavities and large thoracic vessels  and in the myocardium, allowing for the acquisition of dynamic first-pass MR-perfusion data and for a precise control of cardiac output and myocardial perfusion for true validation of perfusion quantification.Development of quantitative MR-perfusion would benefit from the availability of a MR-compatible harware phantom allowing for a realistic simulation of the AIF and of the myocardial signal intensity curves. So far, mathematical phantoms or static samples with different T1 values have been described and a tool for development and true validation of MR-perfusion is lacking.Our MR-compatible phantom resembles the anatomy of the heart and of the thoracic vessels of a 60 kg subject. Water flow (2-4 l/min) is driven into the system by a pump located outside the MR room. Gadolinium injections  are performed in the vena cava by a power-injector . Progressive dilution of the Gadolinium bolus across the chambers generates the AIF. A fraction of the cardiac output perfuses two myocardial compartments  where perfusion can be controlled precisely and independently. Outside the MR room, a control unit allows for precise measurement and control of cardiac output and myocardial perfusion. The phantom was tested in a 3T-scanner . Acquisition of the perfusion sequence was repeated multiple times with a k-t SENSE sequence  using similar flow conditions to demonstrate the reproducibility of the measurements. Different flow conditions were used to assess the response of the system to different myocardial perfusion rates. Quantification was performed by Fermi deconvolution.The system produced realistic dynamic first-pass perfusion data Figure  and reacThis novel hardware perfusion phantom allows reliable, reproducible and efficient simulation of myocardial perfusion. The availability of a direct comparison between the image data and reference values of flow and perfusion will allow for rapid development and validation of accurate quantification methods."}
{"text": "Today's scoring functions are one of the main reasons that state-of-the-art protein-ligand dockings fail in about 20 % to 40 % of the targets due to the sometimes severe approximations they make. However these approximations are necessary for performance reasons. One possibility to overcome these problems is the inclusion of additional, preferably experimental information in the docking process. Especially ligand-based NMR experiments that are far less demanding than the solution of the whole complex structure are helpful.Here we present the inclusion of three different types of NMR-data into the ChemPLP  scoring In the second part the usefulness of INPHARMA data ,5 is sho"}
{"text": "This issue includes a series of papers from the second special issue of the Standards in Genomic Sciences (SIGS) journal organized by the Genomic Standards Consortium (GSC).With this special issue, SIGS makes a significant advance towards its goal of providing a unique forum for publishing standards-compliant literature. With the publication of these articles SIGS is continuing to expand its scope and relevance to the wider scientific community working in the areas of genomes, metagenomes, metagenetics, 'omics and standard ways of describing, analyzing, distributing and publishing data.While the content of SIGS to date has largely consisted of reports on genome sequencing projects - making SIGS the 3rd ranked journal for total number of genome publications to date - the longer-term goal of SIGS is to serve as an open-access, standards-supportive publication for all consensus-building communities working to develop standards and related infrastructure. Joint publication is a key step in the defining the shared interests and goals of communities. This issue contains a suite of multi-author, consensus-driven articles.The papers in this special issue include a series of workshop reports, calls for adoption of new minimum information checklists, and a community call for open access to metagenomic samples. We look forward to seeing the international standards community continue to grow,  and we thank SIGS for providing a novel forum in which to publish critical advances in this field."}
{"text": "Acanthamoeba is opportunistic protozoan pathogen and is known to be one of the most ubiquitous organisms that can produce keratitis and rare but fatal encephalitis. Infections due to Acanthamoeba have increased over the year, which is due to presence of Acanthamoeba in the natural environment and have a direct contact with human in everyday life and is responsible for human diseases. Given the free-living nature of the organisms, it is anticipated that we encounter Acanthamoeba during our normal life. The aim of the present study was to investigate anti-Acanthamoeba antibodies in Pakistani healthy population to combat this pathogen in normal situation.Acanthamoeba isolation from environmental sources  was done using plating assay. Acanthamoeba identification from environmental samples was based on the morphology of cyst and trophozoite forms by non-nutrient agar plates seeded with E. coli K12 and PCR amplification with a genus specific primer pair. The presence of anti-Acanthamoeba sIgA in mucosal secretions of tribal Pakistani population  were determined using Enzyme-linked immunosorbent assays (ELISA).Acanthamoeba was successfully isolated from the water sources of Pakistan during this study. ELISA demonstrated the presence of Acanthamoeba-specific sIgA in mucosal secretions of in different age groups and both genders. A total of 524 samples of 45 tribes, were collected from different age groups ranged from 15 to 60 years. The overall prevalence was 78.8% in males and 73.8% in females. No significant difference was observed between genders. The high level of anti-Acanthamoeba antibodies was observed among the people in 25-30 years of age. Furthermore the prevalence of antibodies was observed high in tribal population of Khyber Pakhtunkhwa province as compared to rest of the country.Here, we for the first time isolated Acanthamoeba from the natural environment of Pakistan and presented the prevalence level of anti-Acanthamoeba secretory IgA antibody in mucosal secretions of the normal Pakistani population."}
{"text": "Despite the promising paradigm offered by high-content screening, the concrete execution of hundred of thousands of visual cell-based experiments has remained highly challenging in terms of both statistical robustness and speed. An efficient computational method for cellular microarrays was developed at Institut Pasteur-Korea that allow for high speed, high content genome-wide siRNA screening. Details of the method and examples of data from genome-wide analyses will be featured in this presentation. In particular, we will demonstrate that the sudden ability to dramatically increase the number of experiments has created the opportunity for automated identification of a drug\u2019s target."}
{"text": "The common sense model of illness (CSM) has been shown to be a useful model to help understand the psychological influences on diabetes-related behaviour and health outcomes. Using the CSM, the aim of this study was to investigate the relationship between cognitive and emotional representations of peripheral neuropathy and diabetes-related foot ulceration in adults with diabetes.One-hundred and twenty-one people with diabetes and peripheral neuropathy were recruited into this one-year prospective cohort study. At baseline, the participants completed two questionnaires- the Patients\u2019 Interpretation of Neuropathy questionnaire and a short questionnaire asking about preventative foot-care behaviour. Basic diabetes and demographic information was also collected. Sequential logistic regression was used to investigate the influence of cognitive and emotional representations of peripheral neuropathy as measured by the PIN and the development of incident foot ulceration.One-hundred and seventeen participants completed the study. The incidence of new foot ulceration was 34.2%. Only two statistically significant independent risk factors for foot ulceration were detected: prior history of foot ulceration  and severity of neuropathy .A consistent association between cognitive and emotional representations of peripheral neuropathy and incident foot pathology was not found. If the CSM is to be clinically useful for people with diabetes and peripheral neuropathy the mediational role of preventative foot-care behaviour should be further investigated."}
{"text": "The sixth sentence of the last paragraph of the Introduction is incorrect. The correct sentence is: AtWRKY11, AtbZIP63 and the DNA-binding domain of AtWRKY33 and revealed their full binding spectra.\"\"We applied this approach to the already known DNA-binding proteins"}
{"text": "To develop a model for determining the level of dose adherence of Antiretroviral Therapy (ART) clients from the first day of ART to the day of interview and to determine the dose adherence levels of the ART clients using the model.A cross-sectional study was conducted using pre-tested standardized questionnaires in exitinterviews in three ART centres and eleven social support groups to determine the dose adherence levels of ART clients in the Eastern Region of Ghana. A dose-adherence model was developed from three types of dose records; the observed doses, the expected doses and the missed doses and the frequency at which clients defaulted since commencement of ART. This model encapsulated the short-term recall of missed doses and the long-term default frequency of ART clients to arrive at the observed / expected adherence level ratio; the expected doses being the theoretical number of doses to be taken from the first day of ART to the time of interview and the observed doses being the difference between the expected doses and the missed doses.Standard adherence levels derived from the model based on literature were 25% , 50% [2]The dose-adherence model complements other methods for deducing client's level of dose adherence by considering the long-term default frequency as an addition to the short-term recall of missed doses or self-report."}
{"text": "Arabidopsis with a special focus on their role in vascular development and functioning.In higher plants phloem and xylem are responsible for long-distance transport of water, nutrients, and signals that act systemically at short or long-distance to coordinate developmental processes. The formation of the plant vascular system is a complex process that integrates signaling events and gene regulation at transcriptional and posttranscriptional levels. Thanks to transcriptomic and proteomic analysis we start to better understand the mechanisms underlying the formation and the functioning of the vascular system. The role of the DNA-binding with one finger (Dof TFs), a group of plant-specific transcription factors, recently emerged as part of the transcriptional regulatory networks acting on the formation and functioning of the vascular tissues. More than half of the members of this TF family are expressed in the vascular system. In addition some of them have been proposed to be mobile proteins, suggesting a possible role in the control of short- or long-distance signaling as well. This review summarizes the current knowledge on Dof TFs family in  The gradual colonization of the land through plant evolution has been possible thanks to the differentiation of complex vascular tissues that provide mechanical support and allow long-distance transport of water and nutrients. In land plants, vascular tissues are comprised of two conducting tissues the phloem and the xylem, and intervening cambium that can generate the different conducting cell types  transcription factor has been identified in maize (ZmDof1) and was shown to be involved in light response and transcriptional regulation of genes involved in carbon metabolism AAAG-3\u2032 core . Along plant evolution, Dof transcription factors might have originated from a common ancestor, likely represented by the single Chlamydomonas reinhardtii gene, and then expanded in the different taxonomic groups of vascular plants through recurrent duplication events  so far analyzed eight to nine Dof TF genes are found     present only in the phloem of infected plants allowed the identification of a virus promoter functional in plants  to confer phloem-specific expression   potentially expressed in vascular tissue at different step of its development.The mining of RNA profiling datasets at the resolution of the vascular tissue  and vascular cell type  , or through plasmodesmata in a short distance (between cell types)  are potential mobile transcription factor RNAs.In addition, cell-type specific expression maps from A direct experimental proof of the intercellular movement of a non-cell-autonomous Dof TFs has recently been brought by Chen et al.  who showDof genes have been found expressed in the phloem, there is so far no evidence for long-distance transport since neither RNAs nor Dof proteins have been found in transcriptome and proteome datasets of phloem sap ], a differentiation-promoting transcription factor of the vascular system , which shows a precocious formation of the interfascicular cambium and its subsequent cell division, Guo et al. cambium initiation and activity  are suspected to be involved in the control of the maintenance of the cambium and/or cambial activity by controlling the cell cycle , and while looking for direct targets of AtDof3.4/OBP1 several core cell cycle genes and transcription factors were identified , CONSTANS (CO), and FLOWERING LOCUS T (FT) genes  have been shown to be expressed in the vasculature throughout the plant and were shown to negatively regulate the transcription of CO  specific H+-sucrose symporter  . Altogether these data suggest that interactions between Dof TFs and TFs belonging to other families are theoretically possible. Experimentally, OBP1 was shown to directly interact with the promoter of a bZIP transcription factor but also with the promoter of a member of the same family AtDof2.3 (Zhang et al., Arabidopsis (Zhao et al., REVOLUTA have also been demonstrated (Kim et al., Arabidopsis vein formation (Gardiner et al., Structurally, like for other zinc fingers, the Dof domain is known to be a bi-functional domain that mediates not only DNA-binding but also protein\u2013protein interactions (Yanagisawa, In the context of the vascular system development and functioning, which integrates a large variety of internal or external stimuli, regulators are needed to fine-tune the responses to changes in the environment. In this review, we present evidences that the Dof TFs family is likely to participate in such fine-tuning of the responses to the different stimuli in the vascular system. By modulating a variety of transcription factors, by protein-DNA and/or protein\u2013protein interactions, the Dof TFs could therefore act at the cross-talk of various developmental pathways directly or indirectly linked to the vascular development and/or functioning. One of the next challenges, besides the functional characterization of the still undescribed Dofs TFs, will therefore be identifying the actors involved in an integrated regulatory network. Combination of the high-throughput data collection at the resolution of the vascular cell types and developmental stages as well as the use of the next generation sequencing technology will certainly allow identifying genes network regulating the fundamental features of the vascular development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "There has been transition in the profile of health risks from traditional risks such as under nutrition and low sanitation towards modern risks such as obesity and overweight. This has resulted in a high burden of non-communicable diseases such as diabetes, cardiovascular diseases, cancers and chronic respiratory diseases. Cross sectional studies, case-control studies and randomised controlled trials have significant challenges in exposure assessments and studying their long-term effects with respect to non-communicable diseases. Cohort studies are ideal for the study of long term effects on NCD outcomes, to study temporal sequence of exposure and potential outcomes, to study changes in exposure and may allow nested case-control studies with prospective exposure assessment.Physical activity plays an important role in non-communicable diseases and despite the initial success, more evidence based advocacy is necessary. There are concerns whether the resolutions of the UN NCD summit can be implemented speedily and physical inactivity is not included in the first set of targets currently under discussion for WHO's monitoring framework. Better methods for quantification of levels of physical activity and assessment of different domains of physical activity are now available and more trans-cultural research in physical activity and health is necessary. Indo-Swiss partnership in this area assumes importance in the above context."}
{"text": "P = .03). The residual lesions that we could find with definitive histology of re excision specimens are related with lesions with ill defined profile. In 77% of the cases of re excision with tumoral residual the lesion was close to the new resection margin, thus the re-excisions couldn't achieve an adequate ablation of the neoplasm. Invasive or preinvasive nature of the main lesion resected for each case and the approach to the evaluation of the first resection specimen adequacy  don't affect the rate of tumoral residual in intraoperative re-excisions. In conclusion, our data are consistent with a low efficacy of intraoperative re excision in obtaining a complete removal of the tumor; intraoperative radiologic evaluation of the first resection specimen is however imperative in defining the effective removal of the target lesion.In the present study we considered the histology of 51 patients who have undergone breast conservative surgery and the related 54 re-excisions that were performed in the same surgical procedure or in delayed procedures, in order to evaluate the role of intraoperative re-excisions in completing tumor removal. In 13% of the cases the re excision obtained the resection of the target lesion. In this study, the occurrence of residual neoplastic lesions in intraoperative re-excisions (24%) is lower than in delayed re-excisions (62%;  Breast oncologic surgery is now widely focussed in conservative treatment with tissue sparing in order to obtain satisfying cosmetic results besides an adequate surgical resection \u20133. ObvioIn recent years, the role of the intraoperative evaluation of surgical specimen in resection margin control was assessed, but the literature is still limited and dissimilar. A group of recent papers on series of conservative resections for breast malignancies proved that the intraoperative examination of resection specimens is useful in decreasing the rate of second procedures, employing gross examination techniques , specimeAssuming that the re-excision procedures are useful tools in obtaining an adequate removal of the neoplastic lesions, thus reducing the risk of persistence of neoplastic foci in residual parenchyma, we believe it could be of interest to make an attempt at quantifying the amount of tumoral mass that lies beyond a margin that is considered close according to the ordinary criteria of intraoperative evaluation . The literature about this topic is still somewhat limited and is mainly based on delayed excisions: two recent works , 15 analThe present survey is based on the examination of histological material from a consecutive series of conservative resections that comprehended re-excision procedures, both in the context of the same session and in delayed surgical treatments. The main goal of this study is the assessment of the extension and of the morphological characteristics of the tumoral residuals in re-excision specimens to define both the role of the re-excisions (and mainly of the limited re-excisions) as a tool to obtain the complete removal of neoplastic lesions in conservative breast surgery and the potential employment of other therapeutic options in obtaining an adequate removal of the target area. As a consequent achievement, we planned to weigh up some of the issues that could be related with the occurrence of tumoral residuals, as the invasive or preinvasive nature of the lesion, the method of evaluation of the first resection adequacy, and the time occurring between the first resection and the re-excision.For the present study, we selected 51 patients consecutively treated in our institution with a preliminary conservative approach, subsequently extended with further (intraoperative or delayed) procedures. Since resection specimen radiogram is considered the most reliable technique of margin status evaluation in our structure, all the first resection specimens were conveyed to the radiology department for intraoperative evaluation, and most of the re-excisions were based on the radiologist's advice. Considering the main lesions reported in final histology for each patient, 28 infiltrating carcinomas , 19 in situ carcinomas (37%), and 4 (8%) benign lesions were resected. All the benign lesions were reported at final histology as sclerosing adenosis.The main histological characteristics of infiltrating and in situ carcinomas are resumed in 112 surgical specimens from 54 procedures (first resections and subsequent re-excisions) were evaluated in this study.Resection specimens were examined in radiology department using two standard projections. The presence of the target lesion in the radiograms was first ascertained; the margins were judged close to the target lesion when the lesion was eccentrically placed in the same mammograms.Space-oriented specimens were examined for the final histology. In the initial resections, the surgical margins were marked with one or two different colour inks. In the re-excision specimens, the new resection margins were inked. Consecutive sections of the area of the neoplasm closest to the surgical margins were obtained in large specimens while the whole tissue was processed in smaller specimens or, in the cases in which the lesion's shape was not clearly identifiable, on macroscopic examination. All macroscopically significant areas were processed. Resection margin was considered close when the distance from the lesions was equal to or smaller than 2 mm.Histological slices were reviewed by two different pathologists.2X test was used for statistical evaluations cited in the results section.52 patients were enrolled for this study, with 54 related re-excisions.We divided the re-excisions in accordance with the time of re-excision and with the method of evaluation that defined the surgical procedure.38 patients (74.5%) were re-excised intraoperatively: in 25, re-excision was supported by the radiological report of close margins after specimen mammogram and, in 13, direct re-excision was supported by clinical evidence of incomplete excisions during surgery; 3 patients of this group had delayed re-excisions performed after definitive histological report of close margins on first resection specimen.The remaining 13 patients (25.5%) had no intraoperative extension, since the ordinary method of immediate evaluation of first resection provided suggestions for further procedures, and were extended subsequently (with 13 related specimens) because of evidence of close margin on histology.The histological definitive diagnosis of the re-excisions specimens (considering the main lesion if the re-excisions consisted of more than one specimen) is reported in The overall occurrence of residual neoplastic lesions in re-excisions selected for this study was 19 out of 54 (35%).In the series of the intraoperative procedures concerning patient with neoplastic lesions, 5 (13%) were effective in removing the target lesion, 9 (24%) harboured residual neoplastic lesions, and 20 (52%) were reported as normal breast parenchyma or contained benign lesions at definitive histology. On the other hand, 4 intraoperative re-excisions (11%) were related to cases with definitive histological diagnosis of benign lesions. Among the 16 delayed re-excisions, 10 (62%) were effective in eradicating residual tumor.P = .03) even considering the re-excision in the patients with final diagnosis of invasive carcinomas .The rate of residual lesions was compared in the two groups of intraoperative re-excisions  and delayed re-excisions (10/16 re-excisions). The difference was statistically significant  in an area of in situ carcinoma in another case. In 3 of the 8 excisions, the in situ carcinomas were poorly differentiated sec Holland.Another re-excision harboured residual foci of a lobular carcinoma with invasive features.In 7 cases (77%), the residual lesion was close to the new resection margin.In order to assess the role of invasive features in the efficacy of re-excision, we evaluated the rate of residual lesions in re-excisions in the two groups of patients with final diagnosis of invasive carcinoma (13/28) and with final diagnosis of in situ carcinomas (6/17). We excluded re-excision from patients in which the re-excision led to the removal of the target lesion (5 re-excisions).P = .45) and ruling out (P = .45) the peritumoral in situ as residual lesion in resection for invasive lesions. No statistical difference in the distribution of the neoplastic residual lesions between the two categories could be stated, both considering .Similar results were obtained considering only the intraoperative re-excisions .We matched the 20 radiology guided re-excisions and the 9 surgeon guided re-excisions. No statistical difference in the rate of neoplastic lesions was ascertained in the two groups  of the re-excisions leads to the resection of the target lesions, supporting the usefulness of this practice in breast oncologic surgery.Considering the efficacy of intraoperative re-excisions in clearing residual parts of the main lesion, the histological definitive examination detected residual neoplasm in 24% of the cases. Interestingly, the rate of successful re-excision in this study is somewhat lower than the rate of occurrence in other studies available in the literature (see introduction) , 14\u201317. If we look at the morphology of tumoral residuals in limited intraoperative re-excisions that were confirmed as neoplastic lesions at definitive histology, mutifocal, ill-defined lesions  were detected, and in the 77% of cases the re-excisions were ineffective in completing the removal of the neoplasm, as the residual lesions were close to the new resection margin. Our data show that invasive or preinvasive nature of target lesion does not affect the rate of neoplastic lesions in re-excisions: it could be expected that the oncological adequacy of conservative surgery is dependent on lesion profile and on detection capability at radiological and clinical examination, more than on evidences of invasion.Postsurgical radiotherapy could be a good option in obtaining the local control of the residual lesion that we detected in our revision. A study on predictive factors of residual-positive re-excisions performed on 115 delayed resections  achievedP = .004) and limiting the analysis to cases with final diagnosis of invasive lesions. Placing these results in the background of the debate about the real implication of the finding of close margins, apart from the evaluation methods, our findings could not confirm the hypothesis of a higher rate of tumoral residual in immediate versus delayed re-excision for the absence of repair processes [According to our data, the efficacy of the intraoperative re-excisions  is lower than the efficacy of delayed surgery after histological examination of first resection specimen, both considering all the re-excisions with cases with final diagnosis of neoplastic lesion (excluding those which harboured the target lesion; rocesses ; on the Considering the evaluation method of the first resection adequacy, we could not ascertain any statistical difference between the efficacy of radiological evidence guided re-excisions and the surgeon's choice dependent re-excisions in completing tumoral excision. Probably, a larger number of cases are needed for a more accurate evaluation of these two techniques, but these results show that surgeon's evaluation of surgical bed has a pivotal role in removing neoplastic residual that are not evident in radiology. Concluding, this analysis suggests that intraoperative re-excisions are mandatory when the intraoperative examination doesn't confirm the presence of the target lesions in the first resection specimen, but is more questionable when the lesion is judged close to the resection margin. The lesions that were re-excised in the same surgical session were mainly ill-defined areas with foci of in situ carcinomas, and these findings suggest the employment of other therapeutic options, such as radiotherapy.Considering the adequacy of the resections, it must be underlined that the practice of conservative breast surgery must now face the recent theory of the \u201csick lobe\u201d which asserts that conservative breast surgery must obtain the complete resection of the whole lobe involved in neoplastic disease . Followi"}
{"text": "The phase-response curve (PRC), relating the phase shift of the oscillator and externally given perturbation , is one Here we propose a systematic and efficient approach of estimating the PRC based on the recently developed method in signal processing called Compressive Sensing (CS) . CS is aUsing simulated and experimental data, we show that our CS-based method can produce a decent estimate of the PRCs particularly when the number of spikes is so small that averaging cannot help Fig. . Further"}
{"text": "Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are major components of the immune suppressive cells that potentially limit the effectiveness of an immunotherapy-based treatment. Both of these suppressive cell types have been shown to expand in tumor models and promote T-cell dysfunction that in turn favors tumor progression. In preclinical studies using transplantable mouse models, we observed that live attenuated bioengineered Listeria monocytogenes (Lm)-LLO immunotherapies have an impact on the suppressive ability of MDSC and Treg in the tumor microenvironment (TME), resulting in a loss in the ability of these cells to suppress T cells. This alteration of immunosuppression in the TME was an inherent property of all Lm-LLO immunotherapies tested and was independent of the tumor model. The virtually total loss in the suppressive ability of these cells in the TME was linked to a decrease in the expression of arginase I in MDSC and IL-10 in Treg. We are further investigating if the MDSC are differentiated into functional macrophages that increase antigen presentation within the TME in order to stimulate T cell immunity. Overall, this study provides insight into a potentially novel mechanism of action of Lm-LLO immunotherapies that may contribute to therapeutic anti-tumor responses."}
{"text": "The repression of competition by mechanisms of policing is now recognized as a major force in the maintenance of cooperation. General models on the evolution of policing have focused on the interplay between individual competitiveness and mutual policing, demonstrating a positive relationship between within-group diversity and levels of policing. We expand this perspective by investigating what is possibly the simplest example of reproductive policing: copy number control (CNC) among non-conjugative plasmids, a class of extra-chromosomal vertically transmitted molecular symbionts of bacteria. Through the formulation and analysis of a multi-scale dynamical model, we show that the establishment of stable reproductive restraint among plasmids requires the co-evolution of two fundamental plasmid traits: policing, through the production of plasmid-coded trans-acting replication inhibitors, and obedience, expressed as the binding affinity of plasmid-specific targets to those inhibitors. We explain the intrinsic replication instabilities that arise in the absence of policing and we show how these instabilities are resolved by the evolution of copy number control. Increasing levels of policing and obedience lead to improvements in group performance due to tighter control of local population size (plasmid copy number), delivering benefits both to plasmids, by reducing the risk of segregational loss and to the plasmid-host partnership, by increasing the rate of cell reproduction, and therefore plasmid vertical transmission. Mutual policing constitutes an important mechanism for the emergence and maintenance of cooperation through the repression of intra-group competition among a population of self-interested individuals. Existing models of mutual policing have been highly abstract and distant from the properties of real biological systems. In this paper, we construct a bottom-up, multi-scale computational model reflecting the biology of, perhaps, the simplest example of such a mechanism: replication control in non-conjugative plasmids, a class of vertically transmitted, molecular symbionts of bacteria. We simulate the emergence of plasmid copy number control through the co-evolution of two interacting plasmid traits: policing, realized as the production of trans-acting replication inhibitors, and obedience, expressed as plasmid-inhibitor binding affinities. We demonstrate and explain the intrinsic replication instabilities that arise in the absence of policing and we show how increasing levels of policing and obedience resolve these instabilities and improve both plasmid stability and host performance. The evolution of cooperation is a fundamental problem in biology: why help another individual to reproduce, if this comes at a cost to one's own reproductive success? This dilemma is reflected in the trade-off between an individual's immediate reproductive gains and its longer-term prospects of success as part of a collective, whose stability and overall performance is undermined by internal competitiveness. The eroding consequences of competition are exemplified by the \u201ctragedy of the commons\u201d A particularly elegant example of a policing mechanism for the repression of competition among individuals within a group is the replication control system of bacterial plasmids. Plasmids are extra-chromosomal DNA elements, organized as, typically circular, collections of discrete genetic modules The plasmid CNC mechanism encapsulates the two fundamental traits of standard generic policing models The CNC mechanism for the collective restraint of plasmid selfishness via mutual policing operates in a clear inter-specific context: plasmids often code for accessory adaptive traits that can provide their hosts with a variety of competitive selective advantages under particular environmental conditions The policing mechanism for the control of plasmid replication is subject to a dynamic evolutionary conflict between two levels of selection In this paper, we explore a range of social dilemmas facing non-conjugative plasmids carrying beneficial alleles. These dilemmas are present in the mechanistic interactions between selfishness, policing and obedience that determine the efficiency of the CNC system. More specifically, we use a mathematical model of the symbiotic relationship between hosts and plasmids in order to investigate how the conflict between intra-cellular selection (favoring plasmid recklessness with respect to replication) and inter-cellular selection  orchestrates the evolution of the plasmid-coded CNC mechanism.Our model for cellular growth and division (or death) is based on the premise that cell metabolism produces biomass and when this increasing mass reaches a certain threshold the cell divides. Specifically, let Changes in biomass rate see . As suchA wide range of mathematical models of varying specificity and complexity have been proposed for describing the autonomous replication of plasmids within a host, mostly based on the replication systems of plasmids R1 and ColE1 Parameters stable characteristic copy numberWe begin by focusing our attention to a single cell that contains a population of plasmids that are identical with respect to their replication profile. We initially ignore the stochastic nature of replication and cell division and consider the copy number to be a continuous variable, with both the host growth and the copy number described by deterministic differential equations see . Our modand  see . SubjectFor any configuration of plasmid replication parameters In the former case (NO-CNC), we observe that the system has a stable non-zero characteristic copy number for an extremely limited region of basal plasmid replication rates Our previous simulations demonstrated that, when stochasticity is ignored, there is only a limited range of The performance of a particular strain in such a stochastic simulation, in which hosts are infected by plasmids with identical replication parameter values, can be evaluated by calculating the average net host growth rate as the difference between the average host division and death rates. see also  and, as The stochasticities in plasmid replication and segregation upon cell division give rise to a distribution of copy numbers in the population that occur across all plasmid-infected hosts over the course of a simulation. We explored the effects of obedience  is obtained when we allow all three plasmid replication parameters tors see . In this low see , so thatWe also investigated the influence of policing costs to the evolution of collective restraint and the overall performance of the population, by introducing an additional cost term mids see .The positive effects of CNC are not limited to hosts but extend to plasmids as well. We evaluated the advantages of CNC for hosts and plasmids by comparing the results of our multi-cellular stochastic CNC simulations  of plasmids to the policing resource (replication inhibitor) that they themselves produce. Hosts in which plasmid obedience to policing is strong or under development, will outgrow fellow hosts in which obedience is weaker or absent, thus motivating the reinforcement of cooperation and the eventual establishment of the CNC mechanism.Text S1Detailed information about the plasmid profile used as well as about the methods and their implementation (i.e. the unicellular deterministic and multicellular stochastic simulations).(PDF)Click here for additional data file."}
{"text": "The different biochemical properties of Nit-ANigWT and Nit-ANigRec discussed in the paper were caused by a significant difference in the primary structures of these enzymes.The authors have retracted this article  due to t"}
{"text": "Optical microscopy and multi-particle tracking are used to investigate the cross-correlated diffusion of quasi two-dimensional colloidal particles near an oil-water interface. The behaviors of the correlated diffusion along longitudinal and transverse direction are asymmetric. It is shown that the characteristic length for longitudinal and transverse correlated diffusion are particle diameter  The dynamic behavior of confined colloidal suspensions has recently received a considerable amount of attentions The diffusion behaviors of particles reflect the influence of the boundary conditions In this paper, we report an experimental measurement of the cross-correlated diffusion of colloidal particles near a water-decahydronaphthalene  interface. It is shown that for larger particle separation, along the line connecting the centers of the particles and the direction perpendicular to this line, the characteristic length is particle diameter Two types of colloidal particles, both with a diameter The experimental setup is shown as in Using an inverted Olympus IX71 microscope, the motion of the colloidal particles was recorded by a digital camera (Prosilica GE1050) at a rate of 14 frames per second. Each image sequence comprises 500 consecutive frames (taken over The PS monolayer is located at a higher position above the oil-water interface than the silica monolayer because the PS spheres are less dense and have a greater surface charge than the silica particles. The average distance The parameter Tracking individual particle's trajectory, we obtain particle's cross-correlated motion via the ensemble of averaged tensor products of the particle's displacements Typically,The mechanism behind the independence of To focus on the influence of the oil-water interface on the correlated diffusion coefficients, first, we averaged the curves of In the perpendicular direction, We compare our results with previous studies for the following boundary conditions: colloidal spheres dispersed in an unbounded 3D bulk, confined by a solid wall or at an air-water interface At first glance, the result that the decay rate of Similar to the mechanism of a membrane near a solid wall The HIs through path I entail that the cross-correlated motion is a function of tion of  . For a ldent of   for . InFor a very high area fraction We experimentally investigated the cross-correlated diffusion of colloidal particles near an oil-water interface that distinctly affects the correlated diffusion coefficient"}
{"text": "Carers of individuals with social care needs , are subject to high levels of carer burden, social isolation and poor psychological outcomes. Carers\u2019 worries and concerns include leaving the individual alone; risks of harm to the care-recipient; or household emergencies in their absence. At present there is a lack of research on the impact of telecare interventions on carer outcomes. It is feasible that carers\u2019 anxieties and level of strain may be ameliorated with concomitant increases in quality of life, with the introduction of telecare systems for their care-recipient.This study investigates the secondary impact of telecare on carers, specifically whether the use of telecare reduces informal carer burden and social isolation and whether it improves carers\u2019 psychological well-being and confidence in leaving the care-recipient alone.We report on the prospective analysis of a pragmatic controlled trial on carers of telecare users and controls within the WSD evaluation of telecare .Carers of individuals with social care needs were identified and recruited to the study via a combination of snowball sampling, light touch visits (to users) and self selection. Over 200 carers completed a questionnaire pack at baseline, and at short and long-term follow-ups; with roughly equal numbers of carers of recipients of telecare and recipients of usual care. The questionnaire pack included measures of quality of life (ICECAP), health related quality of life , psychosocial well-being  and care-giver strain measures .Multi-level modelling of difference in outcomes between carer groups and across time was conducted with appropriate covariates. Specific findings from the Telecare Carers Study are embargoed until these analyses have been peer-reviewed and accepted for publication."}
{"text": "The characteristics of time-driven simulation are a fixed-size simulation step and a fixed-size communication interval . The forThe time-driven environment of the simulator NEST  providesIn general, a time-driven simulator that supports the off-grid framework performs neural network simulations with the same precision and faster than an event-driven simulator . HoweverHere, we present algorithms which are guaranteed to detect all threshold crossings by supplementing the standard test for a super-threshold membrane potential at each check point and that exploit the information about the neuronal state at nearby check points. These additional tests need to be invoked whenever the membrane potential is sub-threshold, which means at virtually all check points. We develop sub-tests of increasing complexity and specificity, starting with simple sifting methods and ending up with a complex expression that faithfully indicates the existence of a threshold crossing between the last and the current check point. An analysis of the test specificities and computational costs results in a cascade of tests which locates all threshold crossings at a low computational cost."}
{"text": "The distribution of synaptic efficacies in neural networks takes fundamental influence on their dynamics and the modification of synaptic strengths forms the foundation of learning and memory. A prominent plasticity rule that has been observed in vitro is spike-timing-dependent plasticity (STDP). While first studied in glutamatergic synapses, recently also STDP of GABAergic synapses came into the focus of experimental and theoretical research .We study random balanced state networks of leaky integrate-and-fire neurons in the asynchronous irregular (AI) regime  that is When introducing excitatory STDP alone, parameters involving the maximal weight have to be fine-tuned in order to keep the network activity stably in the AI regime . For alm"}
{"text": "The issue of missing data is present in every trial. Identification of the missing data mechanism is not straightforward; however it is essential to avoid bias. The mechanism of missing completely at random (MCAR) is seldom appropriate and the distinction between missing at random (MAR) and not at random (MNAR) is not straightforward. Follow-up reminder responses provide excellent source of information for investigating the issue.Improving postal response rates for patient-reported outcome measures often requires some kind of reminder process. Patient-reported outcomes from two stroke rehabilitation cluster randomised trials were used to investigate the usefulness of reminders in the identification of the missing data mechanism. In both trials, the reminder process was set-up from the outset. Missing data in these trials had an intermittent pattern. An approach by Fairclough (2010) was used to determine missingness mechanism.Covariates predicting non-response (from reminder-responders) were first identified to distinguish between MCAR and MAR mechanisms and participants outcome scores were added to model testing for inclusion to check for evidence of MNAR.The advantage of this method is that reminder-responses are considered to be similar to non-responders with the additional benefit of knowing the actual outcome. Furthermore, identification of covariates indicated by this approach can inform the choice of covariates for the appropriate method of data imputation.In trials with potentially high loss to follow-up, reminder strategies can be used not only to minimise loss to follow-up but offer valuable data to examine mechanisms of missingness and ultimately contribute to a robust final analysis."}
{"text": "Presented is further development of the architecture presented in  where a The neural network is built on integrate-and-fire spiking neurons with active dendrites (ADDS) and trained with STDP rule presented in . The ove"}
{"text": "The global plan of reducing the number of new child HIV infections and a reduction in the number of HIV-related maternal deaths by 2015 will require inordinate political commitment and strengthening of health systems in Sub-Saharan Africa where the burden of HIV infections in pregnant women is the highest. Preventing HIV infection in women of child-bearing age and unwanted pregnancies in HIV-positive women forms the cornerstone of long-term control of paediatric HIV infections. To achieve the goal of eliminating paediatric HIV infection by 2015, health systems strengthening to address prevention of mother-to-child HIV transmission cascade attrition and focusing on the elimination of breastmilk transmission is critical. Understanding the pathogenesis of breastmilk transmission and the mechanisms by which antiretroviral therapy impacts on transmission through this compartment will drive future interventions. Identifying and retaining HIV-positive pregnant women in care and committed to long-term antiretroviral therapy will improve maternal outcomes and concomitant reductions in maternal mortality. Research assessing the natural history of HIV infection and long-term outcomes in women who interrupt antiretroviral therapy post-weaning is urgently required. Data on the outcome of women who opt to continue the long-term use of antiretroviral therapy after initiating therapy during pregnancy will determine future policy in countries considering option B+. The prevalence of antiretroviral resistance and impact on survival in infants who sero-convert whilst receiving neonatal prophylaxis, or are exposed to maternal HAART through breastmilk at a population level, are currently unknown. In addition to the provision of biomedical interventions, healthcare workers and policy makers must address the structural, cultural and community issues that impact on treatment uptake, adherence to medication and retention in care."}
{"text": "Pteronotus parnellii and Pteronotus quadridens) and in Rhinolophus rouxi. Recently, it was proposed that heteroharmonic target-range computations are a primitive feature of the genus Pteronotus that was preserved in the evolution of the genus. Here, we review recent findings on the evolution of echolocation in Mormoopidae, and try to link those findings to the evolution of the heteroharmonic computation strategy (HtHCS). We stress the hypothesis that the ability to perform heteroharmonic computations evolved separately from the ability of using long constant-frequency echolocation calls, high duty cycle echolocation, and Doppler Shift Compensation. Also, we present the idea that heteroharmonic computations might have been of advantage for categorizing prey size, hunting eared insects, and living in large conspecific colonies. We make five testable predictions that might help future investigations to clarify the evolution of the heteroharmonic echolocation in Mormoopidae and other families.Echolocating bats use the time elapsed from biosonar pulse emission to the arrival of echo (defined as echo-delay) to assess target-distance. Target-distance is represented in the brain by delay-tuned neurons that are classified as either \u201cheteroharmonic\u201d or \u201chomoharmormic.\u201d Heteroharmonic neurons respond more strongly to pulse-echo pairs in which the timing of the pulse is given by the fundamental biosonar harmonic while the timing of echoes is provided by one  of the higher order harmonics. On the other hand, homoharmonic neurons are tuned to the echo delay between similar harmonics in the emitted pulse and echo. It is generally accepted that heteroharmonic computations are advantageous over homoharmonic computations; i.e., heteroharmonic neurons receive information from call and echo in different frequency-bands which helps to avoid jamming between pulse and echo signals. Heteroharmonic neurons have been found in two species of the family Mormoopidae ( Echolocation allows bats to create perceptual images of complex night environments Griffin, . A key pPteronotus parnellii; O'Neill and Suga, Pteronotus quadridens, Hechavarr\u00eda et al., Rhinolophus rouxi; Schuller et al., Myotis lucifugus; Sullivan, Eptesicus fuscus; Feng et al., Carollia perspicillata; Hagemann et al., P. parnellii and P. quadridens) and one species from the family Rhinolophidae (R. rouxi) delay-tuned neurons are activated by the combination of the FM component of the fundamental harmonic in the call and one of the higher harmonic FM components in the echo -FM echolocation  Mormoopidae is the only family of bats including both CF-FM and sCF-FM species.The \u201cheteroharmonic computation strategy\u201d (HtHCS) was first described in The evolution of echolocation has received much attention in the last decade. Recent molecular phylogenies  HtHCS was found in We discuss how brain adaptations, distinctive characteristics of calls- and echoes- and phylogenetic relationships in mormoopids could have led to the acquisition of the heteroharmonic target-range computation strategy in this family. We argue that the HtHCS provides mormoopids with behavioral and ecological advantages for categorizing prey-size, hunting eared insects, and living in large colonies. By conducting the analysis in the light of recent molecular phylogenies, we are able to explore the evolutionary relationships between HtHCS and CF-specializations. We present the hypothesis that in Mormoopidae, HtHCS echolocation evolved independently from long-CF echolocation, high duty cycle (HDC) echolocation and Doppler Shift Compensation. We make five specific, testable predictions that might help future investigations to decipher the evolution of the heteroharmonic echolocation in Mormoopidae and other families.The most commonly used approach to determine whether a neuron is tuned to echo-delay or not consists in presenting the animal with artificial  pulse-echo pairs with different delays. The response of the neurons is measured as the number of spikes fired by the neuron in response to each echo-delay. If the echo-level is also changed during the recording, then the neuronal response is represented in the two dimensional space of echo-delay and echo-level in the form of a delay response area (DRA). Delay tuned neurons respond only  to a few combinations of echo-delay and echo-level  is followed by one of the upper FM-harmonics in the echo  with a certain delay. Delay-tuned neurons are classified according to their best harmonic combination, i.e., the combination of pulse and echo harmonic that elicits the largest response. In P. parnellii, neurons tuned to combinations of FM1 and FM2, FM1-FM3, and FM1-FM4 have been found  in response to heteroharmonic pulse echo-pair combinations, i.e., FM1/FM2 and FM1/FM3. It has been suggested that neurons tuned to different harmonic combinations could provide information about targets with different acoustic properties i.e., preys of different sizes  is not an exclusive feature of heteroharmonic neurons tuned to echo-delay. For example, combination sensitive responses have been found in mice, birds, monkeys and homoharmonic bat species, among others . Only the family Mormoopidae includes both LDC and HDC species. Although useful as a first approach, classifying bats into FM-LDC and CF-HDC according to their calling strategy is not fine-grained enough to explore the evolution of target-range computation in mormoopids.The examination of call design could provide a better understanding of the evolution of the HtHCS for target-range computation in bats and specifically in the family Mormoopidae. Bats use a highly diverse repertoire of call designs. Biosonar call diversity is observed both across ] broadcast calls with three or more harmonics, as do the remaining Pteronotus and Mormoops species  contain two harmonics  use echolocation calls with one or two harmonics  uses the HmHCS  uses multiharmonic calls with harmonic overlapping  with two or more harmonics without frequency overlap. In addition, it is of advantage if the duration and curvature of the FM components are adjusted for acoustic focusing as a function of distance to target, in correlation with neuronal adaptations for the processing of call design as a complement of the target-range computation strategy. Also it could be predicted that bats that use HtHCS are capable of a precise control of call frequency and intensity. The latter will be explored in the following section.Echolocating bats dynamically change the acoustic parameters of calls  to cope with their environment and perceptual task. A closer view at the common principles used by HtHCS bats to exploit frequency and intensity of calls- and echoes- may help to assess the evolution of their target-range computation strategy. This section focuses on the analysis of frequency and intensity because both parameters are closely related in the heteroharmonic target-range computation strategy. The frequency spectrum of each call is determined by the amount of energy or sound intensity distributed between harmonics, and frequency and intensity are the two main parameters used to characterize the receptive field of delay-tuned neurons (see section Delay Tuning in Auditory Neurons of Different Bat Species).Tadarida brasiliensis  and from the maximum frequencies of the third harmonic . Distinction of insect size will be favored by individual auditory neurons responding to either the echoes from the second or the third harmonics , uses one of the lowest frequencies within the genus Pteronotus  is lowered in frequency and the echo's higher harmonics (FMx) is set at the species resting frequency. In contrast, the non-compensating smaller mormoopids should show best responses of delay-tuned neurons for combinations of the call's resting FM1 and the echoes' shifted FMx.Doppler shift compensation is not linked to the HtHCS. DSC involves lowering the frequency of the next echolocation call to compensate for the flight-induced increase in the frequency of echoes from a previous emission  as a promising feature that would support the HtHCS for target-range computation. In addition, both the most basal and one of the most recently evolved species of Pteronotus computes call-echo delay heteroharmonically  are gleaning bats that emit multiharmonic calls with faint fundamental harmonics, but showing frequency overlap  or to aid in the discrimination of different target sizes.If the ability of HtHCS computation characterized the ancestors of Noctilionoidea it may have prevailed at least in descendent species with limited frequency overlap between harmonics. The genera Noctilio and Macrotus are appropriate candidates to test this hypothesis.Intensity compensation is harmonic-dependent in mormoopids and other bats with HtHCS. Calls and echoes represent different harmonic interests for the heteroharmonic echolocator and therefore the rules describing the dynamic adjustment of call/echo intensity will distinguish one harmonic from the other.If the echolocation calls of mormoopids evolved to hunt eared prey, they will be relatively inaudible to moths if compared to calls from HtHCS bats of comparable size.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases.To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions.Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals  previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans.Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species . The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions.Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. Over the past approximately 40 years, only around 600 chemicals have been tested by the NTPs in their two-year cancer bioassay and only about 5\u20136 times this number have been tested worldwide.There is push to use a broad array of biological data in toxicity testing to improve reliability and provide reasonably quick indications of animal and human toxicity of chemical compounds. The National Toxicology Program (NTP) 's High Throughput Screening (HTS) in vitro results from the various cell lines to the human in vivo context.The goal of toxicity testing is ultimately to protect human health. Even though the two-year cancer bioassay is performed on rats and mice, there is considerable data supporting its use to screen for carcinogens in humans An alternative to the cell-based assays in the HTS and ToxCast programs is the use of short term molecular data  from exposed animals or humans to predict future toxicity or carcinogenicity. Others have used gene expression data based classifiers that would distinguish a toxin or carcinogen from a non-toxin or non-carcinogen A characteristic of gene expression data is the very large features (genes) to samples  ratio. This characteristic contributes to the lack of identification of robust classifiers as demonstrated by In order to gauge quantitative predictive accuracy of a pathway-based prediction model we obtained gene expression data from the livers of mice dosed with 26 chemicals over a period of 90 days. All the 26 chemicals were tested in a two-year bioassay in the same strain of mice dosed via the same respective routes. Thus, the differential liver carcinoma and adenoma rates between treated and control animals from the results of the two-year bioassays are known. Using the data, we derived pathway-based models to predict the differential tumor rates at the end of a two-year bioassay. The use of a pathway-based model would result in a reduction of a model with around 6000 gene features to one with around 200 pathways in the KEGG database 1 mice are summarized in The chemical treatments used in the experiments on female B6C3FTo address the question of species extrapolation, gene expression and tumor data from chemical exposures in Fischer 344 rats were obtained from the literature The pathology review of the treated mice after 90 days of exposure to hepatocarcinogens did not identify liver tumors see . Hence, 2-transformed. The entire set of data sets associated with risk factors for liver cancer is summarized in Genetic risk factors in terms of single nucleotide polymorphisms associated with various human diseases including liver cancer are tabulated on databases like the Genetic Association Database The biochemical pathways used in the analysis in this paper were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database 4 randomizations , cN the number of chemicals . iz is given by ijZ is given by Specifically, the poly-3 statistic for a chemical obtained from the two-year cancer bioassays is assumed to be functionally related to the 90 day gene expression-based perturbation of the pathways :The framework of the so-called Super Learner CV.SuperLearner function implemented in the SuperLearner package. Specifically, the predictions for the chemicals in each of the 5 test sets (corresponding to the 5-folds) are derived from an additional 5-fold cross-validation of the remaining 20 or 21 chemicals in the 5 training tests.Five-fold cross-validation was chosen where the chemicals in each of the five folds were fixed (Table S3) and chosen so that distribution of high and low carcinogenicity values in each fold was more or less the same. Predictions for all the data sets were based on this 5-fold cross validation framework. In order to get \u2018honest\u2019 predictions for the chemicals with data from mice, because these chemical data are used to make predictions for the very same set of chemicals, two levels of 5-folds cross-validation was implemented using the The two year cancer bioassay carcinogenicity calls of the chemicals used in the mice and rats experiments along with the continuous predictions from the model ) derivedSL.randomForest.1_All in importance for each of the biochemical pathways used in the prediction model. The importance of a pathway is a measure of how much it contributes to increases the accuracy of the predictions.Different prediction models were evaluated in terms of their 5-fold cross-validated risk for fitting the model given by The model derived using the mouse data was used to predict the carcinogenicity in mice, rats and humans for the corresponding data sets. In this manuscript, the predicted values were treated as proxies for the continuous NTP carcinogenicity values in The false positives and false negatives in each of the three species at a level of specificity between 56\u201375%  is summarized are This paper presents results only for pathway-based prediction models. Gene-based prediction models were also evaluated and they showed a similar performance in terms of the AUC metric (data not shown) The importance measures for each of the pathway-based features are reported in The predicted dose response for the chemicals in The analyses involved in this paper worked with hepatocarcinogenicity prediction models trained using data from mice and extrapolated to data sets from rats and humans. Alternate models derived from rats to predict carcinogenicity in other species could be attempted. This was not attempted here because of lack of sufficient analogous two-year cancer assay data for the rat and human data sets. The model derived here used data for chemicals at their maximum tolerable dose (MTD) levels. It could be argued that responses at lower doses are the ones with the most human relevance. Again this was not attempted here because of lack of sufficient number of chemicals dosed at lower levels. One possibility of understanding chemical-specific low-dose mechanisms would be the availability to a relatively large epidemiological data set of exposed people . The mice have a relatively high background rate of developing HCC. In humans, HCC is thought to arise in a background of chronic inflammation, necrosis and regeneration, fibrosis and extracellular matrix deposition However, in the predictive toxicology context of the manuscript, in spite of the known differences in etiologies, our hypothesis is that gene expression levels of the precancerous lesions are the similar in mice and humans. This hypothesis is validated by the relatively high predictability of human hepatocarcinogenicity using an independently derived predictive model using 90 day gene expression data from B6C3F1 mice. Further, the work in Hoeneroff et al suggests that this hypothesis is not without justification. In their work the authors found similar gene expression profiles in cells from HCCs obtained from mice and human samples. The situation is analogous to the case of azoxymethane induced colon cancer In summary, we rigorously derive and evaluate a biochemical pathway based hepatocarcinogenicity prediction model. Among the set of alternate prediction models , random forests were found to perform the best in terms of cross-validated risk. The model used gene expression data from a given tissue at the end of a short term study to predict the risk for development of tumors at the end of a longer period of time. Specifically, the model is evaluated using gene expression data obtained from the liver of mice treated with a range of 26 chemicals over a period of 90 days. The model with the information on affected pathways derived using these gene expression data had sufficient signal to adequately predict the two-year liver carcinogenicity risk of the same chemicals as evaluated in the National Toxicology Program's two-year cancer bioassay. The fact that the model was developed at the biochemical pathway level allows one to reasonably expect conserved behaviors of the chemicals at the pathway level across multiple species. This belief was validated using the model developed for mice to predict results in humans and rats. This fact was observed in Figure S1Clustergram of transformed p-values ) representing the enrichment of the 216 pathways across the 26 chemicals treatments in mice, was generated using hierarchical clustering with the euclidean distance metric and average linkage to generate the hierarchical trees of pathways and chemicals using the Cluster and Tree view programs .(PNG)Click here for additional data file.Text S1Provides additional description of the microarray experiments, involved in mice and rats, the data for which are used in the analysis. Also provided are details of generation of (DOC)Click here for additional data file.Table S1List of rat hepatocarcinogen treatment groups from Auerbach et al., 2009.(XLS)Click here for additional data file.Table S2List of chemicals in  that were chosen to be in each of the 5 folds in the cross-validation analysis performed.(XLS)Click here for additional data file.Table S3List of various learning algorithms attempted in the SuperLearner package  and the cross-validated risk for the case of pathway-based continuous predictions.(XLS)Click here for additional data file.Table S4The list of pathways used as predictors along with their importance measures as reported by the random forests learning algorithm . The importance measures for each of the pathways are also reported.(XLS)Click here for additional data file."}
{"text": "Mimetics of secondary structure elements are one promising approach in the design of protein-protein interaction inhibitors, since secondary structure elements are very important recognition motifs in protein-protein interfaces. In helices and turns, the protein backbone provides a scaffold to present the sidechains in the correct orientation for the three-dimensional interaction motif. For both, scaffolds are known that resemble these backbone conformations and can be decorated with sidechains in the right position for mimicking the interaction motif . BenzodiHowever, identifying small chemical scaffolds that mimic turn structures is rather complicated. Turns are irregular structures with a wider variety of possible backbone conformations  and for The results of an exhaustive analysis of turn structures involved in protein-protein interfaces will be presented and the impact on the design of secondary structure element mimetics will be discussed. This is of particular interest since the secondary structure space of protein-protein interfaces is limited and similar interfaces with respect to secondary structure elements exists within proteins showing different overall folds and function . The ide"}
{"text": "Various criteria to terminate resuscitation have been reported. EMTs in Japan are not permitted to terminate resuscitation in the field. The aim of this study is to test the hypothesis that ECG rhythm response to basic CPR and its duration may predict hospital death.The basal data were prospectively collected from 1,437 unwitnessed out-of-hospital cardiac arrests (OHCAs) that were resuscitated by EMTs without the ACLS technique in Ishikawa Prefecture  in hospital. The duration of EMT-performed CPR predicted the outcomes of the OHCAs that were unresponsive to the basic CPR Figure .Responsiveness to basic CPR and its duration may predict unavoidable death in hospital."}
{"text": "F-18 Fluorodeoxyglucose Positron Emission Tomography imaging (F-18 FDG PET) detects malignancies depending on the uptake profile of glycolysis of tumors; however, the role of FDG PET is limited in the evaluation of primary renal malignancy because of low FDG uptake by renal cell carcinoma and also because normal urinary excretion of FDG seen in the images. A patient with renal cell carcinoma whose FDG PET imaging study incidentally shows a photon-deficient mass in the upper pole of the right kidney is present here. The diagnosis is also validated by the histopathological findings of tumor necrosis, hemorrhage, and scars. It is well established that advances in F-18 FDG PET imaging may lead to early cancer detection, more accurate tumor staging and consequently adequate treatment, better monitoring of the disease and enhanced surveillance for recurrences after treatment. The role of FDG PET is limited in the evaluation of primary renal malignancy because of low FDG uptake by renal cell carcinoma (RCC) and because of the normal urinary excretion of FDG seen in the images.A 69-year-old man with a history of having undergone coronary artery bypass graft, cholecystectomy, cerebro-vascular accident with craniotomy and recent hoarseness of voice for eight months had recently invasive squamous cell carcinoma of vocal cord. CT of the neck without contract enhancement showed deformity of the larynx with thickening of the anterior commissure and right vocal cord which are characteristic of a mucosal lesion. He also suffered from new onset of changes in non-specific gastrointestinal symptoms. Therefore he underwent an abdominal CT with contrast medium which incidentally showed a heterogeneously enhancing exophytic mass projecting posteriorly from the upper pole of the right kidney . Four daA case of a photon-deficient area in the upper pole of the right kidney on FDG PET scan , which wRCC is a diagnostic challenge. Among all patients with RCC, 25%\u201339% are asymptomatic and the diagnosis is made from a radiological study obtained for the reasons.In the study of FDG PET in detection of RCC, Ak and Can reported that F-18 FDG PET may have a role in the diagnosis and evaluation of patients with RCC and primary staging of the disease.FDG PET is limited in the evaluation of primary urological malignancies including prostate and urinary bladder cancer.17In summary, a patient with renal cell carcinoma, whose FDG PET incidentally showed a photon-deficient mass in the upper pole of the right kidney is presented; this finding can be explained by non- uptake of the tracer by the tumor, and the histopathological findings of tumor necrosis, hemorrhage, and scars."}
{"text": "The Picardie region is one of the regions in which the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is high  compared to the French national average .That is why the regional center for nosocomial infections control in 2012 made an assessment study on the actions and the resources involved in prevention and control of MRSA and Multi-Drug Resistant Bacteria (MDRB).The survey was proposed to 82 hospitals in the region using on-line or paper questionnaires forms. Data were entered and analyzed using Epi-Info 6.04d software.Overall 41 hospitals  participated in this investigation. 66% of them reported having a system of continuous monitoring of MDRB for the identification of clustered cases and 39% of the hospitals reported having a similar device for the identification of re-hospitalized cases. In addition, 63% of respondents indicated that they did not develop transmission means for the patients with MDRB to inform the hosting facility during a subsequent hospitalization. When a case of patients with MDRB occurs in a hospital, 88% of them track cases of re-hospitalized patients thanks to patient records and not via the administrative software. 57% of the hospitals reported to implement a policy of MDRB monitoring. More than half patients considered to be at risk  was concerned in the majority of sectors welcoming patients with emerging MDRB. The most frequently screened MDRB are respectively MRSA (46%), carbapenemase-producing Enterobacteriaceae (44%), glycopeptide-resistant Enterococci (44%) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (41%).The components of the MDRB control which are collected within the hospitals of the region have shown critical points, especially in the monitoring of patients with MDRB. Specific policy focusing MDRB should be reinforced in the region.None declared"}
{"text": "The today\u2019 s technologies allow an easy way to share information relevant to image by means of different tools. Many solutions are today available that allow to the cytologist to exchange digitalized information about glasses. It is thus arising the need of objective methodologies, such as the ones based on HTA that we have proposed in a previous study focused in tele-pathology , to inveIn a typical today\u2019s architecture there ison-site-server with the scanner or alternatively a tele-pathology third-party-server , for the creation of the virtual glasses named Digital Slides (DS)s,a) an \u2019 centre  at http:andLight-client applications proprietary software tools  for the navigation on the DS which can be installed in remote clients.b) low cost (or free) This new methodology is rapidly largely spreading and it is becoming the core aspect of the formation for future qualified personnel and is more and more asking for user-friendly and effective ICT solutions.Tablet-technology-ICT-solution is recently widely increased as a user-friendly and effective tool to remotely share image information. Thanks to this technology it is possible to navigate into an image  using only the hand-fingers without typing the keyboard or the software interfaces\u2019 keys. This way of image navigation is going to further improve the application of Telemedicine to DP and in particular in D-CYT with particular reference to the remote and/or cooperative decision and diagnosis in cytology.The The methodological flow clearly arises by inviting the reader to navigate in the Public WEB of the University of Leeds named \u201cVirtual Pathology at the University of Leeds\u201d where several digital-slides are available for public use at the URL :http://www.virtualpathology.leeds.ac.uk/public/common_slides.phpsubjectively consider thus the differences. It is thus clear that there is thus strongly the need of considering both the state of art of the Tablet technologies and the design of an objective methodology to assess the technology. The methodological flow faced thus the two basic issues:The reader can try to navigate the DS by means of a PC using the interface of Spectrum Web Viewer (by Aperio) or by means of a Tablet system using the fingers and Analysis of the state of art of the tablet technologies.\u2022 Investigation of HTA solutions [ to assess the technology (Tablet and applications of D-CYT) both in terms of performances and acceptance for the relevant introduction in Telemedicine [\u2022 olutions  to assesmedicine -8, [9,10wearable tablets, portable tablets and not-portable tablets.The analysis with the focus to D-CYT returned that the tablet technologies could be grouped into: wearable tablets comprehend the Smart-phones i.e the devices that can be embedded in a pocket  .1. Further issues relevant to studies of HTA, as from specific experience of mondial networks of HTA such as the EUNETHTA (2. Integration of specific studies on HTA over the NET, as the focus is the D-CYT is the communication over the WAN/LAN.Tablet technologies have been reviewed with the focus to the perspectives of the D-CYT. A HTA specific tool has been proposed to assess the performances and acceptance of the applications in D-CYT based on tablet technologies. Possibilities and limitations of the three different tablet technologies will be deeply investigated by means of the proposed HTA methodology on experts and students approaching the new scenario of digital-cytology.HTA: Health Technology Assessment; DP: Digital Pathology; D-CYT: Digital Cytology; DS: Digital SlideThe authors declare that they have no competing interests.DG MRG wrote the manuscript as major contributors. MP has prepared the review on the wearable and portable and not portable Tablet technologies and is currently caring the experimentation study. EG has reviewed and improved the scientific content and rationale of the manuscript. All authors have read and approved the final manuscript."}
{"text": "The Seal or Varnish study is a pragmatic randomised trial to evaluate the relative cost and effectiveness of pit and fissure sealants and fluoride varnish in preventing dental caries in high-risk children in South Wales. In partnership with the Cardiff & Vale UHB Community Dental Service (CDS), the trial utilises the infrastructure of an existing school-based dental programme to conduct clinical assessments/intervention delivery via mobile dental units.While this research naive setting is novel for a CTIMP, in accordance with the 2012 MRC/DH/MHRA joint guidance for risk-adapted approaches to the management of CTIMPs, the low risk nature of the interventions have allowed justification of several risk-based adaptations to the management and conduct of the trial. In addition, through the use of consultation exercises with a representative parents group, adaptations to the standard NRES templates for participant information sheets/consent forms have also been developed in an attempt to maximise uptake onto the trial.Employment of the risk-adapted approach has minimised additional administrative burden placed on the CDS in implementing the trial compared with the existing dental programme. The adaptations made to the consent process and participant materials have received positive feedback, however consent rates for the trial were found to be lower than previous years' response rates to the dental programme in the majority of schools.This trial represents one of the first experiences of employing a risk-adapted approach to management of CTIMPs, highlighting several areas for consideration when designing and implementing trials involving low-risk interventions in novel environments."}
{"text": "Auditory brainstem calculates horizontal direction (azimuth) of sound from the ITD . Jeffress proposed in 1948 that sound source azimuth is computed by a neural circuit consisting of an array of delay lines . We studWe present our current results as a case study showing multitude of roles of (random versus deterministic) spike timing in a neural circuit. In particular, either phenomenological (excitatory-excitatory and excitatory-inhibitory units), or electrophysiological (excitatory and inhibitory synapses) classification of individual elements of the circuit might be abstracted in an explanation stressing the neural computation in the circuit. We study various parameters of the MSO model and their influence on the output of the model. Finally we evaluate the performance of the model using the concept of ideal observer."}
{"text": "Critical dynamics in complex systems emerge at the transition from random to ordered dynamics and are characterized by power-law distributions of spatial and temporal properties of system events. The occurrence of critical dynamics in neuronal networks is increasingly supported by multielectrode array recordings of spontaneous activity in organotypic cortical slice cultures . System Here, we present three novel transfer-entropy  based meDynamics in our networks change from subcritical to critical to supercritical as the modular topology of the networks is progressively randomized Fig. . All thr"}
{"text": "It has been known for some time that photoreceptors transmit more information when driven by stimuli which have 'naturalistic' statistical properties and that processing of naturalistic visual stimuli involves nonlinear transformations of the input signals. Until now it was not clear which statistical features of the stimuli the neurons are selectively 'tuned' to respond to. Another major difficulty was to elucidate the computational mechanisms which explain differences in coding naturalistic and Gaussian stimuli.Drosophila photoreceptor to fully characterize their underlying computational capabilities. The model was derived based on photoreceptor responses measured in vivo using naturalistic input stimuli, which the system experiences in its natural environment. In order to characterize the nonlinear transformations performed by photoreceptors we analytically computed the higher-order or generalized frequency response functions (GFRFs) of the identified nonlinear photoreceptor model. Using this approach, we demonstrate, for the first time that the observed increase in power of photoreceptor response, and shift towards higher frequencies as the mean light intensity increases, is the result of changes in the operating point of the photoreceptor, which produces a change in the shape of the magnitude of the frequency response functions. This suggests that the photoreceptor adaptation mechanisms are not tuned to fully compensate for the drop in intensity in order to achieve, in an efficient way - by exploiting the photoreceptor nonlinearity - a change in the shape of the magnitude transfer functions, which are optimal for the given mean intensity level.Here we used a functional model of Furthermore, we examined the significance of both local and non-local high-order phase correlations for fly vision. We simulated the photoreceptor model using synthetic stimuli sequences incorporating local phase correlations (edges) and non-local phase correlations (quadratic phase coupling) superimposed with Gaussian white noise. By decomposing voltage output of photoreceptor somata into linear second- and higher-order responses, we explain the nonlinear mechanisms responsible for coding the local and non-local higher-order statistical features in the stimuli as well as improving their signal-to-noise ratio.To validate the results, we carried out electrophysiological experiments using a specially designed stimuli sequence, which allows extracting the nonlinear component of the photoreceptor response directly from data, without a model.The frequency response decomposition employed in this study allowed us to reveal for the first time the quantitative relationship between the higher-order statistical properties of environmental stimuli and processing of these stimuli in fly photoreceptors. In light of the results, we argue that the goal of early sensory coding is to maximize sensitivity to higher-order statistical features of the stimuli that are behaviorally relevant to the animal whilst minimizing sensitivity to non-informative signals, to encode efficiently these features and increase their salience to facilitate further processing. Our framework elegantly explains the differences in coding of naturalistic and white noise signals and how this is achieved efficiently without a change in the response transfer function of the photoreceptor when the mean light intensity is constant. It also explains why and how naturalistic stimuli increase the rate and efficiency of information transmission."}
{"text": "The aims of this study are twofold: (1) the theory-based development of a patient self-report measure of physician warmth; and (2) the application of cognitive interview methodology to understand patients\u2019 perception and interpretation of this new measure.A draft measure was developed based on an in-depth literature review of the concept of human warmth by a multidisciplinary expert group working in integrative medicine. Sixteen cognitive probing interviews were conducted to examine how patients from integrative and conventional medicine perceive and interpret this new measure and to identify potential problems. A content analysis of the interviews was used to evaluate findings.Findings indicate that the WARMOMETER is a short patient self-report assessment of physician warmth, which seems easy and intuitive to understand for every patient. In addition, most respondents were found to share a common concept of physician warmth.Verification of our study hypotheses and confirmation of the theoretical assumptions of human warmth give basic indications that the WARMOMETER seems to be a valid and sensitive patient self-report instrument for assessing the socio-emotional quality of physicians in integrative and conventional medicine. These first promising results of our cognitive interviews suggest that the WARMOMETER may also be used and further validated in future studies on the patient-physician relationship in integrative medicine, also with other healthcare professionals, e.g. nurses."}
{"text": "Levels of precursor proteins of collagen I and III are increased in fibrotic pulmonary diseases. This study determined whether the expression of precursors of type I and III collagen proteins would be increased in small and large airways of COPD patients in various stages of the disease reflecting fibrogenesis.The levels of precursor proteins of collagen I and III were studied by immunohistochemistry and quantified by image analysis in lung tissue of 16 non-smokers, 20 smokers with normal lung function, 20 smokers with stage I-II COPD and 8 ex-smokers with stage IV COPD.In large airways, the subepithelial layer which was positive for precursor proteins of collagen I and III was thicker in smokers and in stage I-II COPD compared to non-smokers. Large airways in stage IV COPD showed reduced expression of precursor protein of collagen I whereas precursor of collagen III was increased. The amount of precursor protein of collagen III was increased in small airways of smokers and stage I-II COPD but reduced in stage IV COPD.Precursor proteins of collagen I and III revealed different expression profiles in large and small airways in various stages of COPD. Smoking enhanced expression of both precursors in large airways with a positive correlation with pack-years. Repeated exposure to cigarette smoke induces persistent inflammation and oxidative stress in lungs, which leads to damage of lung parenchyma and airways and a process of continuous repair and remodeling . It is nThe small airways are the major source of airflow resistance  and thusThere are clear histopathologic differences between asthma and COPD ,11, i.e.Collagens are the classical components of the extracellular matrix. In lung tissue, collagen I is the most common collagen and it confers tensile properties while collagen III permits multidirectional flexibility, contributing to lung compliance . CollageCigarette smoke induces changes in lung tissue that are not simply destructive since the smoke can also trigger an active repair process leading to protein production and small airway remodeling. It is not known whether the destruction of lung parenchyma leads to the compensatory formation of connective tissue in an attempt to preserve lung tissue integrity. The aim of this study was to evaluate the expression of precursor proteins of type I and III collagen in small and large airways of COPD patients in order to determine if the expression of these proteins would change during the progression of COPD.2. COPD was defined on the basis of preoperative lung function: FEV1/FVC less than 70% and no reversibility (bronchodilatation effect less than 12%). The clinical characteristics were obtained from the patient records  undergoing resection for lung tumour were drawn for immunohistochemical studies from the archives of the Department of Pathology, Oulu University Hospital. Due to the fact that the resection of malignant tumors may theoretically have an influence on the adjacent structures, lung tissue specimens of non-malignant lung obtained during surgery for hamartomas were additionally included . In all, 33% of the operations were pulmectomies, 60% lobectomies and 7% bilobectomies. No wedge resections were included. Tissue specimens from tumor-free central bronchi and peripheral lung tissue were selected. The patients were not receiving any corticosteroid therapy  and did not suffer from an asbestos-related disease. In addition, lung tissue from 8 patients  undergoing lung transplantation due to very severe i.e. stage IV COPD were obtained from the Department of Pathology, Helsinki University Central Hospital. These patients were receiving either inhaled or systemic corticosteroid treatment and they were all ex-smokers. The lungs were fixed in inflation. The size of the each lung tissue specimen was approximately 1-2 cmFormalin-fixed paraffin-embedded lung tissue specimens were identified from computerized records. All material was re-evaluated by a pulmonary pathologist and a pulmonologist. Two tissue blocks from each patient were selected, one from the resection line with central cartilage-containing bronchus and the other from the peripheral lung. Four-\u03bcm sections were cut for immunohistochemical analyses. The sections were deparaffinized in xylene and rehydrated in a descending ethanol series. Endogenous peroxidase was blocked by incubating the sections in 3% hydrogen peroxide in absolute methanol for 15 minutes.The primary polyclonal antibodies to the amino-terminal propeptides of human type I procollagen  and type III procollagen  were produced as described previously ,19 and uThe immunohistochemical staining was performed as previously described ,17 usingAll membranous bronchioles with diameters less than 2 mm were analyzed. Digital photographs were taken using a Leica DFC 320 camera attached to a Nikon Mikrophot SA microscope, via Leica IM 50 software. The measurements made are shown in Figures The immunohistochemical expression of precursor proteins of collagen I and III was quantified by the image analysis method. Immunohistochemically stained slides of central bronchi and peripheral bronchioli were photographed digitally so as to include all of the chosen material described in the previous paragraph. The extent of positive expression was measured in large and small airways in each study case. The quantification was based on a measurement of the thickness of the subepithelial band expressing precursor proteins of collagen I and III at 30 random locations and the subepithelial area expressing these precursor proteins between the basement membrane and the inner smooth muscle border. Staining was assessed with an image analysis system using freely available software ImageJ version 1.24o developed at the National Institutes of Health, using the technique described by Kim et al .The statistical analyses were performed with SPSS for Windows software . Continuous data were compared using analysis of variance (ANOVA). When ANOVA results indicated that the groups differed, post hoc comparisons were performed using two-tailed t-tests. Categorical data were compared using Fisher's exact test designed for small sample groups. P-values less than 0.05 were considered statistically significant.The study protocol was approved by the ethical committees of the University of Oulu and Oulu University Hospital, Helsinki University Central Hospital and by the Finnish Natiolegal Board.Peripheral lung samples showed 1-3 transversely cut bronchioles (diameter < 2 mm) per case. Although bronchioles of stage IV (very severe) COPD were collapsed with a small internal lumen area, the other dimensions did not reveal any statistically significant differences between the groups . The precursor protein of collagen I positive subepithelial layer was thicker in the smokers and patients with stage I-II COPD when compared to the non-smokers. The patients with stage IV COPD showed diminished expression of collagen I precursor when compared with the patients with milder disease or the smokers . Figure  The subeThe expression of propeptides for collagen I and III was found to co-localise with spindle-shaped, alpha-smooth muscle actin positive, vimentin negative fibroblastic cells in small airways Figure  and largThis is the first study to investigate the immunohistochemical expression of precursor proteins of collagens I and III as quantified by an image analysis technique in non-smokers, smokers and patients with COPD at various stages of the disease. The levels of both proteins were increased in large airways of smokers and patients with stage I-II COPD. In contrast, precursor proteins were expressed differently in large airways of patients with stage IV COPD i.e. in these patients the amount of precursor protein of collagen I was reduced whereas that of collagen III was elevated. The present study also revealed that the increase of the precursor protein of collagen I and III in the large airways of smokers correlated positively with pack-years. No detectable expression of the precursor protein of collagen I was found in small airways, whereas the amount of the precursor protein of collagen III was increased in the bronchioles of smokers and in stage I-II COPD. Overall, the amounts of precursors of collagen I and III were increased in smokers and stage I-II COPD but tended to decline either in large or small airways in stage IV COPD.The accumulation of the precursor protein of collagen I could represent the synthesis of type I collagen which in turn offers protection from the distension and shearing effects of hyperinflation, while its absence may further contribute to alveolar wall disruption and emphysema formation in conjunction with other mechanisms. In contrast, the expression of the precursor protein of collagen III within small airways was increased in patients at stages I-II COPD and moreover, its amount correlated positively with the results of the lung function tests. The very thin subepithelial layer expressing collagen III precursor proteins in stage IV COPD may be attributable to decreased fibrotic activity in small airways in end-state COPD, and the combination of this defective repair of injured airways with elastin destruction which could evoke diminished compliance and disrupt the elastic properties of lung tissue. Decreased precursor protein of collagen III in stage IV COPD may also be due to the end-stage of the remodelling process, a diminished capacity of the lung cells to produce collagen III, and/or a shift in the balance towards degradation. The discrepancy in the expression profiles of the precursor proteins of collagens I and III reflects the fact that the regulative processes of these two collagens differ in COPD. In addition, there were few spindle shaped alpha-smooth muscle actin positive fibroblastic cells especially in the small airways but these cells co-localised with the expression of the studied collagen propeptides, suggesting that fibroblasts could well be one source of this newly synthesised collagen.We have previously shown that in the developing human lung, the precursor proteins of collagen I and III were expressed through all gestational ages and also in respiratory distress syndrome and bronchopulmonary dysplasia in a rather similar way both in bronchi and in the bronchioles underneath the airway epithelium  Thus, fiThe collagen III deposition which was accompanied by an excess of fibroblasts as detected in the large airways of patients with severe asthma was not observed in COPD . The myoin vitro conditions cigarette smoke can inhibit fibroblast recruitment, proliferation and extracellular matrix contraction [In our earlier studies, we found diminished levels of the rate-limiting enzyme of glutathione synthesis in smokers' lung  and thistraction  as well traction . The dentraction . It has traction .The limitations to this study include the lack of stage III COPD patients, since they have advanced airflow obstruction and operative treatment for their lung tumors is often not possible. Patients in the stage IV COPD groups were younger than those in the other groups, they were ex-smokers and they were heavily medicated often with both inhaled and systemic corticosteroids. Half of the patients with stage IV COPD had alpha-1-antitrypsin deficiency while the other half had normal levels of alpha-1-antitrypsin; however the histopathological destruction of lung tissue showed no difference between these two groups. In addition, no age-related change in the collagen content of the lungs of non-smokers has been found . Little Procollagen I and III are not specific to any fibrotic disease, since these proteins are components of both normal and enhanced remodeling. Our study confirms earlier reports in COPD patients that there is actual fibrosis beneath the basement membrane with increased collagen accumulation . The difWe conclude that smoking induces immunohistochemical expression of precursor proteins of collagen I and III in large airways of healthy and diseased lung and this change correlates with the pack-years. Moreover the amounts of both precursors exhibit variable expression profiles in large and small airways of patients with COPD in various stages of the disease. Accumulation of precursor protein of collagen III is increased in the small airways of patients with mild-moderate COPD but declines in end-state disease, possibly as a marker of the cessation of active fibrogenesis or as a result of enhanced degradation of the protein. These results suggest that smoking can induce the fibrogenesis of airways even in 'healthy' smokers with normal lung function. Furthermore, in COPD not only the small airways, but also the large airways display evidence of fibrogenesis. The effective treatment of the small airway disease in COPD will require a better understanding of the relationship between airway fibrosis and airflow obstruction, and also an awareness of extracellular matrix turnover and its regulation in smoking related diseases.The authors declare that they have no competing interests.TH participated in the design of the study and selection of patient material, performed the morphometric analysis, the statistical analysis and drafted the manuscript. VLK participated in the design and coordination of this study, selection of patient material, and helped to draft the manuscript. PP participated in the selection of patient material and analysis of immunohistochemical results, and helped to draft the manuscript. KS participated in the selection of patient material and helped to draft the manuscript. JR participated in the design of the study and provided the collagen precursor antibodies and helped to draft the manuscript, RK conceived the study, participated in the design of the study and selection of patient material, analysis of immunohistochemical results and helped to draft the manuscript. All authors have read and approved the final manuscript.This work was supported by grants from the Finnish Anti-Tuberculosis Association Foundation, Finnish Association of Respiratory Medicine, Sigrid Juselius Foundation, the Academy of Finland, EVO Funding of the Helsinki University Central Hospital and Oulu University Hospital, and the Jalmari and Rauha Ahokas Foundation."}
{"text": "The comprehensive meta-analysis of Nine of the 10 studies Linear extrapolation is used in radiation protection if cohort strata pertaining to low doses and dose rates have low statistical power. There are, however, indications for non-linear protective effects of low doses delivered at low dose rates for end points related to athero-sclerosis in mice . MoreoveIn this context we note that in the 10 studies analyzed by Our results might have implications for issues of public health in the assessment of risk\u2013benefit ratios for radio-diagnosis or radio-therapy. Thus, we encourage the use of multi-model inference techniques in the analysis of other cohorts. From our experience with the LSS cohort, we would expect lower risk estimates in the lower dose range with a more comprehensive characterization of uncertainties and improved support of the epidemiological data."}
{"text": "Deficits in decision-making have been repeatedly observed in various psychiatric disorders  as well as in frontal lobe patients. Such decision-making deficits are often assessed using the Iowa Gambling task (IGT) . The IGTRecently, these behavioral findings were successfully translated to animal research in a rodent version of the IGT, the Rat Gambling Task (RGT). In common with human studies, it was found that a third of a healthy population of rats exhibited poor decision-making performances . The ratHere we use a model of learning and decision-making in the RGT to answer the following questions: (1) how do the behavioral traits described above influence learning; (2) how is this manifested in terms of their decision-making performance?In order to model the learning and decision process of the RGT, we used a TD-learning algorithm . The modWe found that the model could account for the performances of good and poor subpopulations of decision makers. Additionally, the parameters defining the behavioral traits extracted from the model correlated significantly with those measured experimentally for the poor and good decision makers\u2019 subgroups. The model was also able to predict the inflexibility of poor decision makers during reversal conditions.Our work supports the hypothesis that it is a combination of high scores for risk seeking, sensitivity to reward and cognitive inflexibility that lead to poor decision-making performances. According to the model, behavioral traits affect the learning process of the subjects by altering the estimated value of the received rewards and reducing their ability to reverse their initial estimations. This results in an incorrect perception of the environment, leading to an optimal decision-making according to their world representation but aberrant according to the real outcome of the task."}
{"text": "Aire gene can influence the transcription of such a large number of TRA genes within mTECs. From a mechanistic viewpoint, there are two possible models to explain the function of Aire in this action. In the first model, TRAs are considered to be the direct target genes of Aire\u2019s transcriptional activity. In this scenario, the lack of Aire protein within cells would result in the defective TRA gene expression, while the maturation program of mTECs would be unaffected in principle. The second model hypothesizes that Aire is necessary for the maturation program of mTECs. In this case, we assume that the mTEC compartment does not mature normally in the absence of Aire. If acquisition of the properties of TRA gene expression depends on the maturation status of mTECs, a defect of such an Aire-dependent maturation program in Aire-deficient mTECs can also result in impaired TRA gene expression. In this brief review, we will focus on these two contrasting models for the roles of Aire in controlling the expression of TRAs within mTECs.The discovery of Aire-dependent transcriptional control of many tissue-restricted self-antigen (TRA) genes in thymic epithelial cells in the medulla  has raised the intriguing question of how the single  Aire gene can influence the transcription of such a large number of TRAs within mTECs . Most importantly, none of these cell lines express a reliable level of Aire at the protein level. However, large aspects of Aire\u2019s action on TRA gene expression in the transcription model were deduced on the basis of the effects of lack of Aire expression in mTECs in vivo  and the opposite effects of Aire overexpression in mTEC-\u201clike\u201d cells in vitro . The reality is that there is still a fairly wide gap between these two experimental settings that needs to be bridged.The current prevailing view regarding the role of Aire in self-tolerance is that it is involved in the transcriptional control of many tissue-restricted self-antigen (TRA) genes in medullary thymic epithelial cells (mTECs) . In othein mTECs \u20137. Unforhigh) is another suggested aspect of the Aire-dependent mTEC differentiation program  but not fully competent for TRA expression, have a more globular cell shape and lack transcriptional machinery and/or activity for Aire-dependent TRA genes , and consequently the lack of Aire has little impact on their expression. It is still unknown why some (Aire-independent) TRAs are expressed from the immature stage(s), whereas (Aire-dependent) others are expressed only after they become fully mature. For this reason, it would be important to clarify the exact timing of Aire expression during the course of mTEC differentiation (Regardless of the models employed, there are several important issues related to the molecular regulation of TRAs within mTECs in the context of Aire. Obviously, the transcriptional control of TRAs is different from the regulation seen in their authentic tissues, as exemplified by differences in the transcriptional start sites of individual TRA genes . Althougin mTECs , 20 mighRA genes  (Figure ntiation . Neverthntiation , 22; Airntiation . In thisOne caveat of the transcription model is that expression of Aire and Aire-dependent genes does not always overlap at the single-cell level , 24, 25.involucrin gene was up-regulated possibly due to the transcriptional activity of Aire (in vivo systems suggesting that Aire is required for promotion of the mTEC maturation program. Thus, there is a need to understand the types of effects that can be expected according to the experimental systems employed.Involucrin is an interesting TRA in that it is sometimes used as an example of an Aire-dependent TRA that follows the transcription model: when cultured cell lines were introduced with an Aire-expressing plasmid, transcription of the endogenous  of Aire . However of Aire , 10. Thehigh/CD80high mTECs seen in Aire-deficient mice was considered to explain the lack of Aire-mediated proapoptotic activity, because loss of Aire did not result in augmented proliferation of mTECs (in vivo experimental systems.Regarding the role of Aire in the mTEC maturation program, an important issue that needs to be carefully investigated is whether or not Aire has proapoptotic activity. Introduction of Aire into cultured cells has been reported to result in apoptosis . Accordiof mTECs . Given tof mTECs . Once agin vivo models. Thus, our current understanding of the fundamental function of Aire still seems to be in its infancy, and the proposal and evaluation of different models would doubtless lead to further advances in this fascinating field of research.Finally, there is a need to discuss the implications of these two different models for the mechanisms underlying the defect of negative selection in Aire-deficient animals. In principle, the transcription model restricts the failure of negative selection in Aire-deficient mice to reduced expression of TRA gene products. In contrast, the maturation model suggests that Aire may affect the thymic microenvironment more globally than through simple control of TRA expression levels. Consequently, the maturation model allows for the possibility that regulation of TRA gene expression may not be the major defect of Aire-deficient mTECs responsible for impaired negative selection. Instead, other alterations in the function of mTECs lacking Aire might equally account for the defective negative selection in Aire-deficient mice. These changes could include processing and/or presentation of self-antigens within the mTECs , the proThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Respiratory diseases, including chronic obstructive pulmonary disease (COPD), are major causes of mortality worldwide , therefoIn this issue of the Journal Vitacca and Comini  analyze Understanding and improving patient-clinician communication about end of- life care is the key to high-quality palliative care . UsuallyAnxiety and depression may be important obstacles for frank and clear discussion on palliative and end-of-life care. In the frame of end-of-life care programs treatment of depression with drugs and/or psychological education, behavioural therapy, group and individual counselling may be useful.According to ethical and deontological principles in the frame of a medicine driven by agreed choices, doctors should respect patient\u2019s willingness on the basis of either an informed consent or advanced directives. Advance directives and good advance care planning may represent an opportunity for improving the quality of palliative care for these patients. Nevertheless this mark of civilization is not available in all countries and somewhere patients are left at the mercy of doctors concerned more not to shorten life than to improve quality of life/death.Hospice and palliative care services represent an important opportunity for improving end-of-life care. Such services are again not available in all countries, and may be differently located within the same country. Furthermore clinicians caring for patients with chronic pulmonary disease not always know the best ways to utilize these services.In conclusion clinical decisions on end-of-life care must take into consideration the patient\u2019s clinical and physical circumstances, preferences and likely actions to establish what treatment choice is available. Finally, clinical expertise makes the synthesis of all these considerations and recommends the treatment that the patient prefers . Therefo"}
{"text": "Auditory brainstem calculates horizontal direction (azimuth) of sound from the ITD . Jeffress proposed in 1948 that sound source azimuth is computed by a neural circuit consisting of an array of delay lines . We studWe present our current results as a case study showing multitude of roles of (random versus deterministic) spike timing in a neural circuit. In particular, either phenomenological (excitatory-excitatory and excitatory-inhibitory units), or electrophysiological (excitatory and inhibitory synapses) classification of individual elements of the circuit might be abstracted in an explanation stressing the neural computation in the circuit. We study various parameters of the MSO model and their influence on the output of the model. Finally we evaluate the performance of the model using the concept of ideal observer."}
{"text": "There is an error in the byline noting the equal contribution of the authors. Only authors Anna Siebel and Monica Cubillos-Rojas are equal contributors."}
{"text": "Parallel high-throughput microarray and sequencing experiments produce vast quantities of multidimensional data which must be arranged and analyzed in a concerted way. One approach to addressing this challenge is the machine learning technique known as self organizing maps (SOMs). SOMs enable a parallel sample- and gene-centered view of genomic data combined with strong visualization and second-level analysis capabilities. The paper aims at bridging the gap between the potency of SOM-machine learning to reduce dimension of high-dimensional data on one hand and practical applications with special emphasis on gene expression analysis on the other hand.The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories . SOM mapping reduces the dimension of expression data from ten of thousands of genes to a few thousand metagenes, each representing a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of genes related to specific molecular processes in the respective tissue. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering are better represented and provide better signal-to-noise ratios if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues broadly into three clusters containing nervous, immune system and the remaining tissues.The SOM technique provides a more intuitive and informative global view of the behavior of a few well-defined modules of correlated and differentially expressed genes than the separate discovery of the expression levels of hundreds or thousands of individual genes. The program is available as R-package 'oposSOM'. These resources pose a challenge how to best arrange and to visualize the huge heaps of data in a fashion that enables combination of sample- and gene-centered views on multidimensional expression data to capture the global picture of groups of samples while simultaneously presenting the specific expression pattern within each individual sample.DNA microarray and next generation sequencing technologies allow researchers to screen ten thousands of genes for differences in expression between up to hundreds of individuals or experimental conditions of interest. Not only the progressively increasing data throughput of newest array and sequencing technologies challenges data analysis methods but also the increasing availability of large data sets from public data repositories such as gene expression omnibus (Self-organizing map (SOM) machine learning was developed by Kohonen about thirty years ago . It projIt has been demonstrated that such SOM displays are featured by several important benefits -9: (i) tSOM-based gene expression analyses have been applied, for example, in studies on cell differentiation and development -12, orgaDespite its convincing advantages the SOM method is relatively infrequently applied to high-dimensional molecular data compared with alternative approaches such as hierarchical clustering. Possibly, interpretation of SOM mosaic patterns is less trivial and/or unusual for many researchers because it requires basic understanding of details of the method such as the way how expression of real genes transforms into expression profiles of the metagenes. The lack of availability of this information presumably hampers application of SOM-based methods in a wider number of applications. Moreover, standard analysis tasks such as feature selection, significance analysis of differential expression and functional gene set enrichment analysis require the availability of appropriate algorithms and of suited program tools to generate the desired information. Such approaches must consider the specifics of gene expression analysis  on one hand, but also the specifics of SOM-machine learning on the other hand.We strongly advocate in favor of the SOM method. The present publication aims at bridging the gap between the potency of SOM-machine learning to reduce dimension of high-dimensional data on one hand and its availability with special emphasis on gene expression analysis on the other hand. Our approach includes a series of analytical reports which might support interpretation of SOM metagene data (see below) and an available R-program package. Here we focus on the identification and functional interpretation of metagene clusters using gene set overrepresentation analysis, a novel aspect in the context of SOM analysis, and on the comparison of data analysis based on single and on metagenes.We apply our approach to expression data of human tissues which is well suited as an illustrative example: The selected 67 tissues provide a sufficient large data set of highly diverse expression pattern possessing a complex internal covariance structure. Moreover, the samples are well classified in terms of distinct tissues and tissue categories allowing the clear assignment of expression pattern. The discovery of this human body index data set is also motivated by the argument that tissue-specific RNA expression pattern indicate important clues to the physiological function of the coding genes, suitable as a reference for comparison with diseased tissues. Our analysis thus provides a first step towards a SOM atlas of gene activity in normal human tissues which complements previous work on this objective -18.We address selected methodical aspects of the SOM method which aim at extracting functional information about the expression pattern: Firstly, we complement the gallery of primary SOM images with a number of summary maps characterizing the covariance structure of the data after transformation into latent variables. These summary maps allow extraction of so-called spot-clusters which collect co-expressed metagenes together. This spot-clustering enables to significantly reduce the dimensionality of expression data to a handful of representative expression-modules in an unsupervised fashion. The results of SOM-clustering are compared with the results of alternative methods such as non-negative matrix factorization, hierarchical clustering and sets of correlated genes. Secondly, the detected spot-clusters are linked with biological knowledge to support functional interpretation of the data based on the 'guilt by association' principle. Particularly, we apply gene set overrepresentation analysis to visualization space which is a novel approach to our best knowledge. Thirdly, we analyze the capability of the SOM approach for data filtering and dimension reduction in terms of maintaining representativeness and reduction of noisiness of the data. Finally, we applied SOM analysis in a zoom-in step to a subensemble of tissues to increase the resolution of the method. We use the sample-centered second-level SOM representation to visualize similarity relations between the different tissues and compare the results with independent component analysis.The main paper is supplemented with additional files which provide the full gallery of SOM-images of human tissues, a detailed methodical section addressing issues such as calibration of microarray raw intensity data to minimize possible artifacts due to systematic biases caused by improper preprocessing , the conMicroarray expression data taken from the human body tissue index data set were input into the SOM machine learning algorithm after calibration and normalization of the raw probe intensities as described in the Methods section below and in Additional file The tissues are grouped into ten categories in accordance with the classification used in Hornshoj et al. . Most ofSome tissues combine the characteristic spot pattern of different tissue categories  predominantly group along the edges of the map whereas only a few highly populated tiles are found in its central area. A zone of 'empty' metagenes lacking real genes  clusters in four regions halfway between the centre and the edges of the map. The tile of maximum population  refers to genes with virtually invariant, mostly absent specific expression in all tissues studied  distribution. It provides an overrepresentation p-value for each metagene and each gene set considered. We visualize the distribution of p-values of each gene sets using the same two-dimensional mosaic as used for the original SOM images and appropriate color-coding. The obtained overrepresentation maps allow identification of metagenes containing an enriched fraction of genes from a selected gene set by visual inspection. Note that this map applies to all samples studied because each of the mini-clusters contains the same genes in all samples used to train the SOM. The overrepresentation map thus reflects the global enrichment pattern of a chosen set of genes in the experimental series studied.Figure Overrepresentation analysis is not restricted to single tiles but it can also be applied to the over- and underexpression spots detected in the previous subsection. Accordingly, overrepresentation of selected gene sets can be linked with additional properties of the expression profiles such as overexpression by combining spot selection with overrepresentation analysis. Particularly, the genes associated with each spot are analyzed for overrepresentation of genes taken from the collection of 1454 gene sets downloaded from the GSEA-homepage according to the GO-categories molecular function, biological process and cellular component (see methods section). The hypergeometrical distribution then provides an ordered list of gene sets ranked with decreasing significance of overrepresentation for each of the spots.Figure The heatmap in Figure It is noteworthy that the enriched areas in the overrepresentation maps of the gene sets 'nervous system development' and 'immune response' , then one ranks the data accordingly and finally selects a certain number of features on top of the list for further analysis. The length of the list can be cut by applying different criteria such as a fixed number of features or a significance threshold.SOM analysis enables alternative filtering based on the metagenes as representative features characterizing the expression profiles of miniclusters of single genes. In other words, the metagene profiles itself can serve as a filtered and compressed extract of the original data. Our SOM-method assigns the expression profiles of the N = 22,277 input genes measured in 67 tissues to 3,600 metagene clusters. Each metagene cluster consequently contains G/M = <nk > = 6.2 real genes on the average. Hence, complexity of transcriptome characterization is reduced to about one sixth by utilizing the metagenes instead of the 'real' genes.k = 0 (empty metagenes) and nk = 308  clusters genes of virtually invariant expression profiles. These essentially not-informative features comprise 1.4%  of all single genes but only 0.3%  of all metagenes. Hence, their contribution is effectively down-scaled by nearly a factor of ~1/5 if one uses the metagenes instead of real genes. In other words, SOM clustering itself can be viewed as a sort of selective compression filter reducing the number of features considered by condensing larger numbers of similar single gene profiles into one metagene profile with a profile-specific compression factor, Fkcompression = (nk\u22c5K/N)-1 .Moreover, the local G/M-ratio considerably varies between the different metagene clusters with minimum and maximum values of nMetagene filtering is expected to outperform single gene filtering in terms of representativeness and noisiness because the reduced number of metagenes not only preserves the diversity of single gene profiles but it also amends the resolution of downstream analysis due to the reduced noise of the metagene profiles. With the objective of proving this expectation we compare two options for data filtering by applying top-list selection either to the metagenes or to the single 'real' genes. We used three types of filters to reduce the number of single genes and metagenes, namely fold change (FC)-expression, variance and significance (FDR-) filtering  using either the expression values of a list of real genes or of a list of metagenes of selected lengths. Hierarchical cluster analysis was applied because this method is often routinely run as a first step of data summary in microarray data analysis .One way hierarchical cluster trees obtained from single gene and metagene FC-lists of length 3600, 1000 and 100 reflect similar properties showing that clustering is relatively robust with respect to the chosen conditions Figure . TissuesThe blue immune system tissue cluster splits for both, the single gene and metagene filters in the opposite limit of low stringency using FC-3600 lists. These lists obviously become too long with worse noisiness characteristics. Note, that the FC-3600 metagene list considers all available metagenes whereas the FC-3600 single gene list is still limited to only 16% of all available single genes. Longer single gene lists reduce the quality of the observed cluster structure due to the progressive inclusion of noisy genes (data not shown). In summary, metagene lists are more representative and less noisy than single gene lists of equal length in downstream cluster analysis. On the other hand, also the length of metagene lists is optimal in the intermediate range : shorter and longer lists are suboptimal in terms of representativeness and noisiness, respectively.The cluster trees generated on the basis of single gene and metagene lists reveal another interesting difference  provides still reasonably resolved clusters in the ICA-plot. In conclusion, metagenes are more robust with respect to the quality of secondary analysis than single gene lists owing to their better representativeness. Hence, the reduction of dimensionality provided by SOM analysis improves the performance of downstream hierarchical clustering and ICA analysis. The number of considered features can be reduced by about one order of magnitude without loss of information if one uses metagenes instead of real genes. Clustering and ICA characteristics obtained for the metagene and single gene lists after variance and FDR filtering virtually agree with the results of FC-filtering  illustrating Pearson correlation coefficients for all mutual combinations between the tissues. The PCM-heatmaps shown in Figure The expression profiles of nervous tissues strongly anti-correlate with essentially all the other tissue categories, i.e. a gene overexpressed in nervous tissues usually becomes underexpressed in non-nervous tissues and vice versa. The original expression SOM always reflect this property showing one characteristic overexpression spot in the top left corner , immune system tissues (blue) and the remaining ones. The substructures of the three groups were further disentangled by applying the zoom-in step for each of the three tissue clusters as described above.Guo et al. proposed a second-level SOM analysis step . It mapsnd level SOM provide a similar view on the samples, however with subtle differences. For example, the ICA algorithm distributes the sample points continuously in the coordinate system spanned by the two leading principal components of maximum information content. The mutual separation between the points linearly scales with their distance in units of these components. In contrast, SOM machine learning uses non-linear scale to distribute the sample points in the discrete space defined by the mosaic grid of metasamples. It enables to display differences between the samples with improved resolution in regions of high sample density. In consequence, the individual tissues effectively spread over a larger area in the SOM mosaics than in the respective ICA.In general, ICA and 2As noticed above, most of the samples group into linear clusters which orient along one of the coordinate axes in the two dimensional ICA plots. The orthogonal orientation of most of these clusters indicates that each of them is characterized by genes which vary mutually independently. For example, nervous and immune systems tissues aggregate into such linear and perpendicularly-oriented clusters in the original ICA of all 67 tissues. Note that nervous and immune systems tissues are characterized by their specific spots A and F, respectively. Recall that these spots contain genes which indeed vary virtually independently.Similar orthogonal clusters are found in the ICA plots after zoom-in of the nervous, immune system and diverse tissues. The obtained clusters reveal groups of tissues which are governed by independent sets of genes with enhanced resolution. For example one finds that telencephalon tissues (dark yellow circles in the ICA of nervous tissues) form one linear cluster which can be attributed to a category-specific spot in the zoom-in SOM images . Hence, although very similar, 2nd level SOM and ICA visualize partly complementary aspects of the data which can be studied more in detail using the spot-texture of the individual SOM of the samples studied. Tree-based similarity analysis provides an additional option to visualize the mutual relations between the samples  transform into a slightly more compact cluster in the 2The microarray expression data of 67 human tissues was used as an illustrative example to demonstrate the strengths of the SOM method in disentangling large sets of heterogeneous data. After suited preprocessing and training, the SOM method decomposes the original data into metagene expression profiles representing clusters of correlated single genes. Metagene expression values in the individual samples provide mosaic pictures visualizing tissue-specific over- and underexpression in terms of characteristic color-coded textures. They enable the direct comparison of the expression of individual samples in a simple and intuitive way.Particularly, the tissue-specific patterns of gene expression were readily discernable in the obtained gallery of individual tissue maps. They reveal a series of about one handful stable over- and underexpression spots which selectively characterize different tissue categories such as nervous, immune system, muscle, exocrine, epithelial or adipose tissues. Single tissues of mixed characteristics such as tongue  can be easily identified. Also anti-correlated expression spots are detected which, for example, are overexpressed in nervous tissues but underexpressed in the other tissues and vice versa.To extract the functional context of spot and metagene related lists of single genes we applied overrepresentation analysis with respect to pre-defined gene sets of basically known functional impact. The mapping of overrepresentation of a selected gene set into the SOM mosaic provides a 'functional' map showing areas which are potentially relevant for this function. Tissue related spots typically contain enriched populations of function-related gene sets well corresponding to molecular processes in the respective tissues. This result strongly supports the 'guilt-by-association' principle that coexpressed genes are likely to be functionally associated. It, in turn, implies the ability to define either new gene sets using selected SOM spots or to verify and/or to amend existing ones.The SOM method compresses the original set of high-dimensional data in two consecutive steps: Firstly, similar expression profiles of single genes are collected into metagene clusters, which reduces the number of relevant features nearly by one order of magnitude in our application. These metagene profiles can be understood as a sort of 'eigen-modes' characterizing the multitude of expression pattern inherent in the data. Secondly, the textures of the obtained SOM are decomposed into a few  spots of similarly (over- or under-) expressed metagenes. This 'double compression' sequentially applies global (similar profiles) and local (over-/underexpression in part of the samples) criteria.The use of metagene instead of single gene expression reduces the dimension of the data and leads to an increased discriminating power in downstream agglomerative analysis such as hierarchical clustering and independent component analysis owing to essentially two facts: Firstly, the set of metagenes better represents the diversity of expression pattern inherent in the data and secondly, it also possesses the better signal-to-noise characteristics as a comparable collection of single genes. Due to the better representativeness, metagene lists are less sensitive to downstream filtering than lists of single genes. Metagenes can be seen as a natural choice to detect context-dependent patterns of gene expression in complex data sets. SOM-spot clustering provides groups of genes of higher sample-specificity compared with selected alternative methods such as non-negative matrix factorization, hierarchical clustering and correlated gene set clustering.Our example shows that SOM cartography transforms large and heterogeneous sets of expression data into an atlas of sample-specific texture maps which can be directly compared in terms of similarities and dissimilarities. This global view on the behavior of defined modules of correlated and differentially expressed genes is more intuitive than ranked lists of hundreds or thousands of individual genes. Importantly, the dimension reduction of the data does not entail the loss of primary information in contrast to simple filtering approaches which irretrievably removes part of the data. Instead, the reduction of dimension is attained by the re-weighting of primary information in the aggregation step. The whole set of single gene expression profiles remains virtually 'hidden' behind the metagenes. This primary information together with the respective gene annotations can be extracted in later steps of analysis to interpret the observed SOM textures using concepts of molecular biological function.Finally, the software used in this publication is available as CRAN package 'oposSOM'.m = 1, 2... (m = 1...M) replicates were downloaded from the Gene Expression Omnibus repository as the 'human body index - transcriptional profiling' - data set  of M = 67 tissues each measured in RRaw probe intensities are calibrated and transformed into expression value using the hook method ,34. The 10 E) were transformed into differential expression values relative to the mean expression of the particular gene in the experimental series of tissues considered,Logged expression values of each gene (e \u2261 logEq. (1) thus defines differential expression in units of the logged fold change, logFC \u2261 \u0394e.In the next step, the preprocessed differential expression values of the series of tissue samples, \u0394e, are processed using the unsupervised machine learning method to train a self organizing map (SOM) representing information-rich diagrams. The SOM method applies a neural network algorithm to project high dimensional data onto a two-dimensional visualization space ,36. SOMskmeta =  (k = 1...K). It is trained such that the profiles of the metagenes capture the range of all individual expression pattern observed. Each individual expression profile of a 'real' gene is assigned to the metagene pattern of closest similarity using the minimum Euclidian distance as criterion. Each metagene thus serves as a sort of condensation nucleus for a minicluster of nk 'real' genes with similar expression profiles, \u0394ek,i = , with i = 1...nk and We applied a home-made R-program  which usk,mmeta. This way one obtains a coherent mosaic pattern that is characteristic for each sample owing to the similarity of adjacent metagenes. Since the SOMs assign the same metagene to the same tile in all samples, they can be directly compared to each other allowing immediate identification of biologically interesting groups of genes.The metagenes are arranged in a two-dimensional grid with K = x\u22c5y tiles where x and y are the number of tiles per dimension. Most similar expression profiles of metagenes are located adjacent each to another. The correlation between metagene expression decreases with the mutual distance between the tiles on the mosaic. The degree of similarity between adjacent metagenes depends on the number of genes assigned to the respective metagenes being closer for larger populated metagenes and vice versa. For each condition m = 1...M a SOM mosaic pattern is constructed by color-coding the tiles k = 1...K according to its metagene expression, \u0394e2 - 104 with, on the average, nk = 5 - 100 genes per metagene. The obtained mosaic pattern is usually more homogeneous than typical gene clustering heatmaps containing typically about 102 clusters. This finer granularity of SOM-maps is associated with a fewer number of genes per unit (cluster/metagene) which in consequence gives rise to a more detailed expression pattern.Typically, the number of tiles to 'pixelate' the expression profiles is K = 10 \u00d7 10 - 100 \u00d7 100 = 10The number of tiles per SOM image and also the lattice-type  potentially affects the obtained cluster structure and color texture of the images. In a preliminary study we found that the number of tissue-specific 'spots' converges for x = y > 50 and weakly depends on the chosen lattice type. Under these conditions the number of tiles exceeds the number of relevant expression modules roughly by two-orders of magnitude which allows their resolution with high granularity. The contrast of the SOM images can be adjusted using different color-scales to attenuate different aspects of the expression profiles with the aid of pattern recognition, feature selection and/or data filtering. In the supplementary information we compare three options of contrast variation with the focus on strong-to-moderate differential expression , very strong overexpression  or weak-to-moderate differential expression .http://som.izbi.uni-leipzig.de. The program is also available as CRAN package via http://cran.r-project.org/.Details of these methodical studies are presented in Additional file We define the following supporting maps which provide additional information about the miniclusters defined by each metagene and the associated real genes:(i) The metagene expression profiling map uses a coarse grained mosaic to provide an overview of the courses of the metagene profiles. For visualization purposes we use a coarse grained  mosaic with considerably less tiles than the mosaic grid applied for the SOMs (60 \u00d7 60). The metagene profiles might be plotted together with the associated single gene profiles.k.(ii) The population map plots the number of real genes per metagene in logarithmic scale, log n(iii) The variance map illustrates the variability of the expression profile of each metagene in the samples studied,(iv) The integral over-/under-expression summary maps collect all over-/underexpression spots observed in the individual sample SOMs into one master map.An extended set of supporting maps visualizing the covariance and the Euclidian distance between the genes and metagenes in each tile, the maxima and minima of the metagene profiles in absolute scale and the correlations between the metagenes are given as supporting information . Particularly, we included in total 1454 gene sets in our analysis according to the GO terms 'biological process' (825 sets), 'molecular function' (396 sets) and 'cellular component' (233 sets). We use the term 'overrepresentation' to assign the probability to find members of a given set in a list compared with their random appearance independent of the values of their expression scores. We use the hypergeometric distribution to characterize overrepresentation in terms of a p-value which estimates the probability to find a stronger overlap between the list and the set by chance [Gene set analysis requires the knowledge of predefined gene sets to study their enrichment in gene lists which are obtained from independent differential expression analysis  FC-filtering: the genes/metagenes are ranked with decreasing absolute value of the fold change (FC) for each sample and a certain number  of the top-most features is selected; (ii) Variance filtering: the genes/metagenes are ranked with decreasing variance of their expression profiles and a certain number of top-most features is selected; (iii) FDR-filtering: only genes/metagenes with a local false discovery rate (FDR) smaller than a certain threshold  were selected. The local FDR estimates the probability of false positives in a list genes/metagenes. We used a shrinkage t-score statistics to assign p-values to each single gene the distribution of which then provides its FDR-values. The FDR of the metagenes is simply calculated as log-average of the single gene FDR of the respective metagene cluster. Details of the method will be published separately .The performance of metagene and single gene filters was compared using the following benchmarks  was used to estimate the quality of the clusters.Two-way hierarchical clustering: The percentage of genes/metagenes attributed to tissue-specific clusters for three tissue categories  was used to estimate the representativeness of the list.ICA: The percentage of the variance of the independent components IC1 and IC2 of one tissue category, % = (varIC1+varIC2)one_category/(varIC1+varIC2)three_categories, was used to judge the relative size of the respective cluster.The cluster-specificity estimates the degree to which the expression of a selected cluster differs from ubiquitous uniform expression of all clusters in a given tissue. It can be measured in terms of the entropy ,(3)c,m is the logged expression of the cluster which is calculated as mean value over the expression values of its members. The entropy is calculated for each tissue sample m = 1...M where the sum runs over all clusters c = 1...C. It has units of bits and ranges from zero for tissues with only one highly expressed cluster to 1 for tissues with uniformly expressed clusters.where eFor comparison with the SOM spot-clusters we applied selected alternative methods of dimension reduction: non-negative matrix factorization , hieHW and HB: Conceived and designed this study, performed data analysis and wrote the manuscript. HW: Wrote the R-programs and performed the calculations. ML and MB contributed to finalize the study. All authors read and approved the final manuscript.The additional text describes methodical issues such as the calibration of microarray data and the adjustment of the size and topology of the SOM, additional supporting maps which illustrate the covariance and correlation structure of the metagene clusters, alternative options of contrast of the SOM images, the filtering of metagenes/single genes and the interpretation of cluster trees. Further details of zooming-in of tissue subgroups are given together with the 3D-ICA plots of the tissues studied.Click here for fileWhole set of 67 SOM expression profiles of human tissuesClick here for fileExpression profiles of human tissues in alternative color scales.Click here for fileAgglomerative cluster analyses after single gene and metagene filtering using FDR and variance criteriaClick here for fileTable of samples studied The complete set of results of our SOM analysis of the human tissue dataset can be found on our website: http://som.izbi.uni-leipzig.deClick here for file"}
{"text": "Nat Rev Genet 6: 451-464). In this paper, the probability transition rate and first-passage time in an autoactivating positive-feedback loop with bistability are investigated, where the gene expression is assumed to be disturbed by both additive and multiplicative external noises, the bimodality in the stochastic gene expression is due to the bistability, and the bistability determines that the potential of the Fokker-Planck equation has two potential wells. Our main goal is to illustrate how the probability transition rate and first-passage time are affected by the maximum transcriptional rate, the intensities of additive and multiplicative noises, and the correlation of additive and multiplicative noises. Our main results show that (i) the increase of the maximum transcription rate will be useful for maintaining a high gene expression level; (ii) the probability transition rate from one potential well to the other one will increase with the increase of the intensity of additive noise; (iii) the increase of multiplicative noise strength will increase the amount of probability in the left potential well; and (iv) positive (or negative) cross-correlation between additive and multiplicative noises will increase the amount of probability in the left (or right) potential well.A hallmark of positive-feedback regulation is bistability, which gives rise to distinct cellular states with high and low expression levels, and that stochasticity in gene expression can cause random transitions between two states, yielding bimodal population distribution (Kaern et al., 2005,  As predicted by their theoretical model, temperature-induced protein destabilization led to the existence of two expression states. The result of Isaacs et al. shows clearly the effects of varying the strength of feedback activation on population heterogeneity Click here for additional data file."}
{"text": "Interaction between calcium nanodomains of individual voltage-dependent calcium channels in triggering exocytosis in neurons and endocrine cells is of significant importance for understanding localized calcium signaling in general and synaptic physiology in particular. Such channel domain interaction (overlap) is often experimentally probed by measuring the sensitivity of release rate to the total presynaptic calcium current, which is varied by changing the number of open channels while the single-channel current is kept fixed. Variation in the number of activated channels is in turn achieved using appropriate voltage-clamp protocols, or by pharmacologically blocking a subset of channels. The resulting slope of the log-log regression line between release rate and total calcium current is termed calcium current cooperativity, and is believed to indirectly probe the number of channels contributing to the exocytosis of a single vesicle (reviewed in ). If forDue to the indirect nature of such current cooperativity assay, mathematical and computational modeling proved valuable in the analysis of this experimental protocol -7. Here"}
{"text": "Synchronously firing groups of neurons, or cell assemblies, exhibit excess pair-wise synchronous spiking in parallel recordings of neuronal activity. Experimental work  indirectrial-by-trial basis. Using the difference of phases at which maximal rate changes are observed in two neurons we then relate the magnitude of individual rate steps to the degree of rate co-variation across neurons. By comparing the findings to theoretical calibrations tuned to the experimental rates, we find that although the firing rate modulation is related to LFP phase, the locking of significant spike synchrony does not preferentially occur with large co-varying changes of rate.In a first approach we propose an analysis to identify the largest rate changes in UE analysis windows under the assumption that they represent a rate step that is time-locked to a particular phase angle of the instantaneous LFP oscillation rhythm on a Based on these observations, we replace the parametric distribution of expected coincidences used in the original study  for eval"}
{"text": "The key reference to work of Mortier and Patriarche had been inadvertently omitted from this article . The sta\"Unfortunately, ever since the first report on oxyfluoride GCs, there have been much research on the properties of nano-particles in GCs but no publication has been reported about how to obtain free nano-particles in aqueous solution from the GC-host and how to apply it to the fields mentioned above, especially in biological field.\"The authors amend it as follows:Mortier and Patriarche  showed t"}
{"text": "Post-axial polydactyly is a common congenital hand anomaly with a wide range of manifestations. We report here an unusual case of intra-natal torsion of duplicated small finger which presented as gangrene at birth. The duplication of the little finger is one of the most frequent congenital malformations of the hand. The extent of duplication varies from a soft tissue nubbin to a completely developed digit. The presented case probably represents the first reported case of intra-natal torsion of post-axial polydactyly presenting as gangrene at birth, as an extensive review of the literature and Pubmed search did not reveal a similar published case.A male child presented with gangrene of the accessory digit of the left hand at birth . The chiPost-axial polydactyly constitutes one of the most frequent congenital malformations of the hand and is thought to be the result of an excess longitudinal segmentation representing probably an increased folding of the apical ectodermal ridge. The true incidence of post-axial polydactyly is difficult to determine as many of them are removed by the obstetricians and paediatricians in the nursery. Post-axial polydactyly occurs in approximately 1 in 300 black births and 1 in 3000 in Caucasians and is more frequently seen in male children.1The spectrum of the deformity in post-axial polydactyly ranges from a simple soft-tissue problem to a complex completely developed accessory ray. Post-axial polydactyly has been classified into three types based on the degree of duplication. Type I iThe torsion of pedunculated accessory digit is sometimes seen in Type I duplication, however, intra-natal torsion of post-axial polydactyly has not been previously reported in the literature to the best of our knowledge. The intra-natal torsion of visceral or parietal organs per se is very rare. An extensive search of the literature in Pubmed revealed only one case of intra-natal torsion of a testicular tumour.Post-axial polydactyly is believed to be genetically determined. The Type I pattern is dominant and multifactorial and involves two genes with incomplete penetrance. Type II and III are inherited as dominant traits with marked penetrance. The blacPost-axial polydactyly requires detailed clinical, syndromic and imaging evaluation prior to the treatment. The treatment modalities vary from simple excision to complex skeletal surgeries depending upon the type. For Type I deformities, early excision followed by primary closure and occasionally z-plasty closure  under local anaesthesia is the preferred treatment.6 The use"}
{"text": "In recurrent excitatory networks where the mean current caused neurons to fire, increasing chain connections led to higher network synchrony while increasing convergent connections decreased synchrony . In netwIn the present study, we systematically investigate the influence of second order network motifs on the dynamical state of recurrent networks of excitatory and inhibitory neurons in the fluctuation-driven regime. We simulate networks of sparsely coupled integrate-and-fire neurons, where the connection probabilities are given by the second order network model. We allow the probability of each second order motif to depend on the populations (excitatory versus inhibitory) of the neurons involved in the motif. We again find that divergent connections alone have little qualitative effect on the dynamics. However, both convergent connections and chain connections dramatically affect the onset and magnitude of synchronous network oscillations, either increasing or decreasing oscillations depending on the populations of the neurons in the motif. We explain these results through analysis of a mean-field model of the coupled populations."}
{"text": "Some have suggested the quality of reporting of network meta-analyses (a technique used to synthesize information to compare multiple interventions) is sub-optimal. We sought to review information addressing this claim.To conduct an overview of existing evaluations of quality of reporting in network meta-analyses and indirect treatment comparisons, and to compile a list of topics which may require detailed reporting guidance to enhance future reporting quality.An electronic search of Medline and the Cochrane Registry of methodologic studies (January 2004\u2013August 2013) was performed by an information specialist. Studies describing findings from quality of reporting assessments were sought. Screening of abstracts and full texts was performed by two team members. Descriptors related to all aspects of reporting a network meta-analysis were summarized.We included eight reports exploring the quality of reporting of network meta-analyses. From past reviews, authors found several aspects of network meta-analyses were inadequately reported, including primary information about literature searching, study selection, and risk of bias evaluations; statement of the underlying assumptions for network meta-analysis, as well as efforts to verify their validity; details of statistical models used for analyses (including information for both Bayesian and Frequentist approaches); completeness of reporting of findings; and approaches for summarizing probability measures as additional important considerations.While few studies were identified, several deficiencies in the current reporting of network meta-analyses were observed. These findings reinforce the need to develop reporting guidance for network meta-analyses. Findings from this review will be used to guide next steps in the development of reporting guidance for network meta-analysis in the format of an extension of the PRISMA  Statement. Systematic reviews incorporating meta-analyses (SRMA) have long been used to derive summary comparison measures from multiple sources of evidence, most commonly randomized clinical trials (RCTs), to establish the effectiveness and safety of one treatment relative to another. This approach to evidence synthesis is now considered a standard in evidence based medicine. SRMAs have long been considered a scientifically rigorous means of comparing pairs of different medical interventions. To maximize their transparency, methodologic quality and consistency of reporting, the Quality of Reporting of Meta-Analyses (QUOROM) checklist for authors was developed in 1999 network meta-analysis  to simultaneously compare and rank a network of treatments, subsets of which have been compared in individual studies.Over time, increasingly large numbers of treatments for many medical conditions have provided clinicians with more choices from which to select a treatment strategy for their patients. Regulators have only required evidence of benefit over no treatment and a lack of evidence of harms for approval to market. The resulting absence of motivation for drug developers to compare their products against those of their competitors has promoted analytic methods to establish the relative benefits of new agents relative to existing therapies. Following work by Higgins and Whitehead The frequency of use of network meta-analysis has risen notably since the mid 2000s, The PRISMA statement As part of the development of a statement extending PRISMA to cover network meta-analyses, we set out to examine the findings of the peer reviewed literature on the key limitations in the reporting of network meta-analyses. This literature review will help assess the need for reporting guidance, as well as focus the guideline on those features of most importance to clear reporting of network meta-analysis.A brief protocol was developed prior to initiation of this review. It can be acquired by request from the corresponding author.No ethical approval was required for the performance of this work.indirect treatment comparison, mixed treatment comparison, network meta-analysis, and multiple treatments meta-analysis. The search was peer reviewed by members of the authorship team, as well as by an independent information specialist who employed the PRESS (Peer Review of Electronic Search Strategy) framework. An information specialist designed an electronic literature search to search for studies that assessed the quality of reporting of indirect treatment comparisons and network meta-analyses, as well as related key guidance documents for network meta-analysis. The search included a broad range of terms related to the concept of indirect treatment comparisons and network meta-analysis including We included studies, in full text or abstract form, which assessed one or more aspects of the quality of reporting of network meta-analyses or indirect treatment comparisons. Relevant aspects of reporting included (but were not limited to) the following elements: completeness of literature search description; completeness and adequacy of reporting of statistical methods used for analysis; statement and description of assumptions made for network meta-analysis . Stage 1 screening used a liberal strategy where only one individual had to consider a citation of potential relevance in order for it to be advanced to Stage 2 full text screening. For Stage 2, the same individuals reviewed all potentially relevant works in full text. Final inclusion was confirmed if both individuals felt the study was directly relevant to the objectives of this review. Planned involvement of a third party to deal with unresolved discrepancies was not required.Two members of the team extracted data from each retrieved paper . To enable description of the network meta-analyses reviewed in each study and the types of information collected, we gathered the following information from all studies: authorship list, inclusion criteria for types of meta-analyses, number of network meta-analyses reviewed, frequency of the various methods used, and primary authors\u2019 results and conclusions drawn.Figure S1 presents the process of study selection.The literature search and recommendations from co-authors for additional papers identified a total of 775 citations for review. Stage 1 screening identified a total of 19 studies considered to be potentially relevant and whose full texts or supporting posters (where available) were obtained. Following Stage 2 screening, 9 of the studies were retained . The flow diagram in The six full publications assessed indirect treatment comparisons Narrative descriptions of the findings from the included papers have been stratified below according to the type of publication (full versus abstract) in which the research was described. Bafeta et al Nikolakopoulou et al Tan et al Coleman et al Donegan et al Song et al Three studies described in recent abstractsBased on findings from the included reviews and subsequent discussion amongst co-authors, we categorized the perceived key elements related to reporting of both methodology and findings which were judged most important for consideration in a future reporting guidance document. These elements are summarized in Network meta-analysis represents an increasingly prevalent extension of traditional meta-analysis. In addition to continued training needs, our findings suggest a need to develop and promote guidance for reporting these types of studies to maximize transparency and replicability, a corner stone of all science. Such guidance will benefit systematic reviewers with limited exposure to network meta-analyses. Current guidance from groups associated with NICEThis overview identified a total of nine publications which included some form of assessment of the reporting quality of past network meta-analyses or indirect treatment comparisons. This data has identified several limitations for which reporting guidance could be generated to improve reporting. These components included several aspects related to the replicability and validity assessment of NMAs, important aspects of the approach to data analysis, and the reporting of findings. While not meeting our inclusion criteria, we also reviewed a recent report by Lee There are limitations to note for this review. First, our sampling frame was not extant, which would require a primary search for and risk of bias evaluation of all such studies. In our view, conducting an overview provides an adequate rationale for the need to consider extending the PRISMA statement for reporting network meta-analyses. Second, we did not perform a comprehensive search of the literature to identify all methodologic articles related to the conduct of network meta-analysis, which could also serve as a source of topics possibly worthy of reporting guidance. We relied upon the expertise and experience of our authorship team to identify additional items for inclusion in a Delphi survey exercise which was implemented during the summer of 2013, and the survey participants were also provided the opportunity to do so in the context of the survey. Third, we did not perform a risk of bias assessment of the studies included in this report. However, as our primary objective was to compile a list of potential checklist items for inclusion in the development of reporting guidance for network meta-analysis, this did not detract from achievement of our goal.Currently available literature regarding the reporting of network meta-analyses is sparse. Based on the existing evidence, several deficiencies in the reporting of network meta-analyses are apparent and we believe extending the PRISMA statement to network meta-analyses is the best resolution. This overview provided an excellent basis for a Delphi panel survey held in the summer of 2013 and a subsequent face-to-face meeting of experts in the fall of 2013. Dissemination of work generated from this process will be pursued in the near future.Figure S1The flow diagram for study selection.(TIF)Click here for additional data file.Table S1The Medline search strategy used for this syetmatic review.(DOCX)Click here for additional data file.Checklist S1presents a PRISMA checklist assessment for this review article.(DOC)Click here for additional data file.Protocol S1(DOCX)Click here for additional data file."}
{"text": "Tissue microstructure, in particular the alignment of myocytes (fibre direction) and their lateral organisation into sheets, is fundamental to cardiac function. We studied the effect of microstructure on contraction in a computational model of rat left ventricular electromechanics. Different fibre models, globally rule-based or locally optimised to DT-MRI data, were compared, in order to understand whether a subject-specific fibre model would enhance the predictive power of our model with respect to the global ones. We also studied the impact of sheets on ventricular deformation by comparing: (a) a transversely isotropic versus an orthotropic material law and (b) a linear model with a bimodal model of sheet transmural variation. We estimated ejection fraction, wall thickening and base-to-apex shortening and compared them with measures from cine-MRI. We also evaluated Lagrangian strains as local metrics of cardiac deformation. Our results show that the subject-specific fibre model provides little improvement in the metric predictions with respect to global fibre models while material orthotropy allows closer agreement with measures than transverse isotropy. Nonetheless, the impact of sheets in our model is smaller than that of fibres. We conclude that further investigation of the modelling of sheet dynamics is necessary to fully understand the impact of tissue structure on cardiac deformation. The primary eigenvector of the diffusion tensor has been shown to correlate with the fibre direction in the tissue Cardiac tissue is arranged into a complex architecture. Due to their elongated shape, myocytes are highly anisotropic and their local orientation in cardiac tissue is usually called the fibre direction The laminar structure of myocardial tissue is also important for cardiac electromechanics. It has been established that sheets undergo shortening in the fibre direction, extension in the in-sheet/cross-fibre plane, thickening and shear, whose regional variability and transmural distribution are important for the distribution of strain and stress throughout the ventricle during cardiac motion Two motivations underlie our study. First, we aim to understand whether the use of subject-specific fibres would enhance the predictive power of our model, or whether it would be as informative as simple globally prescribed fibres within our modelling framework. To this purpose, globally defined rule-based fibres were compared with a subject-specific model of fibres that is locally optimised in order to minimise the discrepancy with DT-MRI data Our second motivation is the exploration of the often underestimated importance of sheet dynamics in the common electromechanical models. We want to test the impact of sheet orientation in the mechanics of the left ventricle. This was achieved by (a) comparing transverse isotropic with orthotropic material laws for cardiac tissue and (b) under the orthotropic material properties, testing two global models of transmural variation of the sheet orientation, namely a linear and a bimodal model. The aim of the latter comparison was to see whether the latest findings regarding the discontinuous multiple-population distribution of sheets In order to quantify the effect of the different models of fibre and sheet orientation on contraction, global and local metrics were considered. The global metrics are ejection fraction, wall thickening, and shortening in the base-to-apex direction. We compared their predicted values with those obtained from rat cine-MRI data. The local metrics considered are the Lagrangian circumferential strain, as a measure of contraction, circumferential-radial shear strain, as a measure of the relative twist of sub-endocardial and sub-epicardial layers, and circumferential-longitudinal shear strain, as a measure of torsion A preliminary study of the effect of fibre direction and material orthotropy on contraction had been performed with a simplified electromechanical model (without pressure boundary conditions) No new animal experiment was required for the results presented in this paper. The images used come from a dataset previously published and for which the ethics statement was duly reported In vivo cine-MRI and subsequent ex vivo DT-MRI of rat hearts were acquired on a 9.4T (400 MHz) MR system . The cine-MRI dataset used a 2D multi-frame gradient echo sequence, and consisted of a stack of eight contiguous short-axis slices covering the heart from apex to the atrioventricular separation. Each short-axis slice comprised of 32\u201336 frames acquired throughout the cardiac cycle with an in-plane resolution of GmshWe approximate the left ventricle with a thick-walled truncated ellipsoid. A first coarse tetrahedral mesh was generated with semi-axes and wall thickness estimated from the end-diastolic frame of one of the cine-MRI rat scans described , which whelix angle that defines the fibre direction sheet angle. The vector Tissue structure is defined at the centroid of each element of the mechanical mesh by assigning fibre, sheet and sheet-normal directions. This orthonormal local system of coordinates is assigned according to a well-established approach Different models for the fibre and sheet orientation are introduced in this tissue structure generation framework by modelling the transmural variation of the helix and sheet angle as described below.A set of rule-based globally defined fibres were generated by assigning to each element of the mesh a value of the helix angle The global fibre models are compared with a subject-specific fibre model developed by Karadag et al. The standard approach to the modelling of sheet orientation is that of a smooth variation in the transmural direction At the tissue level the monodomain equations  and (4))deformation gradient tensorGreen deformation tensorLagrangian strain tensor is The mechanical component is coupled to the electrical component via the transmembrane voltage. At the tissue level, the mechanical behaviour is modelled according to finite elasticity theory. Let us consider two systems of Cartesian coordinates, a reference system defined on the undeformed body, The Two models of material passive behaviour were tested representing transversely isotropic and orthotropic behaviour. The stiffness parameters for the orthotropic case are taken from The active stress at the tissue level, The temporal evolution of the intra-cavital blood pressure is approximated by means of a sigmoidal function ranging from Chaste, an open-source simulation package for computational biology developed in our group (http://www.cs.ox.ac.uk/chaste) All simulations were run using in situ, the movement is in the opposite direction, i.e. the atrio-ventricular valve plane moves \u2018downwards\u2019 in the direction of the apex, but in terms of changes in apico-basal length, this parameter offers a satisfactory approximation within the modelling framework used). Here The global measures used to evaluate the simulations are: ejection fraction In order to compare the predicted values with experimental data, we measured these metrics on the cine-MRI dataset used for building the ellipsoidal mesh by applying analogous methods. The measured values are As local metrics we considered the Lagrangian circumferential strain In this section we present the results of the series of electromechanical simulations we performed in order to (a) compare sixteen globally defined fibre models  ejection fraction Changing from the transversely isotropic to the orthotropic material law (with the linear sheet model) has the general effect of increasing the For The shortening in the base-to-apex direction  with peak contraction (systole), we believe that this is unlikely to have had a major effect on our findings related to steady-state comparisons. As for the mechanics, there are rat-specific biophysical contraction models. However, we preferred to use the model of Kerckhoffs et al. In the development of the model we tried to be as species-specific as possible in all the components, with the exception of the reduced range for the cavity pressure, as described in Methods and further discussed later on. The geometry has dimensions taken from rat cine-MRI scans, the parameters of tissue electrophysiology are based on measurements in rat. Regarding the AP model, we preferred the mouse model of Wang and Sobie Various measures were considered, grouped into global and local parameters, in order to study the effect of the fibre model, material law and sheet model on contraction. For the global measures, ejection fraction (case of  . We belidels see ), the exal range , are lowThe Lagrangian strains ad-hoc procedure to estimate the pre-P mesh prior to applying the pressure load: this step should be tackled in a more automatic and rigorous approach, by solving an inverse problem. (d) The reduced range of pressures applied in the model: this is probably the most important limitation of the model as pressure is one of the best characterised physiological parameters of the heart. If we compare the results of the preliminary study we carried out using the model without pressure It is important to discuss the limitations of our model. (a) The use of a simplified geometry: the natural geometrical variability of the left ventricle is not taken into account in this study, including the lack of a neighbouring contracting chamber (right ventricle), or of papillary muscles whose orientation is predominantly axial. Previous studies suggest this might not bring a significant improvement To conclude, we developed and tested an electromechanical model and performed a computational study of the impact of tissue microstructure on contraction of the left ventricle in rat. We showed that the model predicts values of global metrics that are within physiological ranges but, except for"}
{"text": "Synaptic transmission efficacy transiently changes in a short period of time with generation of presynaptic spikes. Depending on changes in releasable neurotransmitters and calcium concentration in presynaptic terminals, the transmission efficacy of the dynamic synapses decreases (short-term depression) or increases (short-term facilitation) . DynamicWe investigate the properties of the network dynamics with the leaky integrate-and-fire based spiking neural network and the corresponding mean field model. Changes in the synaptic transmission efficacy can be modeled with variables that represent the releasable neurotransmitter and the utilization parameter reflecting the calcium concentration. In the case of the facilitation synapses, the transmission efficacy increases with the successive generation of presynaptic spikes as shown in Figure In the neural network with dynamic synapses, the effective network structure can be reorganized; this causes qualitative changes in the population dynamics (bifurcation). In the presentation, we discuss possible network functions on the basis of this mechanism e.g., generation of sequential actions."}
{"text": "In this experimental model, neurons are free of predefined constraints and thus able to re-create networks that exhibit complex and highly variable spatio-temporal patterns of activity composed of synchronized bursts, mixed with random spikes. Starting from this experimental evidence, here we address the questions: does a particular network architecture promote such dynamics? Is it possible to predict the activity of a neuronal network on the basis of its connectivity map?In this work we aimed at investigating the interdependence between connectivity and dynamics in large-scale cortical networks cultured neuronal avalanches  [We determined the dynamic state of the network according to the statistical distribution of ritical) ,2. Due tritical) . Networkritical) . Within ritical) . The maiin vitro. Our results showed that different topologies of connectivity may determine different dynamic states and suggest that a scale-free architecture may account for the variability observed in the experimental data by varying the number of hubs.We used a combined approach involving models and experiments to get an insight into the interplay of topology and dynamics in cortical networks cultured"}
{"text": "Pharmacology has been known to medical students as a hard-to-study subject that includes learning by heart hundreds of receptors and pathways, mechanisms of action, substances and side effects in a very limited time. Once graduated, young MDs are confronted with applied pharmacology without being properly prepared choosing and prescribing the right drug in the proper dose to individual patients.My new approach in teaching pharmacology focuses on the application of pharmacology in up-to-date therapy, stressing information relevant for decision-making and prescription. Exam questions contain patient cases to test prescribing and decision-making abilities. My approach in teaching pharmacology and clinical pharmacology within the curriculum with special focus in therapy was honoured by the students with two \u201cProfessor of the Term\u201d awards and excellent ranking by the students and with outstanding results in the evaluation programme conducted by Innsbruck Medical University. The interest of the students in pharmacology grew, 116 students chose to attend extra classes in pharmacology beyond the curriculum during the last semester."}
{"text": "Plant cells exhibit active movement of membrane-bounded materials, which is more pronounced in large cells but is also appreciable in medium-sized cells and in tip-growing cells (such as pollen tubes and root hairs). Trafficking of organelles  and vesicles is essential for plant cell physiology and allows a more or less homogeneous distribution of the cell content. It is well established that the long-range trafficking of organelles is dependent essentially on the network of actin filaments and is powered by the enzyme activity of myosins. However, some lines of evidence suggest that microtubules and members of the kinesin microtubule-based motor superfamily might have a role in the positioning and/or short-range movement of cell organelles and vesicles. Data collected in different cells (such as trichomes and pollen tubes), in specific stages of the plant cell life cycle  and for different organelle classes  encourage the hypothesis that microtubule-based motors might play subtle yet unclarified roles in organelle trafficking. In some cases, this function could be carried out in cooperation with actin filaments according to the model of \u201cfunctional cooperation\u201d by which motors of different families are associated with the organelle surface. Since available data did not provide an unambiguous conclusion with regard to the role of kinesins in organelle transport, here we want to debate such hypothesis. Chara that are considered the model par excellence in which to investigate this process  disperse in the cytoplasm or aggregate around the nucleus. Melanosomes are transported by kinesin-2, cytoplasmic dynein, and myosin-V, in a way that is dependent on the number of active motors . The rate of organelle transport is likely to depend both on the number of active motors bound to the organelle surface and on the aggregation state of motors . Uncertainty also exists for the single member of the kinesin-6 subfamily and for two putative members of the kinesin-8 subfamily. Analysis of identified kinesins suggests that there is no relationship between affiliation to a subfamily and specific function. The kinesin-4 subfamily contains members localized in the cortical microtubule array and putatively involved in regulating the organization of cellulose microfibrils. The kinesin-5 subfamily contains members that might dimerize allowing the sliding of anti-parallel microtubules; since the role of kinesin-5 in spindle structure/function is conserved between organisms, plant kinesins-5 may have evolved additional roles unique to plants. Some members of the abundant kinesin-7 subfamily might be involved in the regulation of phragmoplast assembly as well as in the interaction between chromosomes and microtubules. The kinesin-10 subfamily is likely to be responsible for the delivery of Golgi vesicles in the phragmoplast. The kinesin-12 members are capable of regulating the formation of the preprophase band while the kinesin-13 motor proteins mediate the interaction between Golgi membranes and cortical microtubules. The kinesin-14 subfamily is the most expanded one and contains members with a C-terminal motor domain likely involved in the sliding of adjacent microtubules as it occurs in the formation/functioning of the mitotic spindle and, putatively, in the assembly of the preprophase band. Recently, some plant kinesins have been shown to be unique because they might work as transcriptional activators during gibberellin biosynthesis and cell growth  was found to be expressed in interphase BY-2 tobacco cells  and possMost of plant kinesins are involved in cell division. The preprophase band is likely to be organized by a number of kinesins such as ATK1 , KCBP B, AtKRP12The involvement of plant microtubules in organelle transport is subtle and often difficult to decipher. Apart from the role of microtubules in chromosome movement, transport of organelle and vesicles along microtubules is documented only by sporadic reports and is limited to few cell types where membrane movement can be studied more easily. The directional grain-to-apex (and vice versa) movement of organelles, accomplished to the focusing of Golgi vesicles in the tip, makes the pollen tube an excellent system where to investigate the contribution of microtubules and microtubule-based motors to organelle trafficking . ConsequArabidopsis mitochondria. Those proteins contain an N-terminal mitochondrial targeting signal and might be a specific subclass of kinesins whose function is currently unknown , were supposed to work inside  unknown . More ge unknown . This su unknown . Bindingc oxidase activity  and a protein isolated from the organelle fraction exhibited immunological and biochemical properties of the kinesin family  was immunolocalized in the tobacco pollen tube and shown to partially overlap with the 58K protein (a marker of Golgi apparatus). However, the motor protein was not found in the pollen tube apex suggesting that it was not critical for the delivery of secretory vesicles  in root meristem cells of wheat. The antibodies localized the antigen in association with aggregates also labeled by Golgi markers  and chloroplasts tend to accumulate in the cortical area of plant cells, exhibiting a movement that is neither linear nor continuous. Unlike other organelles, the movement of chloroplasts is not dependent on the interaction between myosin XI and actin filaments but on the polymerization state of short actin filaments (cp-AFs) associated with the outer envelope of chloroplasts . Howeverin vivo (BC12) is a gene that encodes for a kinesin-4 protein. Like Fra1, bc12 mutants show a significant alteration in the orientation of cellulose microfibrils. Even BC12 is an authentic motor protein but unlike Fra1 is also present in the nucleus and may function as a transcriptional activator  and ending with the synthesis of cellulose microfibrils and the correct assembly of the wall. Historically, microtubules have always been involved in the process of cell wall assembly since first observations of cortical microtubules associated with the plasma membranes . The prein vivo . This apin vivo , the prein vivo . Currentin vivo . The proin vivo . The rolin vivo . Brittlectivator . On the ctivator  thus sugIf kinesins participate in the assembly of the cell wall, where is their contribution necessary? The movement of CesA in the plane of the plasma membrane is definitely independent of a kinesin-based motor process because CesA can move even in the absence of microtubules. In addition, it is likely that microtubules could direct the movement of CesA, but they do not participate in the making of CesA trafficking. Therefore, kinesins may participate in other steps of the cell wall assembly process, especially during the transport of CesA to the insertion points. We cannot exclude that kinesins may also participate in the assembly of the protein complex that makes CesA as active but the few evidence collected so far suggest that kinesins might determine the insertion of CesA in the plasma membrane. If both Fra1 and BC12 are true motors, it is possible that they carry cargoes containing CesA to the insertion points. Recent data helped to clarify the specific cargo carrying CesA toward the plasma membrane. A particular type of membrane compartment has been identified as critical in either transport or recycling of CesA, the so-called MASC  or SmaCCFigure 3). The importance of motor proteins during cell elongation is also documented by the microtubule-based movement of the endoplasmic reticulum in characean algae at a stage coinciding with the onset of cell elongation  isolated from tobacco pollen tubes can move along microtubules so slowly that are incompatible with cytoplasmic streaming . These vin vitro analysis of organelle/vesicle movement along both actin filaments and microtubules  direct the movement of organelles along microtubules while myosins often counteract this activity in order to position organelles precisely . In thisotubules  and by aotubules . As suppotubules . In thisotubules . In planotubules . Althougotubules , we cannotubules . Althougotubules . Althougotubules .Before the discovery of kinesins, organelle trafficking in plant cells was essentially assumed dependent on actin filaments and myosins . Now, weThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Publications from the group in Abidjan indicate the performance of the first 300 cases of open-heart surgery by 1983, the figure increasing to 850 by 1987. Senegal reportedly began performing open-heart surgery in 1995 and is currently a reference point for open cardiac procedures for francophone West Africa. The Ghanaian open-heart experience began in 1964 when surface cooling was used to achieve hypothermia for the successful closure of an atrial septal defect. However, it was not until 1989 that Ghana's National Cardiothoracic Center (NCTC) was established. The NCTC performs regular open-cardiac procedures covering almost the entire spectrum of cardiothoracic procedures including video-assisted thoracoscopic surgery (VATS). The NCTC is equipped with modern cardiovascular/thoracic facilities and has been accredited by the West African College of Surgeons as a center of excellence for the training of cardiothoracic surgeons and has performed creditably in this regard. It is emphasized that open-heart surgery has been practiced in West Africa for decades and continues to be practiced with excellence matching international standards at Ghana's National Cardiothoracic Center.We read with concern the paper of Budzee and colleagues in a recent issue of the Pan African Medical Journal. We wish to draw the attention of the authors and the readership of the journal to gross inaccuracies in the report. The first open-heart surgery in Nigeria is reported to have taken place on 1 We read with concern the paper of Budzee and colleagues in a recent issue of the Pan African Medical Journal . We wishThe West African sub-region is deficient in terms of healthcare facilities, especially those relating to cardiac surgery. However, open heart surgery is not new in the sub-region neither is coronary artery bypass graft, as Budzee and colleagues claim in their publication . It is dOur experience with open-heart surgery in Ghana began in 1964 when Charles Odamtten Easmon, a Ghanaian surgeon used surface cooling as a means of achieving hypothermia to close atrial septal defects in two patients. Subsequently, a myriad of problems stalled the open-heart program in Ghana until 1989 when Ghana's National Cardiothoracic Center (NCTC) was set up by Dr. Kwabena Frimpong-Boateng who was a pioneer of heart transplantation at the Medizinische Hochschule Hannover in Germany where he trained. The NCTC currently performs over 400 cardiothoracic operations a year, roughly a quarter of these are open-heart procedures performed using extracorporeal circulation. Operations performed include surgery for congenital heart disease, rheumatic heart disease, coronary artery bypass graft, and many others. In our 22 years of existence, the NCTC has received referrals from several West African nations including Cameroon and has reported results of open-heart procedures performed on patients from across the West African sub-region . We are It is surprising to us therefore when Budzee and colleagues claim that their institution is the only cardio-surgical center in Central / West Africa, equipped with ultra modern health technologies to offer diverse services. We have been in this service since 1989 and have made and continue to make significant contributions in the sub-region and beyond. We know other centers in the sub-region that have also done quite well until recently.We congratulate Budzee and coworkers for the effort they have made to bring open-heart surgery to Cameroonians. We are well aware of the many obstacles and challenges facing developing countries starting open-heart surgery programs but we consider their report overzealous and historically inaccurate. We wish to emphasize that theirs is not the only cardio-surgical center in West Africa; and coronary artery bypass grafts have been performed (and still being performed) by several indigenous West African teams starting two to three decades before their own.The authors declared no conflicts of interest."}
{"text": "With the use of specific cardiac markers with higher sensitivity, new perspectives have emerged on the nature of myocardial necrosis and injury, which are associated with acute coronary syndrome (ACS). The third universal definition of myocardial infarction3The clinical circumstances associated with elevated values of cardiac troponin (c-Tn) due to myocardial injury have been listed,6Guidelines on the use of high-sensitivity cardiac troponin (hs-cT) markers have recently been set in the consensus statement of the Ethics and Guidelines Standing Committee of the South African Heart Association.The committee recommends that high-sensitivity troponin assays be widely adopted as the preferred biomarker for the diagnosis of myocardial infarction, based on evidence of earlier diagnosis of MI, more reliable ruling out of MI, and shortening of the chest pain triage (to four hours compared to former assays). All cardiac troponin measurements are to be reported in ng/l. The first sample is to be collected on first assessment, followed by a second sample after three hours, should the first value be lower than the 99th percentile (URL) of a normal reference population for the specific assay, or between the URL and the WHO-defined URL for MI. Serial measurements are to be reported as percentage change. A specific algorithm for both hs-cTropT and hs-cTropI is proposed for the diagnosis of MI.The Expert Consensus document on the third universal definition of myocardial infarction4The guidelines defined for South Africa (SA)et al.,In the South African guidelines,The validity of the use of the URL7Furthermore, inter-assay differences concerning reference values for specific populations appear to impact on risk stratification.29et al. and others.27The 20% limit of defining a significant increase from the time of first assessment if baseline values are above the URL has been established within the National Academy of Clinical Biochemistry laboratory medicine practice guidelinesOther complexities of measurement, as eluded to by Thygesen,44et al.et al. on carry-over to subsequent samples with certain analysers, potentially leading to false-positive results.45In addition, Lippi The South African guidelines on the use of high-sensitivity cardiac troponins as biomarkers are timely and of great value, provided that clinicians take up the challenge of applying them clinically."}
{"text": "Limitations of known anatomical circuit rules necessitate the identification of supplementary rules. This is essential for explaining how associative sensory stimuli induce nervous system changes that generate internal sensations of memory, concurrent with triggering specific motor activities in response to specific cue stimuli. A candidate mechanism is rapidly reversible, yet stabilizable membrane hemi-fusion formed between the closely apposed postsynaptic membranes of different neurons at locations of convergence of sensory inputs during associative learning. The lateral entry of activity from the cue stimulus-activated postsynapse re-activates the opposite postsynapse through the hemi-fused area and induces the basic units of internal sensation  as a systems property. Working, short-term and long-term memories can be viewed as functions of the number of re-activatible hemi-fusions present at the time of memory retrieval. Blocking membrane hemi-fusion either by the insertion of the herpes simplex virus (HSV) glycoproteins or by the deposition of insoluble intermediates of amyloid protein in the inter-postsynaptic extracellular matrix (ECM) space leads to cognitive impairments, supporting this mechanism. The introduction of membrane fusion blockers into the postsynaptic cell cytoplasm that attenuates long-term potentiation (LTP), a correlate of behavioral motor activities in response to memory retrieval, provides further support. The lateral spread of activity through the inter-postsynaptic membrane is capable of contributing to oscillating neuronal activity at certain neuronal orders. At the resting state these oscillations provide sub-threshold activation to many neurons at higher orders, including motor neurons maintaining them at a low initiation threshold for motor activity. The integral of the resulting non-specific set of semblances was hypothesized to provide a framework for consciousness  or stabilized as hemi-fused inter-postsynaptic membranes for a long period of time (explaining long-term memories). What ideal properties can allow the inter-postsynaptic functional LINKs to operate between two postsynaptic membranes? Even though the spread of neurotransmitters to neighboring synapses  glycoproteins can induce the formation of membrane hemi-fusion by getting inserted into the host membranes  synapse with postsynapses (dendritic spines) of the neurons in the lateral amygdala. We anticipate functional LINK formation between the postsynapses of different lateral amygdala neurons. In patch-clamp experiments following fear conditioning, an example of associative learning, when thalamic afferents are stimulated to measure the EPSPs at the pyramidal neurons in the lateral amygdala, an increase in the amplitude of the AMPA current is observed  receptors of the excitatory neurotransmitter glutamate have been shown to be necessary for behavioral motor activities indicative of memory retrieval  such that the nervous system becomes capable of retrieving similar memories even when the hippocampi are removed. This explains the process of consolidation of memories  show slow oscillations  in the dendritic tree through the re-activation of a functional LINK by activity arriving from the cue stimulus. Similarly, sub-threshold motor neurons maintained by continuous oscillatory neuronal activity can have a significant role in central pattern generator functions at different locations of the nervous system and in the initiation and maintenance of locomotion.The formation of internal sensations depends on the nature of the semblions formed in response to the specificity of the cue stimulus. The lateral spread of activity through the inter-postsynaptic functional LINKs induces physiological oscillatory neuronal activity, which maintains large numbers of sub-threshold activated neurons at the higher orders. The latter are activated by the arrival of one or a few EPSPs and determine the neurons that are activated by the arrival of the cue stimulus  maintains the required molecular changes and may eventually convert them to near-structural LINKs, and (b) incorporates more new neurons in the circuitry to expand the number of functional LINKs from which a large number of combinatorial semblances can be induced for retrieving different memories. Exposure to rare combinations of sensory stimuli will lead to the formation of specific new sets of functional LINKs at higher neuronal orders. The cognitive abilities that depend on the capacity to associatively learn specific patterns of physical properties of various items in the environment are likely to depend on the available unique combinations of postsynapses that can be functionally LINKed. Many functional LINKs are expected to be formed by simultaneous inputs from the environment that depends on the fixed physical properties of the items. It is possible that the functional LINKs get evolutionarily preserved as structural LINKs and are maintained through genetic mechanisms. In a novice nervous system, synaptic neurotransmission, and the spread of activity through innate structural LINKs between postsynapses will be responsible for innate behavioral responses  required for basic survival needs.It is anticipated that successful stable memories for an item will have excess of net semblances beyond what is required, so that the system can afford to lose some of the functional LINKs without losing the required minimum net semblances for a specific memory (Vadakkan, The gold standard requirement for the operational mechanism of a complex system is an interrelated framework that can explain almost all its functions. The inter-postsynaptic functional LINKs can provide these requirements, which include the retrieval of memories at physiological time-scales, the consolidation of memories (Vadakkan, We have presented a supplementary circuit rule-set that can operate in unison with existing circuit rules and provides interconnected frameworks to explain various nervous system functions. It was imperative to make reasonable assumptions to view the formation of semblances as an emergent property of a system having oscillatory neuronal activity at certain neuronal orders. In such systems, the lateral entry of activity re-activating the inter-postsynaptic functional LINKs provides the horizontal component responsible for the neuronal oscillations along with the formation of basic units of internal sensations; namely, semblions. The concurrent formation of semblances and behavioral motor activity that depends on the frequency of neuronal oscillations provides a finely-regulated system. The present work highlights the importance of developing technologies to measure the summated EPSPs from the soma of the neurons, both at rest and during a cognitive operation, as an initial step followed by developing methods to trace the synapses from where they arrive. Verifying the wiring rules by examining the basic structural mechanisms of operations will help us understand additional information regarding the first-person perspective of different higher brain functions.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The use of Casemix system as providers\u2019 reimbursement method under social health insurance schemes has spread beyond high-income countries. Over the last decade many low and middle-income countries (LMIC) have started to implement Casemix system to replace the conventional yet inefficient fee-for-service as provider payment mechanism. UNU-IIGH launched an international grouper called UNU-CBG in 2010 to support the implementation of Casemix system in LMIC. To date, UNU-CBG has been introduced in 12 countries in different phases of implementation process. UNU-CBG was designed to function as an international grouper that can be customized and adapted to suit the local needs and norms of each country. However inability to provide robust groupings for sub-acute and chronic conditions is a major limitation in the use of Casemix system in these countries. Sub-acute and chronic diseases that account for more than two thirds of disease burden in LMIC should be categorized in mutually exclusive groups if the reimbursement were to be made using Casemix system. Researchers in UNU-IIGH and International Casemix and Clinical Coding Centre of UKM have been working very hard for the past two years to upgrade the capacity of UNU-CBG grouper to classify sub-acute and chronic cases into Casemix group. Additional variables included in the new grouping algorithm are extended length of stay, costly prostheses, drugs, procedures, investigations and scores of Activity of Daily Living. The new version of UNU-CBG launched during this conference provides an opportunity for social health insurance managers in LMIC to use Casemix system as a total solution for provider payment method."}
{"text": "The biomimetic flow at different scales has been discussed at length. The need of looking into the biological surfaces and morphologies and both geometrical and physical similarities to imitate the technological products and processes has been emphasized. The complex fluid flow and heat transfer problems, the fluid-interface and the physics involved at multiscale and macro-, meso-, micro- and nano-scales have been discussed. The flow and heat transfer simulation is done by various CFD solvers including Navier-Stokes and energy equations, lattice Boltzmann method and molecular dynamics method. Combined continuum-molecular dynamics method is also reviewed. Human knowledge is getting enriched from the four billion years' worth of R & D in the natural world of plants and animals and other lower level living creatures and microorganisms, which have evolved through the ages to nicely adapt to the environment. Man has now drawn his attention to soil creatures like earthworms, dung beetle, sea animals like shark and plants and trees like lotus leaf and pastes like termites. In the nature, we see examples of effortless and efficient non-sticking movement in mud or moist soil, high-speed swimming aided by built-in drag-reduction mechanism, water repellant contaminant-free surface cleaning mechanism and natural ventilation and air conditioning, -8. By na\u2022 Replicating natural manufacturing methods as in the production of chemical compounds by plants and animals.\u2022 Mimicking mechanisms found in nature such as Velcro and Gecko tape.\u2022 Imitating organizational principles from social behaviour of organisms like ants, bees and microorganisms.Russia has developed a systematic means for integrating the natural knowledge into humankind's technology using 'Teoriya Resheniya Izobretatelskikh Zadatch (TRIZ)', i.e. the theory of inventive problem solving, which provides an objective framework based on functionality for accessing solutions from other technologies and sciences. TRIZ also prevents waste of time trying to find a solution where none exists. The four main tools of TRIZ are a knowledge database arranged by function, analysis of the technical barriers to progress (contradictions), the way technology develops  and the maximization of resource usage. The biology-based technology 'Biomimetics' suggests new approaches resulting in patents and some into production:\u2022 Strain gauging based on receptors in insects ,\u2022 Deployable structures based on flowers and leaves ,\u2022 Tough ceramics based on mother-of-pearl ,\u2022 Drag reduction based on dermal riblets on shark skin ,\u2022 Tough composites based on fibre orientations in wood ,\u2022 Underwater glues based on mussel adhesive ,\u2022 Flight mechanisms based on insect flight ,\u2022 Extrusion technology based on the spinneret of the spider ,\u2022 Self-cleaning surfaces based on the surface of the lotus leaf .The importance of Biomimetics will increase as the incidence of genetic manipulation increases and the genetic manufacturing is developed. In the result, the area between living and non-living materials, where biology interacts with engineering, e.g. bioengineering and biomechatronics, is benefited.There are innumerable examples of interactions with the environment and balanced and efficient heat, mass, momentum and species transfer through the microstructures in the fluid flow in the manifested living world of plants, animals and other living creatures. Biomimetics involve mimicking these interactions across the functional surfaces with the surrounding environments in the technological design. The physical nature is numerically modelled and simulated using computational fluid dynamics (CFD).Geometrical analogy as well as physical similarity is to be studied to design technological functional surfaces imitating microstructural and biological functional surface morphologies. CFD at micro- or meso-scales and other numerical methodologies are necessary for this -24.The meso- and micro-scale methods are also being developed in parallel with the continuum theory-based conventional CFD techniques-using finite volume method (FVM) and finite element method (FEM). In the mesoscopic lattice Boltzmann method (LBM), fluid flow is simulated by tracking the development of distribution functions of assemblies of molecules. It is difficult to capture the interfacial dynamics, which is essential for multiphase flow, at the macroscopic level. LBM captures the interaction of fluid particles and is, therefore, helpful for multiphase flow with phase segregation and surface tension. Also, the LBM is computationally more efficient than molecular dynamics (MD) method since it does not track individual molecules; the solution algorithm is explicit, easy to implement and parallel computation can be done. Micro/nano-scale simulations in micro/nano-scale geometries and micro time scales are done in MD method and direct simulation of Monte Carlo (DSMD) method. Coupled macro-scale simulation is being done using high performance computer (HPC). This article makes a review of the advances in multiscale biomimetic fluid flow modelling and simulation of difficult physics problems with complex biological interfaces.The locomotion, power and manoeuvring of aquatic animals like swimming fish having superior and efficient utilization of propulsion through a rhythmic unsteady motion of the body and fin resulting in unsteady flow control has been engineered for the transportation in the underwater vehicles. The fish senses and manipulates large-scale vortices and repositions the vortices through tail motion. The timing of formation and shedding of vortices are important. CFD application by mimicking the swimming of fish and underwater dolphin kicking has been utilized to understand active drag and propulsive net thrust and this has resulted in better sailing performance, Olympic ski jumping, Formula 1 racing, Speedo's new Fastskin FSII swimsuit and an optimal kick profile in swim starts and turns. The undulatory propulsion in aquatic vertebrates is achieved by sending alternating waves down the body towards the tip of the tail and causing sinusoidal oscillation of the body, a jet in the wake and a forward thrust. Two modes of propulsive technique utilized by fish are anguilliform and carangiform, Figure The unsteady incompressible Navier-Stokes equations of turbulent flow are solved in the simulation by applying the Reynolds-averaged Navier-Stokes (RANS) equations with usual boundary conditions to obtain the fluctuating velocity fields. The equations in Cartesian tensor form are:x and u are Cartesian coordinates and velocities, respectively, and t is time. Velocity u, density \u03c1, viscosity \u03bc and other solution variables represent ensemble-averaged (or time-averaged) values. Reynolds stress, k is the turbulence kinetic energy, \u03b5 the kinetic energy dissipation rate and \u03bct the turbulent viscosity. C is constant, \u03c3 the Prandtl number. Gk represents the generation of turbulence kinetic energy due to the mean velocity gradients. \u03bct is the turbulent viscosity.where k-\u03b5 work-horse turbulence model for practical engineering flow calculations.The turbulent flow induced by the fish-tail oscillation is characterized by fluctuating velocity fields. The instantaneous governing equations are time averaged to reduce the computational time and complexity which is done in the form of turbulence models like the semi-empirical V with moving boundary is employed:To calculate the flow field using the dynamic mesh, the integral form of the conservation equation for a general scalar \u03c6 on an arbitrary control volume S\u03c6 is the source term of \u03c6 and \u2202V is the boundary of the control volume V.where The flow is characterized by spatially travelling waves of body bound vorticity. The mix between longitudinal and transverse flow features varies with the phase of oscillation and the unsteady velocity field varies throughout an oscillation cycle. The dynamic pressure distribution contour and the effect of the tail movement on the unsteady flow field of the fish-like body will show that there are high pressure zones at the rear of the body indicating strong vortex and turbulence. The kinematic parameters like Strouhal number, wavelength and oscillating frequency are based on the forward locomotion in a straight line with constant speed in the cruising direction. Figure Other example of using CFD to study biomimetic fluid flow problems include simulation of air flow around flapping insect wings, numerical simulation of electro-osmotic flow near earthworm surface and simulation of explosive discharge of the bombardier beetle.Kroger  made a CThe dynamic mesh CFD model is used to examine critical flight simulations of normal aircraft, like the undercarriage lowering at low air speed, or the movement of sweep wings of fighter jets at high air speed. Next to flight applications, the dynamic mesh model can also simulate moving heart valves in the biomedical area, or small flapping membrane valves in micro-fluidics or the flow around any arbitrary moving part in other industry or sports applications.The electro-osmotic flow controlled by the Navier-Stokes equations near an earthworm surface has been simulated by Zu and Yan  numericaA biomimetic CFD study -39 of thC-V hyperbolic equation, which is not subject to the Fourier law assumption of infinite thermal propagation speed, is also not free from anomalies.Nanoscale systems such as GaAsMESFETs and SiMOSFETs semiconductor devices, ultra-fast (picoseconds or femtoseconds) pulsed lasers do not conform to the classical Fourier heat diffusion theory in which the mean free path of the energy carriers becomes comparable to or larger than the characteristic length scale of the particle device/system or the time scale of the processes becomes comparable to or smaller than the relaxation time of the energy carriers. Although numerical techniques like Boltzmann transport equation (BTE) or atomic-level simulation (MD) and Monte Carlo simulation (MCS) can capture the physics in this regime, they require large computational resources. The Finite difference and finite element methods serve well for continuum description of a system governed by a set of differential equations and boundary conditions. However, the problem arises when the system has atomic fabric of matter such as in the case of friction problems and phase-change problems of fluid freezing into a solid or dynamic transition such as intermittent stick-slip motion .When a system is modelled on the atomic level such as in case of MD, the motion of individual atoms or molecules is approximated. The particle motion is controlled by interaction potentials and equations of motion. MD is used for systems on the nanometre scale.Coupling two very different descriptions of fluids at MD-continuum interface is a serious issue. The overlapping region of two descriptions must be coupled over space as well as time giving consistent physical quantities like density, momentum and energy and their fluxes must be continuous. Quantities of particles may be averaged locally and temporally to obtain boundary conditions of continuum equations. Getting microscopic quantities from macroscopic non-unique ensembles is, however, difficult.Several coupling schemes -44 have The two domains are coupled to each other by ensuring that the flux components normal to the domain boundary match. If particles flow towards the boundary, a corresponding amount of mass, momentum and energy must be fed into the continuum. Conversely, any transport in the vicinity of the boundary on the part of the continuum must provide a boundary condition for transport on the part of the particles.Figure Sousa  presenteFollowing the original approach of Olfe  and ModeThe development and optimization of the performance of micro and nano fluidic devices requires numerical modelling of fluid flow inside micro and nanochannels. The nature of the phenomena involved in these devices invariably and predominantly has the interfacial interactions because of high surface-to-volume ratio and is characterized by an inherent multiscale nature -62. The The MD atomistic model in the micro-scale framework is a deterministic method. In this model, the evolution of the molecular system is obtained by computing the trajectories of the particles based on the classical molecular model. The continuum conditions can be applied to molecular domain either by the method based on continuous rescaling of atomic velocities or by the periodic resampling method of atomistic velocities that employs velocity distribution functions such as Maxwell-Boltzmann or Chapman-Enskog distribution for non-equilibrium situations of hybrid simulations in dilute gases employing geometrical decomposition and state coupling. The Maxwell-Boltzmann velocity distribution is the natural velocity distribution of an atomic or molecular system in an equilibrium state defining the probability of one-dimensional velocity components of an atom assuming a specific value based on temperature and the atomic mass. The reflective plane placed at the upper boundary of the boundary condition transfer region maintains every particle inside the molecular domain. This scheme is simpler than the velocity reversing scheme, but this can be applied only to incompressible flows because the normal pressure is a result of the reflected atoms.In the rescaling techniques, in addition to the velocity restrictions, the continuum pressure applies to the atomistic region. The normal pressure is applied through external forces generating a potential energy field. Energy is decreased because of the reduction of potential energy of the atoms moving towards the continuum boundary. The resulting energy oscillations in the molecular system are reduced by velocity reversing of the outermost atoms. This scheme is simple and robust because of uncontrolled transfer of energy. The continuum temperature to the molecular system is accomplished by an energy transfer scheme. The energy is added or removed from the microscopic system to parallel the macroscopic temperature without modifying the mean velocity of the particles. The energy transfer takes place independent of each dimension and is accomplished by the velocity vectors of the atoms ,61-68.Drikakis and Asproulis  applied The task of imitating biological functional surfaces with variety of complex three-dimensional micro- and nano-structures is very challenging in biomimetic flow simulation. The transfer of biological morphologies of plants and animals by imitating both geometrical and physical similarity to technological applications is to be identified -127. StuHard spheres fluids, square well fluids and Lennard-Jones fluids are model fluids in MD. The fluid flow and heat transfer in micro-scale and nano-scale systems get microscopic and nanoscopic insight from MD .A comprehensive and state-of-the-art review of CFD techniques for numerical modelling of some biomimetic flows at different scales has been done. Fluid-fluid interfaces contacting with functional solid surfaces have been discussed. The multiphysics modelling at different scales by Navier-Stokes and energy equations, mesoscopic LBM, MD method and combined continuum-MD method with appropriate coupling schemes have been dealt with in detail.AFM: atomic force microscope; BTE: Boltzmann transport equation; CFD: computational fluid dynamics; DSMD: direct simulation of Monte Carlo; FEM: finite element method; FVM: finite volume method; HPC: high performance computer; LBM: lattice Boltzmann method; LPM: lattice Poisson method; MCS: Monte Carlo simulation; MD: molecular dynamics; RANS: Reynolds-averaged Navier-Stokes; SEM: scanning electron microscope; SPH: smoothed particle hydrodynamic; TRIZ: Teoriya Resheniya Izobretatelskikh Zadatch.The authors declare that they have no competing interests.All authors read and approved the final manuscript."}
{"text": "This is a review of the content and scope of a multi-author volume for readers with an interest in the structure and function of the blood-brain barrier and in drug delivery to the central nervous system. This volume is one of a number in the Methods in Molecular Biology series Volume 686. It is designed as a sequel to \"The Blood-Brain Barrier - Biology and Research protocols which appeared under the same publishers as part of the Methods in Molecular Medicine Volume 89 (2003). The book follows a slightly different structure to previous volumes in that it contains an number of reviews bringing key areas of the subject, which have shown significant recent development, up to date, plus further sections which contain specific protocols for blood-brain barrier study and drug delivery to the central nervous system. The volume is divided into five parts, I \"Biology of the Barrier\", II \"Imaging the Barrier\", III \"Molecular Techniques to Study the Blood-Brain Barrier\", IV \"Models to Study the Barrier\" and V \"Delivery of Therapeutic Agents Across the Barrier\".Part I contains six reviews which bring critical areas up to date. There is a chapter on endothelia cells (Nag), pericytes (Dore-Duffy and Cleary), astrocytes (Nag), the blood-cerebrospinal fluid barrier , the blood-retinal barrier (Runkle and Antonetti) and finally the blood-nerve barrier (Weerasuriya and Mizisin). In this way the opening section reviews the morphology and function of the cell associations forming the barriers of the CNS and directly reviews current knowledge of the different barriers between the nervous system and the systemic circulation.Part II is devoted to imaging the barrier and covers confocal microscopical detection of proteins in endothelial cells , MRI of permeability of contrast agents , pathological investigations with iron oxide microparticles , human blood-brain barrier integrity measured with MRI (Kassner and Thornhill), the blood cerebrospinal fluid barrier in the embryonic rat  and MRI studies of the blood-nerve barrier with MRI (Wessig).Part III moves on to molecular techniques and covers protocols for isolation of endothelia cells and a study of lipid rafts with mass spectroscopy , Laser capture proteomic studies of endothetlial cells, (Murugesan), P-glycoportein expression and function (Chan and Bendayan), and methods to study glycoproteins in the blood-brain barrier using mass spectroscopy .Part IV covers models available for barrier study including novel systems for the eye and brain in Drosophila  and zebrafish brain . Cell culture models for pericyte endothelial interactions in a porcine model , the human outer retinal barrier (Hamilton and Leach), and the peripheral nerve barrier (Sano and Kanda) are then described and discussed.The final part V is devoted to the delivery of therapeutic agents across the barrier and includes, treatment of focal ischemia with viral vector mediated gene transfer (Su and Yang), Treatment of brain tumours with barrier disruption (Blanchette and Fortin), the use of liposome nanocarriers and single domain antibodies for delivery of drugs and contrast agents in the context of drug delivery  and finally chapter on targeting the choroid plexus and cerebrospinal fluid using peptide motifs identified by page display In all this book represents a very useful addition to the series, the reviews and protocols bring important areas within the field up to date in a very accessible format and will be attractive to both established scientists in the area and postgraduate and postdoctoral students establishing a career and wishing to master new ideas and methods. It should be on the bookshelf of every lab with an interest in the blood-brain barrier. Again Sukriti Nag has brought together a panel of world experts to compile a valuable volume.The author declares that they have no competing interests.Sole author."}
{"text": "Veneto Region is currently achieving the integration of health and social services by integrating the tele-surveillance (detection of emergencies) already provided to \u2018socially frail\u2019 people with tele-monitoring, addressed to patients affected by chronic diseases.This strategy is guided by the idea that a better integration between the different levels of assistance is capable of improving the quality and continuity of care and generating synergies that benefit the healthcare system both by enhancing coordination of efforts and by reducing costs.The strategy employs a unique call center at Regional level, that currently performs tele-surveillance services  originally targeted to \u2018socially frail\u2019 people and a more complete tele-monitoring service for chronic patients, thus integrating health and social services. Tele-monitoring consists in the remote measurement of vital parameters (controlled by physicians), and the management of emergencies.This approach to the integration of different assistance levels is being put to the test in the context of the RENEWING HEALTH European Project. The project will assess the services using a multidisciplinary HTA methodology thus providing reliable evidence on the effectiveness and cost-effectiveness on the large-scale implementation of this kind of service."}
{"text": "As the environmental significance of odor pollution is recognized by the public, the demand for accurate assessment of these pollutants has been growing steadily. Hence, the analytical methodologies commonly used for their determination need to be evaluated from various respects. This special issue is thus intended to compile up-to-date knowledge on the determination of odor pollution with emphasis on volatile organic compounds (VOCs) and many key odor components such as reduced sulfur compounds (RSCs), organic acids, carbonyls, and nitrogenous compounds (ammonia and trimethyl amine).The publication of this special issue has been achieved by the warm support and devotion of the contributing authors as well as the important contribution offered by expert reviewers. This special issue is intended to provide a snapshot in the timeline of international research and policy of odorant and VOC pollution and to bring together some of the recent and most exciting developments in the area, and to describe the main trends of their application in the field study. It contains a mixture of papers describing the latest development for their application relevant to air pollution and odor pollution.Ki-Hyun KimKi-Hyun KimDavid ParkerDavid ParkerFusheng LiFusheng LiKea-Tiong TangKea-Tiong Tang"}
{"text": "MR imaging of the heart typically involves the acquisition of standard views aligned with the heart axes. Time-efficient and reproducible planning requires expertise in heart geometry and anatomy. In this study, we evaluate the ability of fully automatic heart view localization software to detect the long-axis views of the heart and compare the results both visually and geometrically with manual localization.27 patients (age range 9-70 years) undergoing CMR for a range of different indications  were examined on a 1.5 T MAGNETOM Avanto MR system . Following rough localization of the heart within the thorax, a stack of slices covering the entire heart was acquired in the approximate short-axis orientation using a single-shot TrueFISP sequence. This stack of slices was used as input to a machine learning-based algorithm [The automatic view-planning software detected the heart in all 27 cases. Visual agreement scores are summarized in Table We have demonstrated in a group of patients with a range of different cardiovascular pathologies that automatic planning of the long-axis views of the heart can be accomplished in the majority of cases with little or no clinically relevant difference compared with manual planning. Consistent with the visual assessment, the angular differences between the manually and automatically planned views increased with increasing visual difference.Siemens AG."}
{"text": "An 11-year-old boy was shot with an air-powered rifle.Where is the entry wound?What type of hemorrhage is present?What are the indications for removal of the foreign body?What is the optimal surgical approach?The patient is an 11-year-old boy who was accidentally shot in the face with an air-powered rifle. The ball bullet (BB) entered through the dorsum of the nose over the nasal radix (Fig 1hyposphagma, defined as an accumulation of blood trapped between the conjunctiva and the sclera. Many small, fragile blood vessels located within the conjunctiva are easily ruptured.The BB traversed the soft tissue causing a subconjunctival hemorrhage Fig . This tySurgical removal of ballistic fragments is usually discouraged, because the dissection necessary to retrieve them can be harmful.The foreign body was excised using an upper lid blepharoplasty incision and can be expected to leave an aesthetically acceptable scar."}
{"text": "There was an error in the fourth paragraph of the \"Identification of novel genes induced in an early response to food deprivation\" section of the Discussion.The text currently reads: \"There have been no citations for scl-2 in the literature and its function remains largely unknown. However, the gene encodes a sterol carrier-like protein domain and may potentially be involved in the transport of steroid hormones or lipid breakdown products. Up-regulation of a gene involved in such processes during food deprivation would be expected. Expression of scl-2 appears to be confined to the intestinal cells at all stages. The intestinal cells represent a major site of fat storage in the nematodes [39]. Therefore, the localised expression of scl-2 in the intestine makes it ideally placed for involvement in fat mobilization.\"The correct text is: \"The function of scl-2 remains largely unknown, but the gene encodes a predicted extracellular protein belonging to the sperm coating protein (SCP)-like domain containing protein family. Expression of scl-2 appears to be confined to the intestinal cells at all stages, which represent a major site of fat storage in the nematodes [39]. Localised expression in the intestine makes it ideally placed for involvement in fat mobilization, but we cannot speculate on its precise role in the response to reduced food intake further.\"The change does not impact the rest of the manuscript or change the findings therein."}
{"text": "Dear Editor,We have read with great interest the article by Mogadam and colleagues on utilization ofgabapentin and diclofenac for management of post-operative pain in patients undergoingtonsillectomy . Perhaps"}
{"text": "Recruitment into surgical trials is often hampered because of surgeon or patient preferences. Qualitative research to explore and standardise methods for communicating clinical equipoise and addressing patient concerns has been shown to be effective in maximising recruitment. Often this research runs alongside the trial without being fully integrated within it. We describe how we integrated qualitative research into the multi-centre By-Band study comparing two surgical procedures for morbid obesity.The integration has the following elements (a) having one screening log which captures patient consent for i) the qualitative research, ii) simple follow up concerning treatment preference, and iii) the randomised trial; (b) capturing details of the audio-recordings taken during the consultation process within the participant case report form; (c) adding functionally to the trial database to capture this information and to allow secure up-load of audio-recordings directly into the database; (d) producing routine reports for the qualitative researchers.Participating sites have found the system straightforward to use. The database is hosted on an NHS server accessed via the NHS clinical portal, so is familiar to centres taking part. Audio-recordings are being received in a timely way and real-time queries in the database have led to high levels of completeness. Up-to-date information on trial progress is provided to the qualitative researchers on a weekly basis, with minimal effort.Integrating the qualitative research fully into the trial has brought benefits for all. The mechanism for transferring audio-recordings is being rolled out to other trials with a qualitative component.This study is funded by the NIHR HTA programme and the views and opinions expressed are those of the authors and do not necessarily reflect those of the HTA programme and, NIHR, NHS or the department of health."}
{"text": "Building on the success of the Stop Smoking Over Mobile Phone (STOMP) trial and the Social Cognitive Theory-Based Intervention (STUB-IT) trial for smoking cessation, this pilot study examined the feasibility of brief intervention (BI) delivered by mobile-health technology to reduce problem drinking and injury among trauma patients presenting to the hospital. We interviewed 30 Maori, Pacific Island, and Pakeha (European/white) patients to explore their perceptions of the proposed mobile-phone\u2013delivered intervention and the barriers and facilitators to participation and compliance. Participants were highly supportive of the intervention concept, noting aspects of message content and delivery that would appeal to the major ethnic communities as well as potential barriers that required attention. Text messages  that were adapted for the cultural context had particular appeal, as was the proposed delivery of one or two motivational messages on Fridays/weekends over a period of up to four weeks following hospital discharge. Collecting injury-outcome data through record linkage to national databases of hospital discharges and claims to New Zealand\u2019s universal fully-funded accident insurance scheme was both feasible and effective. The proposed trial of 6000 participants appears feasible and acceptable to patients from communities of interest, with economies of scale in both the implementation of the intervention and trial methodology. If demonstrated to be effective, this approach to BI has the potential to be cost-effective, highly scalable, and accessible to harder-to-reach communities in New Zealand and elsewhere. As shown in previous trials, this strategy could also reduce ethnic and socioeconomic inequalities in access to interventions."}
{"text": "As a part of the NHS modernisation agenda to ensure high quality clinical care, podiatrists are required to demonstrate evidence of continuing professional development to maintain registration. This study aimed to investigate the experiences of podiatrists in response to the CPD process. It explored the effectiveness of the portfolio in recording CPD, resource as a limiting factor in CPD engagement and the linking of competence with re-registration.The study was of a qualitative design using purposive sampling to select six key informants. Semi-structured interviews were conducted and data was analysed using themaptic analysis.: Called to account - Perceptions of the CPD process indicating poor comprehension and associated anxiety due to lack of effective communication; Proving your worth - Positive views of linking competence with re-registration; Transparent recording device -Support for the portfolio but concern for its ability to demonstrate practical competence; Balancing responsibilities - Experiences of funding depletion and strategies to maximize free CPD.Four main themes emerged from the studyThis study has been valuable in gaining a deeper understanding of the podiatrist\u2019s perceptions of CPD and may assist in informing future process. Podiatrists were in favour of the new regulations but showed anxiety towards the process due to confusion over the requirements. Support was shown for a link between re-registration and competence to ensure patient safety. Funding deficiencies were a concern resulting in the use of free CPD as part of daily practice."}
{"text": "We propose to make use of the wealth of underused DNA chip data available in public repositories to study the molecular mechanisms behind the adaptation of cancer cells to hypoxic conditions leading to the metastatic phenotype. We have developed new bioinformatics tools and adapted others to identify with maximum sensitivity those genes which are expressed differentially across several experiments. The comparison of two analytical approaches, based on either Over Representation Analysis or Functional Class Scoring, by a meta-analysis-based approach, led to the retrieval of known information about the biological situation \u2013 thus validating the model \u2013 but also more importantly to the discovery of the previously unknown implication of the spliceosome, the cellular machinery responsible for mRNA splicing, in the development of metastasis. Despite the development of effective therapies for many cancers Cancer is known to be a genetic disease, implying either alteration of DNA or dysregulation of gene expression In the last decade, the availability of microarray datasets in public repositories has grown dramatically , to allow for a fair comparison between arrays (standardization), and to summarize probe-level intensities to meaningful probe set values et al described the affyprobeminer as a tool to ease the mapping of current knowledge to probe sequences in Affymetrix arrays The last preprocessing step, called summarization, consists of gathering probe-level information regarding the same target. The mapping of the target definition to the probe coordinates on the chips involves a chip definition file (CDF). The annotation of the human genome has improved since the first release of CDFs by the manufacturer (Affymetrix) and several authors have thus reported the need to update the definition of chip definition files Microarray data can be used to track the expression profile of the transcriptome following a hierarchical strategy that involves many levels of interpretation. The first level refers to individual analyses aimed at inferring the positive/negative regulation of transcripts and/or genes, as defined in the chip definition file (probe set definition in CDF). Wet-lab biologists mainly interpret microarray experiments based on the results of this step. Additional layers of analysis are described briefly in the next subsections .t test t test In previous work, we described a relationship between the number of replicates and the selection of the best performing methods After the individual analyses, the list of genes detected as differentially expressed is typically annotated using over-representation analysis (ORA) methods to highlight meaningful information. In a previous work, we described the use of the DAVID webtools to perform such an analysis on the results of microarray studies Small datasets with only a few replicates are still a major hindrance to statistical power in conventional analyses. Gene set analysis and meta-analysis are interesting and common ways to extract more information from the data, and to test higher-level hypotheses with a power level associated with an increased number of available values.Gene set analysis using Functional Class Scoring methodologies (FCS) has improved the understanding of differences in expression profiles, and helped unravel the biological processes underlying experimental data in several ways. First, joint analysis of multiple genes involves a higher number of values than individual analyses, hence providing the potential for a higher power level, even when conducted on small datasets . Second, computation of differential expression from multiple levels of interpretation enriches the qualitative description of biological variations between experimental conditions. The criteria used to define the gene sets consequently guide interpretation of the results . By extension, the comparison of the results of individual and gene set analyses allows, as with ORA methods, to refine the list of candidate genes for further testing, thanks to the criteria-based approach .Over the last decade, various Functional Class Scoring methodologies (FCS) have been developed to analyze gene sets, including 2-step or global methods, competitive or self-contained null hypothesis and inference : GSEA Method-specific biases in the detection of gene sets are associated with methodological choices, and are due to correlations between genes, the simultaneous presence of up/down regulated genes, the level of expression and the number of genes in the set.... In order to detect all kinds of sets with an expression profile that differs between conditions, we developed FAERI, tailored from the two-way ANOVA et al in 1904 Meta-analysis is a natural extension of the dataset-based analysis conducted using individual and gene set methodologies, and examines several datasets relating to similar experimental conditions. A meta-analysis strategy was reported previously by Simpsons To identify commonly regulated genes in multiple datasets, a higher-level analysis must be defined as opposed to the dataset-specific strategies described above. The ideal meta-analysis design would consist of the joint analysis of multiple datasets following a higher-order multivariate analysis procedure. However, post-hoc strategies require less computing time than full-on transversal analyses, which still remains a major concern in the analysis of large datasets. In a previous study, we explored an intersection-based post-hoc strategy, defined as an additional analytical step performed on results generated with several dataset-specific analyses To compare the results of differential expression analyses of genes (or gene sets) across datasets, we reported use of the number of dataset-specific analyses that result in a significant detection of the gene (the number of top-lists in which each gene is present). This score, which monitors systematic differences in expression profiles across datasets, was then used as a selection criterion to define candidate genes. The reported strategy leads to three situations, depending on the strictness of the comparison across datasets: 1) the selection of genes that are detected in all (or the highest number of) datasets  results in a very low number of genes, which are often already well known; 2) selection of the genes detected in at least one dataset  results in too many candidates for further investigation, and does not exclude false positives; 3) a balance can be reached between both situations, with an intermediate selection threshold at the number of DEGs across datasets. That intermediate situation (union of intersections between a given number of top lists) allows for inference of a workable amount of new candidates. Along these lines, several techniques have been developed to describe the intersections between lists of genes We propose to use a set of statistical and bioinformatics tools to reanalyze metastasis and hypoxia-related data to gain further insight into the processes involved. The comparison of two analytical pipelines (ORA and FCS) is used to detect meaningful pathways . The intersection of both lists was then performed, as described in the materials and methods section, to identify candidate genes expected to be involved in both hypoxia and metastasis, while removing potential false detections from the large lists retrieved in the first step. The meta-analysis yielded substantially different results, as shown in The list of the identifiers for the 1156 genes obtained after the meta-analysis step was then entered into the DAVID web tool. A total of 102 pathways containing at least 3 gene members of that list was generated see . Among tTo further assess the significance of the spliceosome pathway in the over-representation results, we first performed 500 random selections of 1156 EntrezGeneIDs among all the identifiers present on the microarray and ran them in the DAVID tool. The EASE scores and number of hits in the spliceosome pathway were then plotted see . The ploMoreover, the spliceosome, whose implication in cancer has been reported by several authors The second part of the analytical pipeline  relies oBoth parts of the analytical pipeline described here have detected the spliceosome pathway as involved in the hypoxic and metastatic phenotypes. Among the 31 genes detected as differentially expressed in this pathway, 11 have recently been shown to be involved in the metastatic process see . The remThe results also demonstrate the potential of sensitive and specific analytical pipelines: new hypotheses can be proposed, and previously known biological features can be used as positive controls. However, comparison of the results between both parts of the analytical pipeline suggests that the two analyses behave differently: over-representation analysis of the most significant genes across datasets detects some important pathways, and the ability of gene set analysis using FAERI to detect slight cumulated differences detects more pathways. Statistical analysis with FAERI detects meaningful differences between samples, even when only small numbers of replicates are available. Nevertheless, both parts of the pipeline lead to detection of relevant information based on current knowledge, and both suggest the involvement of the spliceosome.We implemented a pipeline of bioinformatics tools to explore archived microarray data, from preprocessing to mapping of the results. We used that pipeline to examine metastasis and hypoxia data and found results in keeping with previous reports, as well as a new hypothesis. The combination of high-level analysis  with a meta-analysis step led to the discovery of involvement of the spliceosome in the hypoxic and metastatic processes, and the generation of a list of 20 new candidate genes.Bioinformatics approaches will never replace bench validations; however we were able to form a plausible hypothesis just by re-analyzing available data. Biological investigations should therefore be performed to further refine the interpretation of the relationships between the pathways detected and understand how a hypoxic environment and metastasis affect both general and energetic cell metabolism. Further investigations should be conducted to clarify the results of the statistical analyses and to discriminate between causes and consequences (mechanisms of perturbations and symptoms). However, that validation is out of the scope of this methodological paper.de novo microarray experiments. We think that this work will contribute to the creation of a virtual atlas for cellular biology containing the known characteristics of cells in diverse biological conditions, which is one of the major goals of the bioinformatics community.We think that this analytical protocol could be used successfully in many other biological contexts, wherever several datasets are available. Indeed, we have shown that single gene analysis alone yields poor results, though this is often the only step performed by wet-lab biologists. The methodology presented here allows for improved performance, comparison with previously known information and discovery of recurrent patterns , all of which were performed using freely-available resources and software packages and without the need to perform expensive For the purposes of the study reported here, two sets of criteria were used to retrieve datasets with PathEx , and a set of packages available in the Bioconductor repository (http://www.bioconductor.org).The preprocessing of the data and the individual analyses reported in this paper were performed using R 2.7 and 2.10, available on the website of the R-Project . The 16 dataset-specific lists of the most significant genes were gathered into two groups, according to the experimental design (Hypoxia/Metastasis studies). In each group of datasets, a new list of genes was defined from the list of genes found to be differentially expressed in at least one dataset of the group. Lastly, the intersection of the list of genes from the two groups was performed by selecting genes that were detected in both groups, resulting in a list of 1156 unique gene identifiers  t test treatment, meta-analysis and over-representation analysis (ORA) in DAVID). The right part contains the gene set analysis steps  by FAERI and meta-analysis of the results).The different steps in the analytical pipelines are summarized in Table S1Full list of p-values obtained for each dataset for each of the 1156 genes highlighted in the analysis.(PDF)Click here for additional data file.Table S2List of pathways highlighted in the over-representation analysis using DAVID.(PDF)Click here for additional data file.Table S3Full list of p-values obtained in the geneset analysis.(PDF)Click here for additional data file.Table S4Distribution of the highlighted genes in the spliceosome pathway.(PDF)Click here for additional data file.Table S5R code for the full analysis.(PDF)Click here for additional data file.Checklist S1(PDF)Click here for additional data file."}
{"text": "Vanessa cardui) in untethered, forward flight. These experimental results are then analyzed computationally using a high-fidelity, three-dimensional, unsteady Navier-Stokes flow solver. For comparison to this case, a set of non-deforming, flat-plate wing (FPW) models of wing motion are synthesized and subjected to the same analysis along with a wing model that matches the time-varying wing-twist observed for the butterfly, but has no deformation in camber. The simulations show that the observed butterfly wing (OBW) outperforms all the flat-plate wings in terms of usable force production as well as the ratio of lift to power by at least 29% and 46%, respectively. This increase in efficiency of lift production is at least three-fold greater than reported for other insects. Interestingly, we also find that the twist-only-wing (TOW) model recovers much of the performance of the OBW, demonstrating that wing-twist, and not camber is key to forward flight in these insects. The implications of this on the design of flapping wing micro-aerial vehicles are discussed.Insect wings can undergo significant chordwise (camber) as well as spanwise (twist) deformation during flapping flight but the effect of these deformations is not well understood. The shape and size of butterfly wings leads to particularly large wing deformations, making them an ideal test case for investigation of these effects. Here we use computational models derived from experiments on free-flying butterflies to understand the effect of time-varying twist and camber on the aerodynamic performance of these insects. High-speed videogrammetry is used to capture the wing kinematics, including deformation, of a Painted Lady butterfly ( Insect wings deform to varying degrees during flapping flight, and the kinematics of wing deformation Eristalis tenax, Linnaeus), assuming an approximately linear spanwise wing-twist and a wing camber that was uniform across the span and constant during each half-stroke. Their model showed that camber is more important than wing-twist in determining the aerodynamic performance in the hovering flight of hoverflies. Nakata and Liu Since the inclusion of wing deformation increases the complexity of the analysis, most studies of the aerodynamics of insect flight assume the wings to be rigid and flat e.g. . Some stet al.Schistocerca gregaria in a wind tunnel using stereo videogrammetry. Young et al. Unlike hovering flight where the generation of lift is the key determinant of wing motion, in forward flight, the wings also have to generate a net positive thrust during each flapping cycle to maintain the forward velocity of the animal. This has to be accomplished by the wings by generating positive forward force (thrust) in some phases of the cycle and reducing the negative force (drag) on the wings in other phases. It is therefore not clear if the observations regarding the effects of wing deformation on hovering flight extend to insects in forward flight. An attempt to understand the effect of wing deformation during forward flight was made by Walker Vanessa cardui. These butterflies are large relative to most volant insects and have broad wings with the forewing and hindwing functioning as a single surface, leading to wing aspect-ratios (see In the current study we explore this issue further by studying the effect of time-varying twist and camber on the free forward flight of the Painted Lady butterfly The study employs a Navier-Stokes (NS) based computational model of the flight aerodynamics which are based on a precise reconstruction of the observed twist and camber of the butterfly wings . We thenVanessa cardui), well known for its orange wings with striking black and white spots  as well as the corresponding flat-plate wings are shown in The observed butterfly wing (OBW) with time-varying deformations produced forces similar in magnitude and timing to those measured from the actual animal . The comAs expected, this the OBW model exhibits substantial time-varying deformation in camber  as well g cycle. . The angg cycle. ; during The kinematic features of the flat-plate wing models  are compared to the OBW model in The flow over the wing is driven primarily by the sectional angle-of-attack (AoA) and estimates of this quantity can be obtained as AoAThe instantaneous lift, thrust, and power , the TOW and the FPW models 1\u20133 by comparing the stroke-averaged lift  model has no camber but matches the time-varying AoI of the butterfly wing at every section along the span. The three flat-plate wing (FPW) models  have no The study indicates that the observed butterfly wing (OBW), which incorporates significant time-varying deformation in camber as well as twist, far outperforms all the flat-plate wings in terms of the mean forces  as well as power-specific force generation (lift over power and force over power). The TOW model, which incorporates twist but no camber, comes closest to matching the performance of the OBW. This indicates that the vast majority of the benefits of wing deformation are derived from spanwise twist, despite the relatively low aspect-ratio and large camber of butterfly wings. Spanwise twist allows the proximal and distal portions of the wings to operate at different angles-of-incidence (AoI). During upstroke, the distal part of the wings translates at high AoI, which decreases local AoA; this prevents the generation of a strong LEV beneath the wings that can produce large negative vertical forces. The proximal portion of the wing operates at low AoI and avoids rapid rotation at the end of upstroke, which would generate a large negative lift peak, a positive thrust peak and thus a large power peak see  in . During This study, like most other Navier-Stokes computational fluid dynamic analyses of animal flight, is limited to a single species and flight behavior due to the complexity of data acquisition, modeling, simulation and analysis. The current study is based only a single wingbeat from a single butterfly specimen. Despite the fact that the particular recording was chosen from a multitude of recordings and in our view, is a good representation of level forward flight, the generality of the findings is uncertain and a broad assessment of the effects of wing flexibility and deformation on flapping flight requires comparison of the current results to studies. In this regard, other recent work on deforming flapping wings has focused on the effects of chordwise (camber) deformation"}
{"text": "There is limited evidence for the effectiveness of TH on quality of life (QoL) in patients with COPD. A systematic review in the area inclusive of all respiratory conditions indicated that there were no UK based studies, or randomised controlled trials (RCTs) evaluating the effectiveness of TH for COPD . A more recent systematic review found 6 studies, only two of which measured QoL as an outcome . One of these studies was a RCT and found improvements in QoL at 3 months (Koff 2009), while the other was a non-controlled before and after study which found no difference in quality of life scores at 6 months . Research in this area is plagued by small sample sizes, absence of longer-term follow-ups, insufficient descriptions of the intervention, poor internal validity of whether using the device in the context of a complex healthcare intervention leads to improved outcomes for the patient, and few attempts to measure quality of life in patients with COPD following the introduction of these devices.The current investigation is part of the Whole System Demonstrator (WSD) programme that aims to evaluate the effectiveness of telehealth (TH) for patient reported outcomes with Chronic Obstructive Pulmonary Disease (COPD). The primary objective was to evaluate the effectiveness of telehealth for COPD specific QoL and to examine whether there were improvements in HRQoL and psychological distress at short-term and long-term follow-up in this cohort of patients with COPD.WSD is one of the largest pragmatic cluster randomised controlled trials evaluating TH in the UK. Patients with COPD from three regions in England  were recruited from 179 GP practices randomised balancing for region, practice size, deprivation index, non-white proportion and prevalence of COPD. Over 570 patients with COPD completed a comprehensive battery of questionnaires assessing a range of patient reported outcomes. Measures of generic Health-Related Quality of Life (HRQoL) (Short Form-12), disease specific QoL including perceived control over COPD, fatigue caused by the disease and the emotional impact of the disease (Chronic Respiratory Questionnaire). Psychological distress was measured by depression (CESD-10) and anxiety (STAI).Multi-level modelling was utilised to evaluate the effect of trial arm on HRQoL and COPD specific QoL. Results for intention-to-treat analysis, participants that received the intervention as per the research protocol, complete case analysis for cases with all baseline, short-term and longer-term follow-ups completed and an available case analysis of patients with either a short or long-term follow-up available. The results will be discussed and have important clinical implications for COPD management.Results and conclusions are censored until any findings are published in peer-reviewed journals."}
{"text": "Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer of hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that through electrostatic interactions with of a chloride ion the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common leitmotifs among class-1 fusion proteins. We will discuss the impact of these observations in light of current models of membrane fusion and as potential targets for therapeutic inhibition of viral entry."}
{"text": "Analysis of transcription factor binding to DNA sequences is of utmost importance to understand the intricate regulatory mechanisms that underlie gene expression. Several techniques exist that quantify DNA-protein affinity, but they are either very time-consuming or suffer from possible misinterpretation due to complicated algorithms or approximations like many high-throughput techniques. We present a more direct method to quantify DNA-protein interaction in a force-based assay. In contrast to single-molecule force spectroscopy, our technique, the Molecular Force Assay (MFA), parallelizes force measurements so that it can test one or multiple proteins against several DNA sequences in a single experiment. The interaction strength is quantified by comparison to the well-defined rupture stability of different DNA duplexes. As a proof-of-principle, we measured the interaction of the zinc finger construct Zif268/NRE against six different DNA constructs. We could show the specificity of our approach and quantify the strength of the protein-DNA interaction. The sequence-specific interaction of certain proteins with the genomic DNA is prerequisite for the complex task of transcriptional regulation. Those transcription factors bind alone or in clusters to the DNA and can thus activate or impede transcription. Many of the transcription factors can bind to several, different DNA sequence motifs with varying strength in vivo method chromatin immunoprecipitation combined with microarray analysis (ChIP-chip) in vitro techniques like protein binding microarrays (PBM) Recent developments in high-throughput techniques, for example the Importantly, due to the high concentration of DNA in a bacterial cell or eukaryotic nucleus, the dynamic equilibrium between unbound and bound activated transcription factors is shifted towards DNA-protein complexes. Hence, affinity described by the dissociation constant might not be the best measure to characterize the protein-DNA interaction inside a nucleus. The specificity defined as the ability of a transcription factor to discriminate between a regulatory sequence and the vast majority of non-regulating DNA might be a more suitable quantity. But quantification of the specificity in that sense means to determine the complete list of dissociation constants for all possible DNA sequences or a constant calculated from those dissociation constants The Molecular Force Assay (MFA) developed in our lab 2-His2 class Zinc finger motifs are one of the most abundant DNA binding domains in eukaryotic transcription factors The standard Molecular Force Assay (MFA) consists of two molecular bonds in series, a reference and a sample bond, clamped between two surfaces. The two surfaces are separated with a constant velocity so that a force builds up in the two molecular bonds until the weaker one ruptures. A fluorophore conjugated to the linker sequence between the two molecular complexes indicates the intact molecular bond. Hence, the ratio of the fluorescence intensity before and after the force loading of the molecular constructs is a measure of the strength of the sample bond in comparison to the reference bond. An alternative view of this assay is that the force greatly enhances the off rate of the bond under investigation and reduces the otherwise extremely long spontaneous dissociation times towards seconds In the configuration of the MFA used in all former studies, the ligand-DNA interaction is not directly probed, but the ligand stabilizes the molecular bond and is thus detected. We here describe our new variant of the MFA that can probe the protein-DNA interaction directly and compare it to a reference bond. For this purpose, the fusion protein construct consisting of an N-terminal ybbR-tag In a first test of our assay, we determined the binding of the zinc finger protein to a no binding sequence and a high affinity binding motif. The bond strength was compared to two reference sequences, a 20 bp double-stranded DNA and a 40 bp double-stranded DNA, both in shear geometry, by measuring the Cy5 fluorescence intensity of the transferred DNA after the contact and separation process. transfer to the maximal number of functional proteins Fintact protein is defined as the Normalized Fluorescence, NF. The NF is calculated by dividing the pictures after background subtraction pixel-by-pixel Click here for additional data file.Supplement S1Materials and Methods.(DOC)Click here for additional data file."}
{"text": "The multiple etiologies of schizophrenia prompt us to raise the question: what final common pathway can induce a convincing sense of the reality of the hallucinations in this disease? The observation that artificial stimulation of an intermediate order of neurons of a normal nervous system induces hallucinations indicates that the lateral entry of activity  at intermediate neuronal orders may provide a mechanism for hallucinations. Meaningful hallucinations can be de-constructed into an organized temporal sequence of internal sensations of associatively learned items that occur in the absence of any external stimuli. We hypothesize that these hallucinations are autonomously generated by the re-activation of pathological non-specific functional LINKs formed between the postsynaptic membranes at certain neuronal orders and are examined as a final common mechanism capable of explaining most of the features of the disease. Reversible and stabilizable hemi-fusion between simultaneously activated adjacent postsynaptic membranes is viewed as one of the normal mechanisms for functional LINK formation and is dependent on lipid membrane composition. Methods of removing the proteins that may traverse the non-specifically hemi-fused membrane segments and attempts to replace the phospholipid side chains to convert the membrane composition to a near-normal state may offer therapeutic opportunities. Schizophrenia has been viewed as a neuro-developmental disorder  receptor-blocking conditions. In these contexts, the contrasting but complementary pieces of the disease puzzle may provide clues to understanding the pathology and verifying the operating mechanisms for internal sensations of higher brain functions. An abstract of this work was presented at the Society for Neuroscience annual meeting in 2009  in the environment. As the distance between the sensory receptors and the item increases, the sensory input traveling at the highest velocity reaches the nervous system faster than the others Figure . The abiHallucinations induced by the stimulation of an intermediate path by pathological irritation are expected to share some basic features with that of memory retrieval. What kind of reductive approach is required to understand the nature of the internal sensations within the nervous system? An episodic representation of an event is organized into an order of events that unfolds as a mental replay of the event spread over time Tulving, . Interna4 dendritic spines (postsynapses or postsynaptic membranes) on its dendritic tree  Normally, oscillatory neuronal activity is expected to produce sub-threshold activation of those neurons at the higher orders that receive fewer EPSPs than required for spatial or temporal summation capable of inducing an action potential. When additional EPSPs reach these sub-threshold activated neurons, it will lead to their autonomic activation and result in the transmission of activity to higher neuronal orders, activating many previously formed specific functional LINKs and inducing meaningful hallucinations Figure . (b) TheIn summary, (a) non-specific inter-postsynaptic functional LINK formation can induce a universal effect at the neuronal orders above the oscillating orders such that no separate functioning areas exist that can identify the hallucinations as unreal. (b) In the presence of the continuous arrival of activity through the pathological non-specific inter-postsynaptic mis-LINKs, the sub-threshold-activated neurons maintained by oscillatory neuronal activity start firing, re-activating the normal inter-postsynaptic functional LINKs at higher neuronal orders so that the hallucinations become autonomous in nature. (c) The convincing sense of reality of the hallucinations indicates that beyond the origin of autonomous activation of non-specific functional mis-LINKs, the system is operating by using the normal mechanism of formation of semblances for memory retrieval, using previously formed inter-postsynaptic functional LINKs from associative learning events; but their formation occurs in a wrong context, inducing hallucinations. (d) The hallucinations are similar to the perception of sensory stimuli from the environment due to the inter-postsynaptic mis-LINKs at the early neuronal orders in the auditory cortex .A delusion is a belief held with a very strong conviction by the subject, even in the presence of a counter-argument provided by a second person. This indicates that there is a compelling internal sensation experienced by the subject who is perceiving the delusions and that the subject lacks an operational mechanism within the remaining nervous system that identifies the internal sensation of delusions as unreal. The formation of these delusions can be explained as resulting from their autonomous activations from pathological non-specific inter-postsynaptic functional LINKs. Since the latter leads to the activation of a non-specific set of otherwise normal inter-postsynaptic functional LINKs at higher neuronal orders in the entire nervous system, the subject autonomously continues to perceive items or events (a) that were not associatively learned in the past and (b) that were not associatively learned from the environment from which their nervous systems continue to make associations.In many locations in the nervous system, the postsynaptic membranes belonging to different neurons are apposed to each other with minimal visible extracellular matrix volume, especially in locations where sensory inputs converge; for example, the hippocampi. One of the feasible mechanisms for the generation of functional LINKs between the postsynaptic membranes is the formation of reversible membrane hemi-fusion. A large number of studies have shown reversible hemi-fusion occurring between biological membranes  into the postsynapses through the cell body of the neuron  images of the synapses from previous studies were examined. By the time rodents reach adulthood, it is expected that they have experienced a large number of associative learning events. Therefore, hemi-fused inter-postsynaptic membranes at various locations in the nervous system are expected to be found. Even though limited resolution sometimes reduces the view of the membrane lipid bilayers to only single layers, overlapping of the adjacent postsynaptic membranes can be observed from the results of different studies  and acyl transferase  and docosa-hexaenoic acid (DHA), both derived from essential fatty acids (EFA), in the Sn-2 position in neuronal cells  gene causes deficiency of its protein, leading to reduced catabolism of dopamine and further leading to the latter\u2019s accumulation and resulting in an increased susceptibility to schizophrenia  serial EM sections is necessary to examine the entire surface of a dendritic spine to visualize membrane hemi-fusion. We anticipate hemi-fusions only at very short lengths of the apposed postsynaptic membranes, necessitating a thorough examination of the entire dendritic spine\u2019s (postsynapse\u2019s) membrane bilayer. Since it is possible that inter-postsynaptic hemi-fusion can take place even farther away from the synaptic cleft, a large-scale re-construction of EM sections is required to visualize such hemi-fusion. The probability of finding hemi-fusion is high at regions where sensory inputs converge; for example, the hippocampus.Work toward examining the ultra-structural changes of the postsynaptic membranes is needed to test the possibility of membrane hemi-fusion as a mechanism of inter-postsynaptic functional LINK formation. Since EM examination uses sections with a thickness of 5\u2009\u00d7\u200910Adolescents with the prodrome (Yung et al., The present work provides the framework of a mechanism for the clinical features of schizophrenia, a disease found to be associated with a multitude of genetic and environmental factors. Non-specific hemi-fusion between postsynaptic membranes at certain neuronal orders is hypothesized to be the final common path that can induce autonomous meaningful hallucinations and cognitive defects. We expect that various other pathways that are implicated in schizophrenia, which are not mentioned in this work, can find suitable entry points into the present framework. The final path explains the implications of the involvement of both NMDA and dopamine neurotransmitters. By examining the formation of basic units of internal sensations resulting from the lateral entry of activity at the synaptic level, it was possible to attribute the diverse features of auditory hallucinations, cognitive impairment, and defects in consciousness to pathological structural changes; these changes also serve as an explanation for the beneficial effect of EFA reported from a randomized double-blinded control trial (Amminger et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Submicron scale domains of membrane-anchored receptors play an important role in cell signaling. Central questions concern the stability of these microdomains, and the mechanisms leading to the domain formation. In immune-cell adhesion zones, microdomains of short receptor-ligand complexes form next to domains of significantly longer receptor-ligand complexes. The length mismatch between the receptor-ligand complexes leads to membrane deformations and has been suggested as a possible cause of the domain formation. The domain formation is a nucleation and growth process that depends on the line tension and free energy of the domains. Using a combination of analytical calculations and Monte Carlo simulations, we derive here general expressions for the line tension between domains of long and short receptor-ligand complexes and for the adhesion free energy of the domains. We argue that the length mismatch of receptor-ligand complexes alone is sufficient to drive the domain formation, and obtain submicron-scale minimum sizes for stable domains that are consistent with the domain sizes observed during immune-cell adhesion. In the past years, microdomains of proteins in cell membranes have emerged as a central aspect of cell signaling Several mechanisms have been proposed for the formation of TCR-MHCpeptide domains during T-cell adhesion. These mechanisms are based on the actin cytoskeleton In previous work, we have derived general expressions for the critical receptor and ligand concentrations required for domain formation. These general expressions depend on the length mismatch between the receptor-ligand complexes and on the bending rigidity of the membranes In this article, we determine the free energy and stability of clusters and domains of long and short receptor-ligand complexes. Our main results are general expressions for the line tension and adhesion free energy of the domains in terms of the concentrations and affinities of the receptors and ligands as well as the length mismatch of the receptor-ligand complexes. These general expressions fully include the effects of membrane shape fluctuations and the translational entropy of the receptors and ligands, and depend only on experimentally accessible quantities. Our expressions lead to estimates for the minimal size of stable TCR-MHCpeptide microdomains that are consistent with the submicron-scale sizes observed during T-cell adhesion.To describe the conformations of the two apposing membranes in a cell adhesion zone, we divide these membranes into small patches. Each patch can contain a single receptor or ligand molecule The energy of a membrane conformationThe rigidity-dominated elastic energy of the membranes has the form via long and short receptor-ligand complexes to the problem of a membrane with effective rigidity The equilibrium proporties of the membranes can be determined from the free energy tial see . The twoThe effective potential can be generalized to cases with more than two receptor-ligand complexes, or with additional repulsive molecules The effective potential helps to determine and illustrate the equilibrium behavior. If the two wells of the effective potential are relatively shallow, thermal membrane fluctuations can easily drive membrane segments to cross from one well to the other. If the two wells are deep, the crossing of membrane segments from one well to the other well is impeded by the potential barrier of width ells see . Beyond We have previously found that the critical potential depth for domain formation isIn this article, we determine how the adhesion free energy and line tension of the domains depends on the depths as well as on the width We use a combination of Monte Carlo simulations and scaling arguments to determine the free energy difference and line tension of membrane domains that are bound in the two potential wells of the effective potential A scaling analysis see  indicateIn the Monte Carlo simulations, we attempt local Monte Carlo moves in which the rescaled separation The free energy of domains of long or short receptor-ligand complexes can be determined from the effective double-well adhesion potential of the membranes see . We consThe function and  see . With eqWe use classical nucleation theory to determine the line tension between domains of long and short receptor-ligand complexes. Equilibrium properties of the membranes, such as the line tension between the domains of receptor-ligand complexes, can be obtained from the effective double-well adhesion potential of the membranes shown in We determine the critical radii of domain nucleation from Monte Carlo simulations. The simulations start from pre-equilibrated initial conformations with a circular nucleus of radius ll 2 see . The preNuclei with a radius grow see . To quanAccording to eq. (22), the line tension now follows as ases see . The lintion see .To derive a general relation for the line tension For small and intermediate values of  on  see . This liThe critical potential depth The values of the rescaled well depth dth  see . We therysis see , we obtaThe scaling function  in  see . From thvia long integrin complexes and that forms microdomains of short TCR-MHCpeptide complexes if foreign MHCpeptides are present on the apposing cell surface. According to classical nucleation theory, the critical radius beyond which these microdomains are stable is We consider now a situation in which a domain of long receptor-ligand complexes To estimate the magnitude of the rescaled effective binding energy For T cells, the length difference via partial integration in the partition function. These general relations for the line tension and adhesion free energy of the receptor-ligand domains depend only on parameters that can be directly related to experimentally accessible quantities. Using typical values for T-cell adhesion zones, we find that stable submicron-scale domains of TCR-MHCpeptide complexes may form solely because of their length mismatch to integrin complexes. The role of the T-cell cytoskeleton thus may be limited to the observed transport of TCR-MHCpeptide microdomains to the contact zone center via weak frictional coupling of the cytoskeleton to the TCRs While the line tension and stability of lipid domains has been investigated for a long timeAppendix S1Dimensional analysis.(PDF)Click here for additional data file.Appendix S2Free energy of a membrane in a single-well potential.(PDF)Click here for additional data file."}
{"text": "Nesting of patients within care providers in trials of physical and talking therapies creates an additional level within the design. The statistical implications of this are analogous to those of cluster-randomised trials, except that the clustering effect interacts with treatment, leading to different ICCs across treatment arms. In some cases, the clustering effect may be restricted to one or more of the arms, resulting in a \"partially nested design\". The statistical model that is recommended at the trial-level includes a random effect for the care provider but allows the provider and patient level variances to differ across arms. The care provider variance is constrained to equal zero where there is no clustering in partially nested trials. Evidence suggests that, while important, such within-trial clustering effects are rarely taken into account in trials or in meta-analyses of these trials.This paper proposes summary measures and individual-patient-data (IPD) methods for meta-analysing randomized trials with nested clustering effects. It extends methods for incorporating trials with unequal variances and cluster-randomisation to allow for between-trial and between-arm heterogeneity in ICC estimates. The work is motivated by a meta-analysis of trials of counselling in primary care, where the outcome of interest is the Beck Depression Inventory and the control is no counselling. We begin by outlining the example and presenting the statistical model at the trial-level. We then extend standard summary measures and IPD approaches to meta-analysis of mean differences and illustrate the proposed methods with our example. Fixed and random effects meta-analysis models are contrasted."}
{"text": "ATL is a highly aggressive leukemia/lymphoma which was first proposed as a new disease entity in 1977. The long clinical latency and low incidence of ATL indicate that some genetic changes are involved in malignant transformation and monoclonal expansion of HTLV-1-infected cells. Monoclonal proliferation of HTLV-1-infected cells is observed in a part of the virus carriers, who are considered to be the high risk group for development of ATL [We reviewed the process of senescence and how proteins allow the monoclonal proliferation of ATL cells.Constitutive activation of STAT as well as functional impairment and stabilization of p53 protein found in the PBMCs of ATL patients are supposed to be one base for ATL development ,3. In adFurthermore, the soluble form of CD30 (sCD30) is elevated in serum of ATL patients and correlates with the aggressiveness of ATL  (Our obsNot only the inhibition of senescence by impaired function or constitutive activation of proteins in ATL cells, but also immune regulation by soluble proteins in serum of HTLV-1-infected patients must be required for the progression of ATL."}
{"text": "Although patients with anorexia nervosa (AN) present positive responses to family therapy, the key features of therapeutic changes still require identification. This study explores the role of conflictual communication and affiliative nonverbal behaviour in therapeutic change in brief strategic family therapy (BSFT) for AN patients.Ten female AN patients and their parents were included in the sample and took part in a 6-month follow-up of BSFT. The durations of conflictual communication and of affiliative nonverbal behaviour estimated by eye contact were compared between the first and the last sessions of family-based treatment using nonparametric statistical tests.An increase of the Body Mass Index associated with an increase in the conflictual communication expressed during BSFT sessions were observed. Moreover, affiliative nonverbal behaviour expressed by the father and the patient decrease, after a BSFT follow-up, in conflictual situations only. By contrast, no significant difference was observed in affiliative nonverbal behaviour expressed by the mother.The present study demonstrates that the impact of the BSFT differs between members of a family: the AN patient and the father have established a new form of emotional functioning with a decrease in emotional involvement. The study of the combination between verbal and nonverbal communication can represent an important step in the understanding of the mechanisms of therapeutic change. Several follow-up studies of patients with anorexia nervosa (AN) have shown positive responses to family therapy From a general point of view, conflictual communication can be considered as interactions between persons that express opposing interests, views or opinions Conflictual communication produces emotional responses in participants that are reflected in affiliative nonverbal behaviour From a therapeutic perspective, these studies suggest that family therapy may improve the conflictual communication skills of families by promoting a decrease in emotional involvement during these situations. Therefore, the affiliative behaviour revealed by eye contact could be important variable to monitor during therapeutic interventions in order to assess emotional involvement during conflictual communication. The present study reports the evolution of both conflictual communication and affiliative nonverbal behaviour in families with AN patients during brief strategic family therapy (BSFT) This study was approved by an independent ethics committee  and adhered to the tenets of the Declaration of Helsinki.The selection and inclusion of the families was conducted at the Addictology Department of the University Hospital (CHRU) of Lille (France). Each participant received a study information sheet and provided her written, informed consent to participation. The patients and their parents were informed about this study by a psychiatrist at admission to the Department of Addictology in our inpatient unit. The parents were all aware of their child's difficulties prior to their participation in the study. Prior to inclusion in the study, all patients were hospitalized in our inpatient unit for life-threatening physical and/or mental states. After, written consent was given by the patients and their parents, the therapists met the parents and patient in order to define the therapeutic objectives of the brief strategic family therapy (BSFT).The first session of BSFT occurred in post-hospitalization where the patients received an outpatient treatment at Department of Addictology. In outpatient treatment, all patients received the same supportive medical care by psychiatrists and physicians.Ten families were included in the sample and participated in the study. They included the father , the mother  and the AN patient . The patients resided at home with both parents. Socioeconomic status of families was divided into three levels: 50% from social classes I and II, 40% from social classes III and V and 10% from social classes from VI and VIII The female outpatients were selected according to the DSM-IV criteria for anorexia nervosa restrictive type, i.e., without the binge-eating and bulimics As in the structural family therapy tradition Enmeshment is modified by increasing the interpersonal distance between over-involved individuals and by creating a stronger boundary between the parental subsystem and the sibling subsystem;Detouring is reduced by helping the marital subsystem reduce focus on the problems of the anorexic patient;Transactional rigidity is reduced by encouraging greater flexibility in modes of communications;Restructuring also involves enhancing the family's ability to engage in and resolve conflict;Fostering positive parenting and parental skills.Family therapy was conducted by a therapist over a period ranging from five to six months and a frequency of one session per month . Each session lasted one hour and was videotaped. The treatment was terminated on the basis of the mutual decision of family members and the therapist. The two therapists (psychologists) involved in the study had more than six years of experience in the family therapy of AN patients.Semi-structured interviews allowed to obtain details of the history and clinical manifestations of the illness as well as the psychosocial functioning of the patient At the end of family treatment, each patient's overall outcome was categorised using the following classification Good outcome: Patients in whom menstruation had returned with no evidence of bulimic pathology and whose weight was within 15% of the average body weight (20 kg/m2\u2264BMI\u226423 kg/m2).Intermediate outcome: Patients who had reached a normal weight but without the return of menstruation or who reported bulimic symptoms.Poor outcome: Patients whose BMI was below 18 kg/mIndividual assessments were conducted by a clinical psychologist independent of the BSFT. Individual assessments were performed a week before BSFT and at the end of BSFT.Family interactions were assessed off-line using videotaped recordings of two sessions: an initial session (Si ) at the beginning of BSFT and a final session (Sf ) at the end of BSFT. Verbal communication between family members were rated for conflictual/non-conflictual content intra-family affiliation and eye contact toward the therapist was considered as extra-family affiliation. The absence of the eye contact with another family member or therapist and the orientation of the gaze to one's feet, the wall or the floor were classified as non-affiliative behaviour.Affiliative behaviours of the family members were assessed using the eye contact measure The encoding procedure was tested for inter-rater agreement. The inter-rater agreement was assessed on the two possible encoding categories of verbal interaction behaviour and on the four possible encoding categories of nonverbal behaviour. Seven family therapy sessions were separately encoded by two clinical psychologists independent of the BSFT. The Kappa-coefficients of inter-rater agreement of the verbal interaction behaviour (median score: 0.64) and the nonverbal behaviour (median score: 0.59) were considered satisfactory For each family and each session, our initial measurements correspond to the duration (in sec.) of eye contact from a family member to four possible targets: the two other family members (intra-family affiliation), the therapist (extra-family affiliation) and other targets (non-affiliative behaviour). These measure were obtained for both conflict and non-conflict communication. We denote Due to the encoding strategy, the duration The evolution of conflictual communication between Si and Sf in the families of AN patients was characterised using the fraction of the session duration with conflictual communication denoted Since the fraction of non-conflict communication . The Data for these indices were summarised as median and minimum-maximum intervals. The exact Wilcoxon-Mann-Whitney rank test for paired data was used for each of these indices, and the effect size was computed when a significant evolution was reported. Since several dependent and independent statistical tests were performed simultaneously, we controlled the possible spurious positives using the Bonferroni correction which is the simplest and most conservative approach. Thus for an initial level The evolution of family conflictual interactions during the follow-up of BSFT was tested using the fraction of conflictual communication The evolution of affiliative behaviour between Si and Sf was tested using non-parametric cluster analysis The main steps of non-parametric cluster test are illustrated for conflictual situations as an example. For each family, the matrix: For each cluster (i.e. family member), a cluster-based statistics was computed as a statistical weight defined as the sum of the differences between the threshold statistics and the experimental statistics if a significant difference has been observed and zero if no significant difference has been observed. A second permutation test is then issued on the cluster-based statistics (i.e. weight). This test allows to determine the distributions under the null hypothesis of the weight of the clusters. Only the clusters for which the cluster-based statistic is higher than that of the permutation distribution . At the end of BSFT, the increase in average weight (BMI) was statistically significant. We also observed significant improvement in nutritional (MRnut), psychosexual (MRpsex) and psychosocial (MRpsoc) functioning. No significant difference was observed in mental state (MRment) and menstrual functioning (MRmens). The average MR score (MRave) was significantly improved between Si and session Sf.At the end of BSFT, there was a significant increase in conflictual communication between family members (Initial session: medianSignificant correlation was observed between the normalized change in the percentage of conflictual communication and the improvement in BMI see , , . No The evolution of affiliative nonverbal behaviour between Si and Sf for each family member was tested independently for conflictual and non-conflictual communication using a non-parametric cluster test.For non-conflictual communication, no statistical weight computed for each cluster exceeded the threshold computed from bootstrap (i.e., patient cluster For conflictual communication, statistical weight for the patient and father (resp. d Sf see . For theThe present study assessed the evolution of clinical symptoms of AN patients and conflictual communication in their families during BSFT. The observation of changes in clinical indices between the first and the last session of BSFT in AN patients demonstrates an improvement in clinical symptoms and in psychosocial functioning of restrictive-type eating disorders as measured by BMI and the MR scales. In addition to these clinical improvements, a significant increase in conflictual communication in the families of AN patients was observed. This increase in conflictual communication was significantly correlated with the improvement of BMI.Families of AN patients have been characterised by deficit of emotional expressiveness, especially concerning conflicts and a lack of conflict resolution Three studies provide the most direct comparison with the present one. First, Robin et al. The second central goal of the present study was inspired by clinical research which have shown that affiliative behaviour is a sign of emotional engagement between participants These results can be enlightened by recent studies which show that the ability to inhibit the gaze predicts adaptive social functioning in adulthood Although the majority of studies of family therapy focus on verbal behaviour Several perspectives can be envisioned. First, a further study after the end of the family treatment is needed to verify the stability of the new pattern of communication and affiliative behaviour in conflictual situations and the generalisation of these new abilities to other peer interactions. Moreover, the specificity of changes in affiliative nonverbal behaviour should be evaluated in regard to other highly emotional situations. Finally, the behavior of the therapist is another putative element of the therapeutic changes which cannot be studied in the present article. The same quantification of verbal and nonverbal behavior should be applied to the therapist and be included in the study of the global pattern of interactions to infer his/her implication in the therapeutic changes."}
{"text": "The temporal and spatial properties of responses to complex stimuli in the central nucleus of the inferior colliculus (ICC), the main converging station in the auditory midbrain, can provide evidence for coding principles in the auditory system and are relevant for the design of neuroprosthesis.We study responses from guinea pigs to a set of eleven species-specific vocalizations which show a wide range of spectral contents, envelope types, frequency and amplitude modulations. The envelopes of the acoustically presented stimuli are characterized as complex or periodic impulses and have various degrees of periodicity. The frequency content ranges from harmonic strucutres to broad spectral distributions. The data analyzed were multi-unit recordings taken simultaneously from 32 positions in the ICC of guinea pigs using a double shank electrode. Peristimulus time histograms (PSTHs) of the high dimensional recordings were classified by linear discriminant analysis in order to evaluate the spatial and temporal distribution of stimulus-related information without the assumption of a specific coding scheme. Neighboring neural populations respond in a similar manner and have highly correlated PSTHs. Combining responses from different positions improves the classification performance for distant postions which do not show correlation, but not for adjacent positions.Separability of responses along the tonotopic gradient of the ICC to vocalizations shows great variation according to their spectral properties. Low-frequency stimuli are found to be better separable in low characteristic frequency (CF) lamina than complex envelope or broad spectral stimuli. Some stimuli of the latter type  are nearly perfectly discriminated in multi-units with high CF whereas discrimination for low-frequency stimuli is less good (60 - 70 %) in this region, see Figure We interpret the results as a consequence of the combination of several frequencies in the vocalizations that are better covered by the widely tuned receptive fields of the neurons in the mid-frequency range than by the receptive fields of the units with CFs in the extreme frequency ranges."}
{"text": "The inferior colliculus (IC) plays a strategic role in the central auditory system in relaying and processing acoustical information, and therefore its age-related changes may significantly influence the quality of the auditory function. A very complex processing of acoustical stimuli occurs in the IC, as supported also by the fact that the rat IC contains more neurons than all other subcortical auditory structures combined. GABAergic neurons, which predominantly co-express parvalbumin (PV), are present in the central nucleus of the IC in large numbers and to a lesser extent in the dorsal and external/lateral cortices of the IC. On the other hand, calbindin (CB) and calretinin (CR) are prevalent in the dorsal and external cortices of the IC, with only a few positive neurons in the central nucleus. The relationship between CB and CR expression in the IC and any neurotransmitter system has not yet been well established, but the distribution and morphology of the immunoreactive neurons suggest that they are at least partially non-GABAergic cells. The expression of glutamate decarboxylase (GAD) (a key enzyme for GABA synthesis) and calcium binding proteins (CBPs) in the IC of rats undergoes pronounced changes with aging that involve mostly a decline in protein expression and a decline in the number of immunoreactive neurons. Similar age-related changes in GAD, CB, and CR expression are present in the IC of two rat strains with differently preserved inner ear function up to late senescence (Long-Evans and Fischer 344), which suggests that these changes do not depend exclusively on peripheral deafferentation but are, at least partially, of central origin. These changes may be associated with the age-related deterioration in the processing of the temporal parameters of acoustical stimuli, which is not correlated with hearing threshold shifts, and therefore may contribute to central presbycusis. The inferior colliculus (IC) occupies a strategic position in the central auditory system. Almost all of the ascending projections from the lower auditory regions  converge in the central nucleus of the IC, thus making this structure a converging hub of the ascending as well as the descending auditory pathways of the auditory system Beyerl, . SimultaWith respect to its internal composition, the rat IC is subdivided into three major parts, the central nucleus and the dorsal and external  cortices. This division is visible in most histological and immunohistochemical stainings  and calcium binding proteins (CBPs) in the higher levels of the rat auditory pathway, including the IC and auditory cortex  are present  are either large fusiform cells or smaller oval neurons, in both the second and third layers of the EIC. The GAD-ir neurons in the EIC resemble some types described with Rio-Hortega Golgi staining in the rat IC by Malmierca et al. . EspeciaThe clusters of small neurons and intensely stained neuropil in the second layer of the rat EIC described by Chernock et al.  are cleaAs already mentioned, the GABAergic neurons represent a substantial part of all neurons in the IC. In rats, the portion of inhibitory neurons in the IC seems to be larger than in the cat or bat; specifically; the CIC of the rat contains more than 30% of GABAergic neurons, whereas in the same structure of the cat or the bat they represent approximately 20%  , CB, PV, and CR, represent major fast cytoplasmatic calcium buffers in the central nervous system and thus protect neurons from insults that induce an elevation of intracellular CaThe distribution of calbindin-immunoreactive (CB-ir), calretinin immunoreactive (CR-ir) and parvalbumin-immunoreactive (PV-ir) neurons in the central nervous system of the rat was first described in summary by Celio  and R\u00e9siPV-ir neurons are present in all three subdivisions of the rat IC  neurons , which identifies neurons capable of producing nitric oxide  with a wide variety of morphological, physiological and behavioral differences, including differently preserved hearing function with age . We found similar significant age-related changes in CB immunoreactivity in the dorsal and external cortices of both Long Evans and Fischer 344 rats. The changes included a decrease in the number of CB-ir neurons and a significant decline in the average volumes of CB-ir neuronal somas (DIC only). In western blotting, the age-related changes were even more pronounced and resulted in a significant decline in the levels of calbindin in the whole IC of old rats of both species of almost 50%. In calretinin immunoreactivity, a tendency toward an age-related decline in the number of CR-ir neurons as well as a significant decrease in the mean volumes of the remaining CR-ir neuronal somas were found in the dorsal and external cortices of the IC. Western blot analysis demonstrated a significant decline, however, less pronounced when compared to calbindin and GAD, in calretinin protein levels of 22% in both rat strains   in the IC observed in aging studies cannot be easily attributable to a general neuronal loss, because in our previous experiments we found that the reduction in the total number of neurons in the IC of old Long-Evans and Fischer 344 rats in Nissl-stained sections does not exceed 10% (unpublished data). This finding is in agreement with the data of other authors, who reported no significant changes accompanying aging in the total number of neurons in the rat inferior colliculus  are mainly the consequence of decreased ascending inputs from the deteriorated periphery or rather part of the changes in the aging brain itself. Most immunohistochemical experiments concerning age-related changes in the GABA-mediated inhibition of central auditory system were undertaken in animal strains with a pronounced hearing loss and deterioration of the peripheral sensory organ with aging, which represented a complication for determining the cause of the observed changes (for review see Frisina, Hearing function was shown to be altered in the absence of any significant damage to the peripheral sensory organ, since the age-related worsening of gap detection thresholds, the gap duration difference limen and the disappearing middle latency response to an increasing stimulus repetition rate are not correlated with hearing threshold shifts in Long-Evans rats (Suta et al., Similarly, in electrophysiological studies on aging Fischer 344 rats, the reduction in the maximum discharge rate or the increased number of units responding poorly to an auditory stimulus in the IC was not correlated with the observed hearing threshold shift. In addition, for spontaneous activity, first spike latency or dynamic range, no significant declines were observed with aging (Palombi and Caspary, In a recent age-related study, (Rybalko et al., Therefore, we may suggest that the age-related decline in GAD expression in the rat IC and AC, as demonstrated in our experiments, does not depend exclusively on peripheral deafferentation but is, at least partially, of central origin. The age-related alterations in the IC involving the GABA-mediated inhibitory system and the decline in the number of neurons expressing glutamate decarboxylase and CBPs may significantly contribute to the observed behavioral impairment.The potential long-term reversibility or compensation of the age-related changes in the expression of glutamate decarboxylase or CBPs is open to further investigation. However, it is known that changes in the expression of selected neuronal markers in the IC neurons, including CBPs that are induced by experimental manipulations may be reversible to some extent.For example, following monoaural cochlear ablation in the ferret, the CR-ir plexus in the contralateral CIC increased its optical density and the area of immunostaining (Fuentes-Santamaria et al., With respect to studies on aging, similar data are very limited. At the cortical level, a partial recovery of age-related deterioration was shown by De Villers-Sidani et al. . The ageThe inferior colliculus may play an even more prominent role in the central auditory system of rats than usually thought, since the rat IC contains more neurons in total than all other subcortical auditory structures combined (Kulesza et al., Along with the auditory cortex, the IC plays a key role in the processing of the temporal parameters of sounds, which is strongly dependent on the function of the inhibitory systems. Both temporal parameter processing and GABA-mediated inhibition are known to be altered in aged rats Syka, . The decCentral presbycusis represents a complex process that includes alterations present in the subcortical auditory nuclei, the auditory cortex and other non-auditory regions, as well as the development of partial compensatory mechanisms. The potential reversibility or compensation of these age-related changes is open to further investigation. A better understanding of the mechanisms underlying impaired neuronal processing in the central auditory system with aging, resulting in the poor recognition of complex environmental sounds, species-specific vocalizations in animals and speech in man, may have important implications for the treatment or amelioration of the negative aspects of presbycusis in the future.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "There was information omitted from the Funding statement.The correct statement is: This work was funded by the Italian Ministry of Health (GR program 2010-2311017) and the Associazione Italiana per la Ricerca sul Cancro (AIRC) program MyFAG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."}
{"text": "The Liverpool Care Pathway (LCP) is the accepted gold standard in the documentation of end-of-life care in the UK. A computerized version of the LCP in the form of a digital proforma (DP) exists as an option on our unit. Some clinicians choose to use free-text (FT) entry citing as this can be more comprehensive. Our study investigates whether usage of the DP is likely to result in a greater degree of compliance with LCP standards than FT alone.All deaths occurring between 1 January 2009 and 30 June 2009 were identified from the record of ITU admissions. Cases of cardiac arrest and brain stem death were excluded. Quality of documentation was scored by a nurse and doctor assessor . The average of the total scores for each case was calculated. Performance of the DP was analysed by comparing average total scores for DP versus FT alone using simple nonparametric descriptors.There were 52 deaths and 45 after exclusions. Use of the DP resulted in considerably higher total average scores  than use of FT alone . Statistical significance is suggested by the lack of overlap in the range values. See Figure Using the DP for end-of-life documentation is highly likely to improve compliance with accepted standards in end-of-life care. Doctors using FT alone were unlikely to document all of the broad issues that require consideration. The use of a DP can function as a useful checklist ensuring patients receive the best care when organ support is withdrawn."}
{"text": "Tobacco mosaic virus (TMV) has been studied for many years. The RNA of TMV moves cell-to-cell in a non-encapsidated form in a process depending on virus-encoded movement protein (MP). Here, we discuss the current state of the art in studies using TMV and its MP as a model for RNA transport. While the ability of plants to transport viral and cellular RNA molecules is consistent with RNA transport phenomena in other systems, further studies are needed to increase our ability to visualize viral RNA (vRNA) in vivo and to distinguish RNA-transport related processes from those involved in antiviral defense.Studies during the last 25 years have provided increasing evidence for the ability of plants to support the cell-to-cell and systemic transport of RNA molecules and that this process plays a role in plant development and in the systemic orchestration of cellular responses against pathogens and other environmental challenges. Since RNA viruses exploit the cellular RNA transport machineries for spreading their genomes between cells they represent convenient models to investigate the underlying mechanisms. In this regard, the intercellular spread of  Tobacco mosaic virus (TMV) is a rod-shaped virus with a positive-sensed RNA genome that encodes 126 kD and 183 kD subunits of replicase, a 30 kD movement protein (MP) and a 17.5 kD coat protein (CP). The virion consists of the viral RNA (vRNA) protected by 2130 subunits of assembled CP. The virus has been a paradigm for RNA virus movement since the requirement of its MP for virus movement was defined    interacts with microtubules (Wright et al., It will also be important to determine how far the observations described for TMV and summarized herein also apply to the movement of other RNA viruses. Mechanisms involved in the cell-to-cell movement of viruses have been reviewed in several recent overview articles Lucas,  and showHowever, a role of RNA-enriched mobile particles in the transport of RNA viruses and other RNA molecules is certainly consistent with similar observations in other systems. These include neuronal granules for transport of mRNAs along axons and dendrites for localized translation at synapses (Kiebler and Bassell, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This presentation will discuss the outcomes and evaluations of the organisation and delivery of the 2013 \"At home with eating disorders Conference\"With the emergence of evidence based treatments, including Maudsley Family Based Therapy parents and carers play a crucial role in early detection and efficacious treatment. But they do it in the face of significant challenges - lack of information or education, difficulties in navigating the health system, difficulty in finding suitable clinicians, and suffer significant personal and financial burdens in the process.The conference was organised by- F.E.A.S.T- The Butterfly Foundation- Eating Disorder Outreach Service (EDOS)- ANZAEDThis conference aimed to provide access for parents and carers of people with an eating disorder to a range of expert knowledge and skills so they can be better prepared and empowered to take an active role in the treatment of, and recovery from, the eating disorder.- Online evaluations pre and post conference- Attendance,- Range of Speakers and Workshops- Budget management- Successful SponsorshipsConclusions about the extent to which the conference met its aims, as well as recommendations for future carers conference planning will be made.Care in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the"}
{"text": "Alzheimer\u2019s disease (AD) is the most common neurodegenerative disease. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients revealed stepwise breakdown of the cellular machinery during the progression of AD at semi-quantitative level. At the early stage of AD, the accumulation of A-beta oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism, likely a response to the reduced level of nutrient and oxygen supply. At the intermediate stage, the progression of the disease leads to enhanced signal transduction, also likely an adjustment to the deteriorating environment. The late stage is characterized by the elevated apoptosis due to the excessive regulatory and repair burden. Interestingly, the elevated apoptosis at the late stage is accompanied by elevated anti-apoptotic signals, suggesting an adaptive survival strategy even at the late stage of AD. These findings can serve as theoretical basis for pharmaceutical intervention of Alzheimer\u2019s disease."}
{"text": "The Whole Systems Demonstrator pilots introduced telehealth and telecare into three local authority areas using an integrated approach to deliver health and social care to those with high care needs and long-term conditions. Proponents of these technologies have given cost savings as one rationale for advocating their introduction and widespread implementation; proponents have also advocated their potential to improve the quality of life for their users. Until recently, evaluations of telehealth and telecare in high-income countries have been based on relatively small-scale pilots; few such evaluations have been designed as randomised controlled trials. The WSD study was a pragmatic cluster-randomised control trial, representing the largest-scale trial of telehealth and telecare to be carried out in the UK. This presentation focuses on the results of the WSD telecare questionnaire study.To examine the costs and cost-effectiveness of telecare compared to standard support and treatment.Economic evaluation conducted in parallel with a pragmatic cluster-randomised controlled trial of Telecare. 2600 people with social care needs participated in a trial of a community-based telecare intervention in three English local authority areas. Approximately half of the participants in the telecare trial also consented to participate in the WSD telecare questionnaire study, which collected information on a number of patient-reported outcome measures and also on the self-reported use of a range of health and social services. Health and social costs were calculated by attaching nationally applicable unit costs to self-reported service use data. The unit costs of telecare support and treatment provided were calculated drawing on administrative and financial data sources and interviews with key informants. The primary outcome for the cost-effectiveness analysis was the quality-adjusted life year (QALY). Secondary outcomes included measures of health-related quality of life and well-being. We employed multivariate analyses to explore the cost-effectiveness of the interventionThe presentation will describe the results of the economic evaluation of telecare, addressing the cost of care and treatment packages used by those participating in the telecare questionnaire study and the results of the cost-effectiveness analysis. These results will be available by the time of the presentation.These will be available by the time of the presentation."}
{"text": "Several studies have used neuroimaging methods to identify neural change in brain networks associated to emotion regulation after psychotherapy of depression and anxiety. In the present work we adopted a meta-analytic technique specific to neuroimaging data to evaluate the consistence of empirical findings and assess models of therapy that have been proposed in the literature. Meta-analyses were conducted with the Activation Likelihood Estimation technique, which evaluates the overlap between foci of activation across studies. The analysis included 16 studies found in Pubmed (200 foci of activation and 193 patients). Separate meta-analyses were conducted on studies of 1) depression, post-traumatic stress disorder and panic disorder investigated with rest state metabolism ; 2) depression, post-traumatic stress disorder and panic disorder investigated with task-related activation studies ; 3) the previous studies considered jointly; and 4) phobias investigated with studies on exposure-related activation . Studies on anxiety and depression gave partially consistent results for changes in the dorsomedial prefrontal cortex and in the posterior cingulated gyrus/precuneus. Several areas of change in the temporal lobes were also observed. Studies on the therapy of phobia were consistent with a reduction of activity in medial temporal areas. The cluster of change in the prefrontal cortex may refer to increased recruitment of control processes, as hypothesized by influential models of emotion regulation changes due to psychotherapy. However, not all areas associated with controlled emotion regulation were detected in the meta-analysis, while involvement of midline structures suggested changes in self-related information processing. Changes in phobia were consistent with reduced reactivity to phobic stimuli. In the last few years, neuroimaging approaches to psychotherapy research have provided considerable evidence of changes in brain networks accompanying treatment Several reviews of neuroimaging studies on psychotherapy of depression and anxiety have noted that treatment results in changes in brain areas that play important roles in emerging models of emotional processing and emotion regulation This model is supported by numerous important findings. Several studies have independently reported increased activation in limbic areas, such as the amygdala, during the exposure to emotionally arousing stimuli in disorders characterized by affective dysregulation and impulsivity Taken together, these findings support the validity of a core construct of emotional dysregulation generally applicable to affective disorders and their therapy, and of the role of cognitive control processes in containing enhanced reactivity to emotional stimulation. Applying a model based on this construct to summarize a wide range of findings, DeRubeis and colleagues To address the issue of direction of change in studies of psychotherapies, it is important to consider the existence of two large groups of experimental settings: studies of changes in baseline activity, largely based on quantitative approaches such as PET, and studies of changes of task-related activation, based on more recent BOLD-EPI methodologies. Studies of task-related activation test the model of emotion regulation directly, either by eliciting signal in limbic structures associated with the exposure to emotionally arousing stimuli , or by investigating neural correlates of cognitive demanding tasks where distracters are made more disruptive by manipulating their emotional content (to assess efficiency of cognitive regulation).In contrast, studies of baseline metabolism or resting state may be indicative of mental activity free of the constraints of tasks or stimuli (\u2018default mode\u2019 function). This activity is believed to arise at least in part from self-referential and unconstrained thinking, such as thoughts arising spontaneously while resting in the scanner The present work complements the several reviews that have discussed the findings of neuroimaging studies on psychotherapy In the present study we adopted Activation Likelihood Estimation [ALE], a meta-analytic technique specifically developed for neuroimaging studies Within the group of task-related activation studies, we conducted a separate meta-analysis of studies of the psychotherapy of specific phobias. This choice was motivated by specific characteristics of these therapeutic approaches and of the studies in the literature, suggesting possible systematic differences relative to studies of depression and other forms of anxiety, even if the core construct of affect dysregulation may be commonly applicable. Therapies of specific phobias are characterized by exposure to the same stimulus that is used in the neuroimaging studies to activate the brain-behavioural phenotype of this disorder . This contrasts with paradigms used in other studies, which cannot make recourse to stimuli of this degree of specificity . Accordingly, studies of the effects of the psychotherapy of phobias can focus more narrowly on the neural substrate activated by the stimulus directly addressed by therapy. This differs from common models of the effects of psychotherapy, which posit effects on prefrontal areas onto which control processes are mapped Referring to the dual-process model of dysregulation in affective disorders and their therapy, we were specifically interested in addressing the following issues:to test the prediction of dual-process models of emotion regulation, according to which psychotherapy is associated with increases in activity in these prefrontal areas, accompanied by a decrement of activity in the limbic system, in task-related studies.the involvement of specific areas in the prefrontal cortex and the limbic system in accounting for changes ensuing during therapy in resting state studies;to verify the possible concordance of areas detected in task-related and baseline types of studies.Note that the direction of changes cannot be the same in task-related and resting state studies. First, in a task-related activation study, the control condition enters on the subtraction side in the contrast task vs. control. To the extent that this control condition is more akin to a baseline To address this issue, we computed a first group of meta-analyses in which baseline and task-related studies were examined separately. This first series of analyses allows examining the data without reference to the model of the possible antagonistic relationship between instructed and spontaneous thought. A final meta-analysis including both studies was also carried out to quantify evidence of concordance between these two types of studies, after changing the sign of effects of baseline studies.The evidence on the existence of a form of affective dysregulation shared between depression and anxiety, discussed above, does not imply the absence of psychopathological criteria that may differentiate between these disorders (or indeed between subtypes within them). However, there are very few studies in the neuroimaging literature of psychotherapy addressing aspects of psychopathology that do not fall within the scope of the emotion dysregulation construct (a rare example of such studies is http://www.ncbi.nlm.nih.gov/pubmed/) using the keywords \u201cpsychotherapy neuroimaging\u201d. The literature showed considerable heterogeneities across studies in experimental design and therapy approach. To limit the meta-analysis to studies of sufficient consistency of scope, a selection was carried out following criteria base on (a) the diagnostic category, (b) the psychotherapy approaches, (c) the experimental design and (d) methodological issues.Neuroimaging studies comparing patterns of activity in psychiatric patient before and after psychotherapy were collected through searches in PUBMED  in stereotactic space and whole brain statistical analysis. One study on depression The studies identified using the criteria described above were 16 .Activation Likelihood Estimation (ALE) evaluates the overlap between foci of activation found in different studies and treats them as probability distributions centred at the coordinates reported http://brainmap.org/ale/) ALE meta-analysis was carried out using GingerALE 2.0.4 software distributed by the BrainMap project . No significant clusters of increased activation were found in exposure therapy studies.The meta-analysis on phobic patients treated with exposure therapy included symptoms provocation paradigms. There were 5 studies in this meta-analysis, based on 57 participants and 38 foci. In the meta-analysis of the contrast post- versus pre-therapy, a significant cluster of decreased activation in limbic areas was detected  suggests that a more complex model of control may be required to explain the data. A second explanation refers to the relative lack of consistency of the findings of prefrontal involvement in depression and anxiety. For example, previous systematic reviews and meta-analyses of task-related changes in depression have shown the effects in DLPFC to be complex However, the analysis detected a modulation of prefrontal activity in the DMPFC in both resting state studies and emotional-cognitive tasks studies, even if without a concomitant effect in DLPFC. This finding may be consistent with an emotion dysregulation model of affective disorders remedied by psychotherapy in which improvements in emotional control refer to self-observation and rumination activities, which may be expected to be present both in spontaneous thinking in the absence of an external stimulus to control A second finding of this meta-analysis was the failure to detect significant foci of activity change in limbic areas such as the amygdala in the studies of psychotherapy of depression and anxiety. This finding is disappointing given the evidence showing that this area is usually hyper-activated in depression and anxiety Another finding of this meta-analysis was the detection of clusters of significant change in the left inferior and middle temporal cortex increased their activation in the resting state and decreased during task execution. The middle temporal gyrus is most often involved in verbal comprehension versus post-psychotherapy), instead of the interaction between the variable time and the variable group (patients versus controls). For this reason it is difficult to conclude that the effects observed are related with psychotherapy treatment, as they may be confounded with the natural course of the condition under therapy. A second limitation ensues from the considerable heterogeneity of techniques and study designs. We consider this limitation unavoidable, as few incentives exist for replicating existing studies exactly. However, considering emotional stimuli presentation in passive viewing or during cognitive tasks execution separately could describe more accurately the mechanisms underlying psychotherapeutic change, and the consideration of disorder-specific stimuli used in the experimental paradigms could be useful in explaining specific psychotherapy effects for specific patients. Yet another limitation concerns studies that had to be excluded from analysis because of reporting only region of interest results. The existence of these reports poses a difficult methodological problem, since including them may bias the analysis toward the regions of interest examined in the original studies, and excluding them may engender the opposite bias. One may hope that the introduction of meta-analytic techniques in this field will have the positive effect of encouraging the adoption of designs and reporting standards that enable the subsequent consolidation of results across studies.The present study cannot be considered as conclusive because of some limitations. A first methodological limitation concerns the amount of data available for analysis. Several studies had small sample sizes, and others did not include suitable control groups in the experiment. Some studies reported only the simple contrast including the variable time (pre- In summary, the present meta-analysis summarized the evidence on the neural correlates of psychotherapy changes. Although some of the results of the present meta-analysis are consistent with some hypothesis proposed in psychotherapy research and neuroscience literature and with studies about neural correlates of psychopathology, the findings considered as a whole suggest a more complex picture than the one posited by the contrast between limbic system and prefrontal areas. The location of identified clusters appears to be most consistent with involvement of self-representational processes in the therapy of depression or anxiety, and with a reduction in reactivity of the medial temporal lobe in exposure therapy of phobias. Other cerebral and mental mechanisms may be involved, such as semantic processes, but more studies are required in order to clarify the influence of these less studied mechanisms on psychotherapy."}
{"text": "The government seeks to build a healthy community through quality, generic drugs that are available, accessible and affordable. On the other hand, self-medication among different community segments has grown in popularity. In this paper, we want to argue that if the government fail to regulate and to supervise informal drug dispensaries, the community - particularly the poor - is more likely to gain harmful effects through the practice of self-medication and the use of unregulated informal drug stores. This study aims to: determine the pattern of self-medication in the province of Yogyakarta, identify the type of drug dispensaries that self-medication users seek in their communities, and to evaluate the effectiveness of ministry of health\u2019s regulations and supervisions on drug dispensaries.This study used data from the 2009 Indonesian Family Life Survey available from the Rand Corporation. Qualitative data were obtained from field observations and in-depth interviews with informal drug dispensaries and officers from provincial and district health authorities.The practice of self-medication is popular among urban and suburban population. The prevalence of self-medication varies across districts. The sub-urban districts shows a relatively high use of self-medication ; Bantul (65%); and Sleman (69%). It is surprisingly that the use of self-medication practice is 90% in Yogyakarta city. An increasing number of informal drug dispensaries run without necessary supervision and regulation both from district and provincial health authority. Community dispensaries were found to obtain drug supply from non-authorized pharmaceutical distributors.There is an increasing tendency for the community, the poor and the better off, to use self-medication as health seeking practice for minor illness. In contrast, the Ministry of Health lacks control over informal drug dispensaries. It is recommended that the government puts in place regulation and supervision strategies toward community based drug dispensaries."}
{"text": "What do young people and families living with an eating disorder need from a public health service system? What do clinicians and services need to provide treatment, particularly family-based treatment? How do we go about creating a public health system which provides early, equitable and quality access to evidence-based treatment for young people?The first priority of the Victorian Centre of Excellence in Eating Disorders (CEED) is supporting the provision of family-based treatment for eating disorders across public child and youth mental health services. Inspiring change for the person  and for the public health treatment context is central in CEED's work towards this priority. The engagement on the ground with metropolitan and rural services across Victoria has resulted in developing initiatives in training, case consultation and service system development.This presentation aims to inform service leaders and clinicians about key aspects of implementing family-based treatment in public mental health services. It will provide an outline of CEED's approach to dissemination and implementation, and provide data about Victorian services utilization of family-based treatment as an evidence-based first-line treatment model. Key challenges and controversies will be canvassed.Children and Youth Treatment and Service Development stream of the 2013 ANZAED Conference.This abstract was presented in the"}
{"text": "The structure-based design of small molecule modulators of protein-ligand binding and protein-protein interaction is a key component in drug discovery. The underlying protein interactions can be regarded based on structural similarity of the involved secondary structure elements .The most prominent example is the protein fold of a protein domain that is more conserved than the amino acid sequence and proteins with similar fold but dissimilar sequence and function can bind similar ligands. Similar ligand binding can also occur between different proteins that have a similar spatial arrangement of secondary structure elements around the ligand binding site (\"ligand-sensing cores\") independent from the overall fold . AnalogoThese similarities in otherwise unrelated proteins can be useful in the design of protein function modulators. The successful applications in molecular design described in literature using predicted polypharmacology in protein-ligand binding will be shown and the analogy in the design of protein-protein interaction inhibitors and the potential of polypharmacology prediction will be discussed."}
{"text": "Many Finnish emergency departments (ED) serve both primary and secondary health care patients and are therefore referred to as combined emergency departments. Primary care doctors are responsible for the initial assessment and treatment. They, thereby, also regulate referral and access to secondary care. Primary health care EDs are easy for the public to access, leading to non-acute patient visits to the emergency department. This has caused increased queues and unnecessary difficulties in providing immediate treatment for urgent patients. The primary aim of this study was to assess whether the flow of patients was changed by implementing the ABCDE-triage system in the EDs of Espoo City, Finland.The numbers of monthly visits to doctors were recorded before and after intervention in Espoo primary care EDs. To study if the implementation of the triage system redirects patients to other health services, the numbers of monthly visits to doctors were also scored in the private health care, the public sector health services of Espoo primary care during office hours and local secondary health care ED . A face-to-face triage system was applied in the primary care EDs as an attempt to provide immediate treatment for the most acute patients. It is based on the letters A (patient sent directly to secondary care), B (to be examined within 10 min), C (to be examined within 1 h), D (to be examined within 2 h) and E (no need for immediate treatment) for assessing the urgency of patients' treatment needs. The first step was an initial patient assessment by a health care professional (triage nurse). The introduction of this triage system was combined with information to the public on the \"correct\" use of emergency services.After implementation of the ABCDE-triage system the number of patient visits to a primary care doctor decreased by up to 24% (962 visits/month) as compared to the three previous years in the EDs. The Number of visits to public sector GPs during office hours did not alter. Implementation of ABCDE-triage combined with public guidance was associated with decreased total number of doctor visits in public health care. During same period, the number of patient visits in the private health care increased. Simultaneously, the number of doctor visits in secondary health care ED did not alter.The present ABCDE-triage system combined with public guidance may reduce patient visits to primary health care EDs but not to the secondary health care EDs. Limiting the access of less urgent patients to ED may redirect the demands of patients to private sector rather than office hours GP services. Non acute and non-urgent visits to the emergency department (ED) may cause significant problems since they consume resources that should be allocated for acute patients -4. TriagThe health system in Finland is divided into private and public primary care (GP) services and in addition to primary care ED and secondary care ED services. EDs and most of the office-hours primary care are funded by the public health system. In other words, they are non-profit making. Emergency services in Finland have been provided by both hospitals and health centres since the 1970s. Out-of-hours services in health centres are run by primary health care staff and GPs while the EDs of the secondary care hospitals are run by different medical specialities. Primary care out-of-hours units were increasingly incorporated into hospital emergency units due to centralization at the end of the 20th century. These EDs came to be known as 'combined emergency departments' . GPs areThe situation in Finnish primary care has recently deteriorated due to difficulties in recruiting GP:s into the public health system. As a consequence, access to public daytime services has worsened  and EDs Emergency services must be capable of providing quick, high quality and effective treatment to patients with acute medical problems. This capability is compromised if the ED is too crowded . InternaThe primary aim of the present study was to determine whether this type of triage system combined with public guidance related to the proper use of EDs alters the patient flow (monthly number of visits) in the GP driven department  and the specialist driven  ED also in other systems and in other municipalities than the city of Vantaa. A secondary aim was to study if the introduction of ABCDE-triage in the ED alters the number of patient visits in other public or private primary health care services. To know what kind of cases there are in E group, we also recorded the patient's reasons for entry to the ED.This study was performed in the city of Espoo. At the time of the study Espoo had a population of around 230,000 inhabitants. In the present work, unselected primary care patients constituted the study population. Intervention was performed and data collected from the primary care led ED:s. One of them is located in Jorvi hospital. Since secondary health care is also provided in Jorvi it is defined as a combined ED. It is equipped with out-of-hours laboratory and X-ray facilities, and primary care ED is carried out there only out of office hours. The other ED in Puolarmets\u00e4 is more like a traditional Finnish primary health care out-of-hours unit. There is no specialist care provided, and the laboratory and X-ray facilities are available only during office hours. Puolarmets\u00e4 ED was not open during the night-time but only in the evenings and at weekends. Altogether, the data obtained from Jorvi and Puolarmets\u00e4 EDs were pooled together as Espoo ED's data to study the effect on the patient currents in different main compartments of the local health care.http://www.kuntaliitto.fi) classification that was performed by the triage nurses. No ethical approval was required because this study was made directly from the patient registry without identifying the patients. The registry keeper  granted permission to do the study.The data was obtained from the electronic health records of Espoo primary health care (Effica- patient chart system) and Jorvi secondary health care ED . The Social Insurance Institution of Finland (SII) provided the data about the use of the private primary health care doctors. In Espoo, the follow-up was performed between March 2004 and February 2008. The number of monthly visits to doctors was scored in each study department before and after implementation of the ABCDE triage system (1.3. 2007). Thus, we could study the situation before and after the implementation of ABCDE-triage in the EDs. In the case of those patients allocated to triage group E, the reasons for entry to the primary care EDs were recorded by using ICPC 2  directly to appropriate daytime services. There was also lively public and political debate about emergency services going on at the same time. Feedback was actively gathered both from patients and the staff with questionnaires and interviews. The Numbers of visits to doctors and nurses and assessed patients were frequently measured. Similarly, patients assessed in triage groups, waiting times and diagnoses in different triage groups were irregularly measured. In order to discuss the implementation process and problematic patient cases, follow-up meetings were organized every month.The impact of introducing the ABCDE-triage tool in emergency services was enhanced by increasing simultaneously the education of the staff in EDs and the publicity about the issue. A discussion was also raised in the media around these services and information was delivered both to professionals and the public outside EDs. The main message to the public was that those who require immediate medical help should come to EDs but EDs are not overflow services of office-hour services. Guidelines were written for the staff about triage. The staff also got training and encouragement by the project workers and leaders. The training was arranged for public health care inside EDs and in office-hour services. Altogether 60 nurses were trained in four 4-hour seminars in primary care EDs to perform the triage. The general public was informed of the project through the media, and all the information focused on the transparency of the system. Necessary data was also available via Internet, and both the public and staff had access to the internet pages of the campaign The triage system was introduced at the beginning of March 2007. The frequencies of monthly patient visits in the three previous years were compared to the number of patient visits in the respective months of the next year (March 2007-February 2008), e.g. after the triage was applied. One-way ANOVA of repeated measurements followed by t-test with the Bonferroni Correction was chosen as the method for statistical analysis. . After ist March 2007) was 37589. The number of the monthly GP doctor visits in the ED (out-of-hours) decreased by about 24% (962 visits/month) from the numbers of the last control year (March 2006-February 2007) after the introduction of the ABCDE- triage system  before intervention the number of doctor visits in Espoo Primary care EDs was 49141, two years (March 2005-February 2006) before 50248, and one year (March 2006-February 2007) before 49219, respectively. The number of these visits one year (March 2007-February 2008) after beginning of the triage (1Doctor visits to the private sector GP:s in Espoo increased after the beginning of the intervention. This increase was about 324 visits/month when compared with the number of doctor visits of the last control year (March 2006-February 2007) before implementing the triage , the Canadian Triage and Acuity Scale (CTAS), the Manchester Triage System (MTS), and the Emergency Severity Index (ESI) -14. TriaThe idea in the ABCDE-triage system is to evaluate and treat those primary health care patients who usually are at low risk and who come to ED's with a reasonable use of resources. Stronger scientific evidence is needed to determine which of the vital signs and chief complaints have the greatest prognostic value in the triage. Patients may have a life-threatening condition, but show normal vital signs. Inter rater agreement (reliability), validity, and safety of triage scales need to be investigated further, and head-to-head comparisons are needed to determine whether any of the triage scales have advantages over others . NeverthImplementation of ABCDE-triage combined with public guidance was associated with a reduction in the use of a primary health care ED services. This intervention did not seem to increase the workload during office hours in the public primary health care or in secondary health care. Strict ABCDE-triage combined with public guidance may decrease total use of public primary health care and redirect part of the patients to the private sector.ED: Emergency department; GP: General practitioner.The authors declare that they have no competing interests.JaK led and performed the intervention planned the analysis and wrote the manuscript. RM led and performed the intervention and arranged the data from Espoo. TH led and performed the intervention. JM arranged the data from tertiary health care. KJM planned the analysis and wrote the manuscript. TK arranged the data from the private sector, analyzed the data, planned the experimental setting and wrote the manuscript. All the authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-227X/12/2/prepub"}
{"text": "Long non-coding RNA have emerged as an increasingly well studied subset of non-coding RNAs (ncRNAs) following their recent discovery in a number of organisms including humans and characterization of their functional and regulatory roles in variety of distinct cellular mechanisms. The recent annotations of long ncRNAs in humans peg their numbers as similar to protein-coding genes. However, despite the rapid advancements in the field the functional characterization and biological roles of most of the long ncRNAs still remain unidentified, although some candidate long ncRNAs have been extensively studied for their roles in cancers and biological phenomena such as X-inactivation and epigenetic regulation of genes. A number of recent reports suggest an exciting possibility of long ncRNAs mediating host response and immune function, suggesting an elaborate network of regulatory interactions mediated through ncRNAs in infection. The present role of long ncRNAs in host-pathogen cross talk is limited to a handful of mechanistically distinct examples. The current commentary chronicles the findings of these reports on the role of long ncRNAs in infection biology and further highlights the bottlenecks and future directions toward understanding the biological significance of the role of long ncRNAs in infection biology. Recent large-scale, high-resolution transcriptome analyses of several vertebrate genomes, including that of humans, has confirmed the transcriptional potential of large tracts of the vertebrate genome and further opened up new vistas in the study of transcriptomics, RNAs, and their subclasses  has been determined to be dysregulated post-infection  influencing the overall outcome of infections depending upon their ability to either increase or decrease patient susceptibility to infections (Vigneau et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Local field potentials (LFP), the low-frequency part of the electric potential recorded extracellularly in the brain, is a well-established measure of neural activity at the population level. However, the origin and the nature of the LFP make it harder to interpret than other electrophysiological signals such as spikes. Two problems intertwine here: first, the extracellular field spreads over significant distances from the generating population; second, the recorded signal is typically a combination of contributions from several sources. The former problem is often addressed by reconstructing the underlying currents using Current Source Density (CSD) analysis. To solve the latter issue we have employed in the past the combination of CSD and Independent Component Analysis (ICA) .Here we test the combination of CSD analysis  and ICA"}
{"text": "Analysing the effects of mechanostimulation on pulmonary cells improves the understanding of the stress-strain relationship in the lungs. While there are plenty of different methods to apply strain on cells and thereby to analyze intracellular and extracellular processes, it remains difficult to measure the resulting strain, in other words the forces produced by cells to counteract the applied strain. Recently we presented a bioreactor to cyclically deflect cells by co-deflecting them with a carrier membrane . The airDifferent alveolar epithelial cell lines (A549 and RLE-6TN) were grown on RGD-coated, highly flexible polydimethyl siloxane membranes and were mechanically stimulated in a bioreactor ,2. AfterStretching pulmonary cells bidirectionally led to a loss of intercellular connections and/or loss of integrin-binding sites to the RGD-labeled carrier membranes as indicated by comparing microscopic images before and after application of strain to cell monolayers. This was accompanied by a loss of the cell's counterforce on strain.The investigation of cell forces with our strain applicator allows us to analyze mechanical properties of cell constructs at the same time as we can track visually changes in cellular morphology. Strain-related cell damages as found in this study could play a role in development of ventilator-induced lung injury."}
{"text": "According the literature data about Familial Mediterranean Fever (FMF), with the combination of Henoch- Sheilen purpura (HSP), as well as the results of the work done by the former of our studies we attempt to identify and compare membranes aspects of pathogeneses of FMF and combination of FMF with HSP.The aim of our study is to identify speed of lipid peroxidation (LPO) and the role of degradation of membrane phospholipids (PL) of FMF and combination of FMF with HSP.2 activity, intensity of LPO, as well as the level of citotoxic - Lysophatidylcholines( LysoPCH ). The activity of phospholipase A2 and LPO was determined by the spektrofotometrik methods. The fractions of separate PL in erythrocyte membranes were carried out by thin-layer chromatography methods.Clinical studies conducted in 61 non complicated of amyloidosis FMF children in the Republican FMF Children Center, Center \u201cArabkir\u201d. The age of the patients varies from 5-15. Three patients of FMF are accompanied with HSP. We are selected as a control group of 11 healthy people in practice.Biochemical studies carried out in Hematological Center of Armenia. In erythrocytes of membrane we determine the following index: phospholipase A2 , with sharp increase of citotoxic- LysoPCH  and intensity of LPO .It is noteworthy, that in the second group of our patients (FMF with HSP) these indices will be raised. Therefore, the mentioned follows that the second group of patients treatment is more difficult and requires a special, single-minded approach.The results of our research showed that FMF is followed by rising the activity of phospholipase AThe results in our experience are discussed to find possible ways of increasing efficiency of treatment FMF with HSP.None declared."}
{"text": "Randomised trials vary in methodological quality, and flaws in trial conduct can lead to biased estimation of the intervention effect. If a meta-analysis makes no allowance for methodological flaws, there's a danger that the results could be biased and over-precise, or that some lower-quality trials could be given too much influence in the meta-analysis. Cochrane review authors now use a specific \u2018Risk of Bias' tool for assessing potential biases in the trials included in their review. This information is a valuable resource, but it is currently not clear how to use the \u2018Risk of Bias' information to reduce the impact of suspected biases on the meta-analyses presented in the review.In this work, we are developing a method for adjusting trial results for biases in meta-analysis, making use of \u2018Risk of Bias' information for each trial and also generic external evidence on biases. We aim to integrate two existing methods for adjusting for bias in meta-analysis, in order to gain the advantages of both. One of the existing methods uses generic evidence on bias from an external collection of meta-analyses, while the other method relies on detailed assessment of the methodological quality of each trial and elicitation of opinion about the degree of bias likely to result. We consider several different approaches for integrating generic and trial-specific evidence on bias and discuss the practicalities of these."}
{"text": "One of the objectives of the Paediatric Regulation (EC) No 1901/2006, is to foster high quality ethical research on medicinal products to be used in children. To achieve this objective, the EMA is responsible for developing a European paediatric network of existing national and European networks and centres with specific expertise in research and clinical trials relating to paediatric medicines. The purpose of this article is to disseminate knowledge of the structure and goals of ENPR-EMA and to highlight the cultural and organizational difficulties for its implementation.Following the publication of research quality requirements, a set of recognition criteria, which have to be fulfilled to become a member of ENPR-EMA were agreed. So far, 32 networks and centres (of 62 identified networks) submitted self-assessment reports indicating whether or not they fulfill the agreed minimum criteria. Sixteen networks (26% of 62 identified networks) fulfilled all minimum criteria and became therefore members of ENPR-EMA. The Family Paediatricians Medicines for Children Research Network (FIMP-MCRN), established with the aim of developing competence, infrastructure, networking and education for paediatric clinical trials, became member of the ENPR-EMA responding satisfactorily to all the points of the self-assessment report. One of the objectives of the Paediatric Regulation (EC) No 1901/2006, is to foster high quality ethical research on medicinal products to be used in children FINPedNet (Finnish Investigators Network for Pediatric Medicines)EUNETHYDIS (the European Network for Hyperkinetic Disorders).EPOC (A European Paediatric Oncology off patent medicines Consortium)FIMP-MCRN (Family Paediatricians - Medicines for Children Research Network)UKPVG (United Kingdom Paediatric Vaccines Group)PENTA (Paediatric European Network for the Treatment of AIDS)MICYRN (Mother Infant Child Youth Research Network)Scotmcn (Scottish medicines for children network)GNN PRINTO MCRN-NL(Medicines for Children Research Network - The Nederland)Networks still having to clarify some issues before fulfilling criteria:EBMT (European Group for Blood and Marrow Transplantation)CLG (Children Leukemia Group)CICPed Networks currently not fulfilling minimum criteria:BPDN (Belgian Pediatric Drug Network)AMIKI EuroNeoNet JSWG of PRES (Juvenile Scleroderma Working Group Pediatric Rheumatology European Society)Neo-circulation (Network in Neonatology)PENTI (Paediatric European Network for the Treatment of Infection)RIPPS (R\u00e9seau d'Investigations P\u00e9diatriques des Produits de Sant\u00e9)IPCRN BLF (Swedish Peadiatric Society)NCCHD IPTA FUTURENEST CLINICAL RESEARCH ESPGHAN Once that was set up on ENPR-EMA with the inclusion of the 16 networks, it was considered necessary to think about the next step for its completion which provides for the organization of the Third Workshop on European Network of Paediatric Research at the EMA .The Workshop will be held in London from 11 to 12 March 2011 at the headquarters of the EMA and will be organized into two separate days.The first day of the workshop will be dedicated to discussions between networks to establish the Coordinating Group of ENPR-EMA and to discuss and to define priority tasks of the coordinating group.The second day is being organised with the assistance of TOPRA  where ENPR-EMA will be introduced to all stakeholders, particularly patient organisations and clinical researchers and pharmaceutical industry staff responsible for paediatric studies. The aim is to define the expectations of the various stakeholders and to offer the possibility for industry engaged in paediatric clinical trials and networks to interact.The main objective is to conduct clinical trials of pediatric medicines conducted on an ethical basis, with the methodological quality necessary and with the character of independent research .The EUPR wants to link together and coordinate existing networks, establish a platform for communication and exchange of information between European networks and share the skills and expertise in order to cut to shape and influence future development in paediatric research.The purpose of this article is to disseminate knowledge of the structure and the goals of ENPR-EMA and to highlight that networking is necessary to build up the competence, to make co-operation easier and to avoid duplication of studies.The Family Paediatricians Medicines for Children Research Network (FIMP-MCRN), established with the aim of developing competence, infrastructure, networking and education for paediatric clinical trials, became member of this European network. Quality and ethicality of research are becoming important end-points of Family Paediatricians during their education and during the sponsoring of health and prevention in the paediatric age groups. These possibilities could grant new paediatric medicine research opportunities and challenges for FIMP-MCRN and could guarantee further exchange of experience and competence, being an important wedge in the cultural mosaic of paediatric research .The author declares that he has no competing interests.EN conceived of and wrote the manuscript.Ettore Napoleone is the Chair of FIMP- MCRN (Family Paediatricians -Medicines for Children Research Network), Member of Paediatric Working Group AIFA  and Past President S.I.P  - Molise"}
{"text": "Myocardial infarction is a major cause of death and morbidity in many countries, including China. The aim of this study was to analyse a Mandarin Chinese translation of the Cardiac Depression Scale for a hierarchy of items according to the criteria of Mokken scaling.Data from 438 Chinese participants who completed the Chinese translation of the Cardiac Depression Scale were analysed using the Mokken scaling procedure and the 'R' statistical programme using the diagnostics available in these programmes. Correlations between Mandarin Chinese items and Chinese translations of the Hospital Anxiety and Depression Scale and the Beck Depression Inventory were also analysed. Fifteen items from the Mandarin Chinese Cardiac Depression Scale were retained in a weak but reliable Mokken scale; invariant item ordering was evident but of low accuracy and the Mokken scaled items of the Chinese Cardiac Depression Scale correlated with the Hospital Anxiety and Depression Scale and the Beck Depression Inventory.Items from the Mandarin Chinese Cardiac Depression Scale form a Mokken scale and this offers further insight into how the items of the Cardiac Depression Scale relate to the measurement of depression in people with a myocardial infarction. It is well recognised that myocardial infarction (MI) remains a major cause of death and morbidity in the West and has profound consequences on health-related quality of life (HRQoL) and this is strongly related to the depression experienced by people who have had an MI. A scale specific to the measurement of depression in MI, the Cardiac Depression Scale (CDS), has been developed  to overcThis study was designed to analyse the Ch-CDS using exploratory Mokken scaling  to invesThe Ch-CDS is a 25-item scale with a seven option Likert-type response format from 'Strongly agree to 'Strongly disagree'. Data, with reverse scored items re-coded, were entered into Statistical Package for the Social Sciences (SPSS) version 16.0 and imported into the Mokken scaling analysis for polytomous items (MSP) software . MSP is As previously explained, Mokken scaling is a method related to item response theory and recent publications -8 have ep < 0.05.The diagnostics required to evaluate Mokken scaling analyses include Loevinger's coefficient (H) which is used to select items from larger items sets into undimensional item clusters; H > 0.3 indicates weak scale with H > 0.4 indicating a medium scale and H > 0.5 a strong scale with higher values of H indicating greater accuracy in person ordering. The reliability of Mokken scales is estimated using Rho which is a test-retest reliability coefficient with Rho > 0.7 considered to indicate a reliable scale . A BonfeT) is used to investigate the accuracy of the ordering of the resulting item set [IIO exists where the order of items in a scale, ordered by mean item scores in a group of respondents, is the same at all levels of the latent trait being measured . The abiitem set ; values item set .p = 0.00026). The ordering of items from the most readily to the least readily endorsed runs from 'My memory is (not) as good as it should be' through lack of pleasure and getting less done worrying about dying and there being 'only misery in the future for me'. These 15 items showed IIO but this was at a very low level of accuracy (HT = 0.11). Pearson's correlation between the Ch-CDS scores on the Mokken scaled items and the Ch-HADS were -0.60 and -0.65 for the Anxiety scale and the Depression scale, respectively (p < 0.001) and with the Ch-BDI was 0.75 (p < 0.001). Taking the direction of scoring for both these instruments into account, these correlations indicate that the greater the level of depression rated using the Ch-CDS the greater the level of anxiety and depression rated using the Ch-HADS and the Ch-BDI.The results of the Mokken scaling analysis are shown in Table The present study has established that there is a unidimensional hierarchical arrangement of a sub-set of items from the Ch-CDS and that this scale shows concurrent validity when correlated with two separate measures of depression and anxiety. The scale has face validity in the sense that items with descriptors such as 'my problems are not over yet', 'I (don't) feel in good spirits' and 'I get hardly anything done', which are readily endorsed, represent less psychological distress than, items such as 'I feel like I'm living on borrowed time', 'the possibility of sudden death worries me' and 'there is only misery in the future for me'. The value of Mokken scaling has been demonstrated in that it relates the score on the Ch-CDS not only to the overall level of the latent trait but to a specific descriptor of the level of distress being experienced. This is analogous to previous work on Mokken scaling of the General Health Questionnaire 30 item version (GHQ-30)  where itThe Mokken scale derived from the Ch-CDS showed IIO but at a very low level of accuracy. This does not obviate the utility of the Mokken scale; it remains a useful instrument for ordering individuals on the basis of their total mean scale score. However, lack of accurate IIO means that the items are not, necessarily responded to in the same order across all levels of the latent trait by all respondents. Investigation of IIO for polytomous items-such as those in the Ch-CDS-is in its infancy with very few publications demonstrating this analysis. Ligtvoet et al  only recThe Ch-CDS Mokken scale derived here is useful but further development is possible to select items that show IIO and to confirm this structure using Mokken scaling . The MokA reliable hierarchy of 15 items within the 25-item Ch-CDS has been identified and this shorter scale has face validity and shows concurrent validity with two established measures of psychological distress. The scale is likely to have clinical utility and could be further developed by seeking items with IIO.BDI: Beck Depression Inventory; CDS: Cardiac Depression Scale; Ch-CDS: Mandarin Chinese translation of the CDS; GHQ-30: General Health Questionnaire 30 item version; HADS: Hospital Anxiety and Depression Scale; HRQoL: Health-related quality of life; IIO: Invariant item ordering; MI: Myocardial infarction; MSP: Mokken scaling analysis for polytomous items; SPSS: Statistical package for the social sciencesThe authors declare that they have no competing interests.RW conducted the Mokken scaling analysis and drafted the manuscript. WW participated in the design of the study and collected the data. DH provided expertise on the CDS and helped to draft the manuscript. CS participated in the design of the study and helped to draft the manuscript. DT conceived the study and participated in the design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript."}
{"text": "The abundant use of cross-sectional imaging has markedly increased the diagnosis of small renal masses (SRMs) . A stricRMB aims to determine eventual malignancy, type and grade of the evaluated SRM with high specificity and sensitivity for the presence of malignancy. The diagnostic accuracy of RMB has improved through the last years, as has been demonstrated in a recent meta-analysis by lane et al.  The authThe recent evolution of minimally invasive treatment options for SRMs highlights even more the important role of the RMB, before cryotherapy or RFA where no biopsy is possible . CT guidThe traditional concern of needle tract tumor seeding is based on only six reports published before 1993 . The majRepeat RMB is suggested in cases of a non-diagnostic result due to an inadequate or insufficient specimen . In ordeNowadays, RBM has become an established tool for the management of SRMs as indicated in the recent European Association of Urology (EAU) guidelines . It is r"}
{"text": "Most of the literature regarding communication between health professionals and patients at the end of life and their families has focused on specific topics, like breaking bad news and discussing treatment decisions such as CPR and advanced directives. Conversation about end-of-life issues often takes place over time rather than as a single discussion. The objective of this paper is to explore the optimal content and phrasing of information when discussing the dying process and E-O-L issues with terminally ill cancer patients and their families.We conducted focus groups and individual interviews with 20 palliative care patients and their families treated in Clinical Hospital Stip in the past 12 months. The focus groups and individual interviews were fully transcribed. Further individual interviews were conducted until no additional topics were raised. Participant's narratives were analyzed using qualitative methodology.Distinct content areas emerged for discussing E-O-L issues: treatment decisions at the E-O-L; potential future symptoms; preferences for place of death; the process of dying; what needs to be done immediately after death; and existential issues. When discussing process of dying participants are recommended: exploring the person's fears about dying; describing the final days and unconscious period; and the reduced need for food and drinks. Many participants identified the dilemma regarding whether to discuss potential complications around the time of death.This paper provides strategies, phrases and words that may inform about the process of dying and E-O-L issues. This will be useful especially for patients' families. Further research is needed to determine the generality of these findings."}
{"text": "In addition, the two-column format of PLOS ONE PDFs and typographic alignment of the PDF and online versions prevent some equations from being formatted correctly. Please view an alternative, correct version of the article here:"}
{"text": "Hepatitis C virus (HCV) is an important cause for the development of serious hepatic disease such as chronic hepatitis and liver cirrhosis. Though the pathological mechanisms are poorly understood, it is well established that CHC plays an important role in several immune mediated conditions, including rheumatoid arthritis. We focused on the clinical particularities of patients with CHC and associated RS and we specifically investigated the anti-inflammatory role of IFN-alpha concerning the rheumatic symptoms. Clinical particularities of patients with both CHC and RS can help identifying these patients as early as possible. A correct diagnose is needed especially due the complicated management of these patients as many drugs used for the rheumatic manifestations, including corticosteroid and immunosuppressive medication, can be harmful for the liver status .The results match the medical literature data as rheumatic manifestations are acknowledged to be more frequent in women [The age related distribution shows the predominance of the patients with CHC and RS belonging to the 5th decade of life.1]. On the other hand, studies indicate a higher incidence of rheumatoid arhtritis in patients belonging to the 4-5th decade of life but they also show that CHC is more frequent in the 6th decade of life :Body mass index was taken into consideration due to the fact that negative factors for the prediction of sustained virusological response include a high body mass index for various reasons [- decreased immunity - occurance of steatosis that reduces the response to interferon - negative impact on the pharmacokinetcs of interferon 3]: The clinical features of the CHC associated rheumatoid syndrome often resamble reumatoid arthritis .- the second form involves one or very few joints, especially large and medium ones :Certain studies focused on the immunoregulatory and anti-inflammatory properties of IFN-alpha suggesting a variety of mechanisms through which this drug might reduce the inflammatory process [- the ability of the IFN-alpha to reduce IL-1 - down-regulation of pro-inflammatory gene products- the induction of IL-10 - elevated response from the hypothalamic-pituitary-adrenal axisIn our study, the anti-inflammatory and immunoregulatory activity of the IFN-alpha is proven by the down-regulation of the inflammation marker levels and the benefit to the rheumatic symptoms for all patients that underwent this type of therapy. We statistically evaluated the common anamnestic particularities of 25 patients with CHC and RS who initiated treatment with Peg-IFN\u03b12a\u2013ribavirine, which are important in order to better understand the clinical profile of patients with CHC and RS for an early diagnose and treatment onset.Also, we investigated the evolution of the rheumatic symptoms and of the inflammation markers -erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)- at the beginning of treatment, 3 months later and at the end of therapy by reviewing their medical charts. The majority of patients in our study were women, mainly from the rural area and almost half of them were in their fifth decade of life. Body mass index varied but we mainly encountered normal weight patients.All patients experienced typical rheumatic inflammatory manifestations at the initial moment of our study including: symmetrical arthralgia concerning maximum 3 joints, of various intensity ; morning stiffness for less than 30 minutes; functional disability regarding each affected joint . The pattern of the RS for our selected patients mentained the joint symmetry, affected a small number of joints and involved especially medium joints. We focused on the inflammation process included in the pathology of CHC-related rheumatoid syndrome and also on the anti-inflammatory function of IFN-alpha that was the basic treatment for our patients. The results of our study show that, when used in the treatment of patients with CHC and associated rheumatoid syndrome, Peg-IFN\u03b12a anti-inflammatory activity can improve the rheumatic manifestations by down-regulating the inflammation markers and reducing the rheumatic inflammatory symptoms."}
{"text": "Obtaining Arnold tongues provides useful insight into the organization of mode-locking behavior of neurons under periodic forcing. In this study we obtained the regions of existence of various mode-locked states on the frequency-amplitude plane, which are called Arnold tongues, for Izhikevich neurons (see Figure Many neurons in the auditory system of the brain must encode amplitude variations of a periodic signal. These neurons under periodic stimulation display rich dynamical states including mode-locking and chaotic responses . PeriodiDifferent mode-locked regions that are shown in the Arnold tongues diagram are predictors of mode-locking of auditory system neurons to sound, which in turn predict the formation of harmonics and sub-harmonics of the sound in the brain."}
{"text": "In the Acknowledgments Section of the original Hypothesis & Theory article, the last sentence erroneously reported grant number FFI2014-61888-EXP as part of funds supporting the work. The only grant was #FFI2013-43823-P, provided by Spanish Ministry of Economy and Competitiveness.This error does not change the scientific conclusions of the article in any way.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Discharge of the term newborn is a critical issue in perinatal care. The average length of stay of the mother-infant dyad after delivery declined steadily from 1970 until the mid-1990s   have repThe recent pronouncements of scientific societies  and the"}
{"text": "It\u2019s well known that dental caries is one of the common diseases worldwide. Dental caries is manifested by demineralization of tooth tissue and results from carbohydrate metabolism of microorganisms that reside in the oral cavity. While fluoride supplementation has helped reduce caries rate, implementation of modern principles of the translational medicine may also help to reduce the impact of dental caries. Studies carried out in twins suggest that about 80% of factors contributing to dental caries inheritable. Physiological factors and functional tooth resistance are linked with centrifugal transport of dental fluid exchange. The phenomenon of Dental Fluid Transport is suggested to be a primary mechanism of the resistance to dental caries.The present study is intended to identify effective dental caries prohylaxis measures. Accordingly, the possibility of predictive personalized prevention of dental caries is studied on child population. In previous studies the bio-prediction test of dental enamel resistance (TER \u2013 test on enamel resistance) prior to dosed etching of enamel surface was used. It helped to identify the period of the year associated with decline of acid resistance of enamel (February - March) which is likely related to vitamin C. Subsequently, and based on these observations, a prophylaxis program was proposed and implemented. The program consisted of a 3 day administration of ascorbic acid in maximal doses for an age-specific group starting at the end of February. Yearly implementation of the program has reduced all the indicators of dental caries and has stabilized them at the point DMF 0.8 for the 12-year-old children. The program has included 100.000 subjects for 9 years. The results of the study have helped us to recommend a time-targeted predictive approach in dental caries prophylaxis programs.Continued efforts should help with:1. The establishment of unified diagnostic models for monitoring of persons from different dental caries risk groups by means of expanding of the bio-predictors including genotypic, allowing to make reasonable and appropriate diagnostics of preclinical process stages;2. The development of pharmacy-prevention measures for correction of the decline in dental functional resistance, giving the ability to offer an individual protocol of the targeted personalized predictive treatment to a specific individual."}
{"text": "PLOS ONE editors have identified a number of concerns about the article:The authors of the article \"Arsenic Sulfide Promotes Apoptosis in Retinoid Acid Resistant Human Acute Promyelocytic Leukemic NB4-R1 Cells through Downregulation of SET Protein\" recently requested the retraction of this publication. During the evaluation of this request, the Tumor Biology, published three days after the PLOS ONE article:The article reports the same work as the publication below in 4S4) promotes apoptosis in retinoid acid -resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET proteinTetra-arsenic tetra-sulfide :3421-30. doi: 10.1007/s13277-013-1452-1.PLOS ONE article includes an additional author as first author, Yuwang Tian, who has not been included in the author list of the publication in Tumor Biology. The first author was added to the author list of the PLOS ONE article after the manuscript had been editorially accepted and before its publication.The PLOS ONE without their knowledge by a contractor hired to edit the language and that the first author Yuwang Tian is not a member of their research team.We have followed up with the authors in relation to these concerns and they have indicated that the manuscript was submitted to PLOS ONE editors have contacted the Xi'an Jiaotong University to request an institutional investigation.In the light of the concerns about the duplicate publication of the same work and the difference in the author list for the two articles, the PLOS ONE editors are issuing this Expression of Concern to alert readers of the concerns about this publication. We will take further steps in relation to this article as necessary according to the outcome of the institutional investigation.The"}
{"text": "A number of observations have radically expanded our knowledge regarding the signaling pathways that regulate the tumor suppressor PTEN. These findings are derived from the molecular characterization of cancer-associated dominant-negative PTEN mutants, as well as the identification of alternative forms and intracellular localizations of PTEN.PTEN-null tumor cell lines or transgenic mice engineered to carry one wild-type (WT) copy and one null allele of PTEN (PTEN+/\u2212). However, a paper published in 1998 by the group of Eng and co-workers reported that PTEN loss-of-function mutations might not contribute to tumorigenesis to the same extent as the genetic loss of PTEN. This study was conducted on patients affected by Cowden disease, a PTEN hamartoma tumor syndrome, and revealed that patients with missense PTEN mutations in the phosphatase domain developed higher numbers of lesions compared to patients with truncating mutations (Cell (The lipid and protein phosphatase PTEN (Phosphatase and tensin homolog located on chromosome 10) is one of the most common tumor suppressors that is lost or mutated in several human cancers. Different mechanisms contribute to PTEN loss of function, which include post-translational modifications, interaction with other proteins, missense and truncation mutations, as well as gene deletions. The role of PTEN as an oncosuppressor has mainly been characterized through the study of different ns  transfer into the mitochondria and the initiation of apoptosis -based biosensor, which is capable of detecting signal-dependent PTEN conformational changes in live cells , may repThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics. A (GABAA) receptor agonists, alpha adrenergic receptor agonists, N-methyl-d-aspartic acid (NMDA) receptor antagonists, dopamine receptor antagonists and opioid receptor agonists operate to achieve the common function of reversible loss of consciousness  that prevents gross muscular response to a surgical incision in 50\u00a0% of patients. At around 0.3\u20130.5 MAC, the ability to respond to verbal commands is lost in 50\u00a0% of patients, and the onset of unconsciousness is reached. Above 1.0 MAC, immobility to noxious stimulus is achieved  to a neuron ranges from approximately 5600  to 60,000 (monkey motor) Cragg . A synapThe semblance hypothesis was developed to explain the basic mechanism of the formation of first-person internal sensations of various higher brain functions to which only the owner of the nervous system has access. Continuous quantal release of the neurotransmitter takes place all the time from single vesicles in the presynaptic terminals to the synaptic cleft. In addition, the arrival of an action potential at the presynaptic terminal triggers the release of a volley of neurotransmitter into the synaptic cleft. In both these conditions, the postsynaptic terminal develops potentials as a result of the release of the neurotransmitter from its presynaptic terminal. Activating the postsynaptic terminal in the absence of the release of the neurotransmitter from the presynaptic terminal was hypothesized to induce units of internal sensations generating semblance of the arrival of activity from the presynaptic terminal.Potentials arriving at the postsynaptic terminal through a LINK (the word \u201clink\u201d is highlighted to emphasize its importance) from the neighboring postsynaptic terminal can evoke units of internal sensations eliciting the semblance of the arrival of activity from the presynaptic terminal. An inter-postsynaptic functional LINK is expected to form between the abutted postsynaptic locations as a function of the simultaneous arrival of activity from two different sensory inputs during associative learning between two stimuli Fig.\u00a0a. The rePhenomenal properties of consciousness such as subjectivity and intentionality can be viewed only from a first-person perspective Velmans . ConscioThe dendritic spikes indicate that potentials are spontaneously generated at several postsynaptic terminals. The resistive properties of the long thin spine necks result in large potentials at the spine heads . There are two findings that need a matching explanation. First, the postsynaptic terminals are abutted to each other at the apical tuft area. The second one is the presence of surface or extracellular recorded oscillatory potentials. Since the oscillating potentials require a mechanism for their horizontal components, an innate mechanism whereby several postsynaptic terminals form islets of inter-LINKed postsynapses Fig.\u00a0 is expecPulvinar, mediodorsal, intralaminar and midline nuclei of the thalamus receive major inputs from cortical layers 5 and 6 and project back to the cerebral cortex to form cortico-thalamo-cortical pathways Guillery  that canContinuous formation of semblances occurs during dendritic spikes and other spontaneous activations of the postsynaptic terminals . The composition of all the background semblances induced in a modular fashion at different cortices in the resting state leads to the formation of C-semblance (the net semblance for consciousness) responsible for consciousness Fig.\u00a0 Vadakka. Since lThe inputs from both the thalamus and those that directly reach the cortex are expected to maintain an appropriate frequency of the oscillating potentials. Any disturbance in the inputs from the thalamus or the reticular formation can disturb consciousness, which is reflected in the frequency of the waveform of potentials recorded from surface or extracellular electrodes. This indicates that the conformation of net C-semblance occurring through the composition of units of internal sensations for the systems property of consciousness in the cortex is dependent on the frequency of oscillating potentials. Factors that regulate the optimal frequency of oscillatory potentials determine the optimal conformation of the C-semblance for consciousness. The computational process of composing the semblances that provides optimal conformation of C-semblance Vadakkan  requiresAlteration in consciousness is associated with a reduction in the frequency of surface oscillating potentials; this indicates that either the contribution of the horizontal component increases or that of the vertical component decreases. One of the potential sources of surface recorded potentials is the spontaneous activity at the dendritic spines (postsynapses) that lead to dendritic spikes at the apical tuft area of the cortices. Dendritic spikes that spread to other postsynapses through inter-postsynaptic functional LINKs are a candidate mechanism for the horizontal component of oscillating potentials. An innate mechanism that inter-LINKs several postsynapses is a possible method for the horizontal spread of potentials. Evidence that the discontinuous electroencephalogram (EEG) waveforms in very premature infants , an electrophysiological experimental finding that correlates with the surrogate behavioral motor activity indicative of the formation of the internal sensation of retrieved memories, helps us understand the probable mechanism of inter-postsynaptic functional LINK Vadakkan . SeveralPostsynaptic membranes at the lateral edges can get constantly exchanged with vesicle membrane lipid bilayer segments during exocytosis and endocytosis of the GluA1 subunits of one type of the glutamate receptors called \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors  of expected (four) lipid membrane layers  has to overcome a high energy barrier  of synapses that abut each other. This change in spine geometry is found to be critical in AMPA receptor expression  in the EEG. This state is termed paradoxical since the anesthetic, intended to induce unconsciousness, results in excitation  space. It is known that pressure in the middle ear can get transmitted to the perilymph and then to the cerebrospinal fluid (CSF) Martinez , primariHow does the pressure gradient arriving at the ECM reverse the anesthetic-induced inter-postsynaptic functional LINKs? Based on Le Chatelier\u2019s principle, when the pressure on a system at equilibrium is disturbed, the equilibrium position will shift in the direction necessary to reduce the pressure. One of the effects of increased pressure is the extrusion of anesthetic molecules from the lipid membranes to the ECM volume, and then these molecules get displaced through the paravenular space into the venous system. This in turn will reintroduce the hydrophilic region between the postsynaptic membranes, reversing the inter-postsynaptic functional LINKs induced by anesthetics Fig.\u00a0. ReversaThe gas phase pressure mechanism is based on Dalton\u2019s law of partial pressures that estimates the total pressure of a mixture of gases as the sum of the partial pressures of all the gases in the mixture. Gas phase pressure reversal can be made to occur by increasing the external pressure of the gas mixture, which will change the partial pressure of dissolved gases in the blood and eventually that of the extracellular matrix volume. During pressure reversal, partial pressure change reduces the solubility of anesthetic molecules and leads to their displacement from the lipid membranes into the ECM. In addition, the direct effect of external pressure on the middle ear that transmit through the perilymph, CSF, and paravascular space route as described for the effect of hydrostatic pressure can also occur. The displaced anesthetic molecules will then escape through the paravenular space into the venous system.The effect of externally applied pressure in non-anesthetized humans Bennett  and animThe internal sensation of memory was explained in terms of semblances induced by the reactivation of inter-postsynaptic functional LINKs (26). The LINKs that are readily reversible explain working memory. Since they mimic the readily reversible action of anesthetics, the inter-postsynaptic functional LINKs induced during associative learning can be considered to take place via direct contact between specific postsynaptic membranes by excluding the inter-membrane hydrophilic region between them. Knowing that the natures of inter-postsynaptic functional LINKs formed to explain working memory (specific ones) and anesthetic action (non-specific ones) are similar provides an opportunity to examine the effect of anesthetics on memory. Low doses of anesthetics leave very short-term memory intact, such that patients can carry on a conversation and appear to be lucid (Wang and Orser A low dose of isoflurane [one-fifth required for immobilization (nearly 0.2 MAC)] suppresses learning and the explicit memory of verbal cues in healthy volunteers (Newton et al. When the frequency of oscillating potentials is reduced both during sleep consciousness is altered (Alkire et al. An emerging consensus view on the possible link between Alzheimer\u2019s disease and anesthesia is being examined following reports by several studies of a positive correlation between them (Baranov et al. Disruption of the intactness of pachymeninges can prevent the external pressure from getting transduced through the CSF space to the paravascular space and finally to the ECM. This is expected to prevent the reversal effect contributed through the hydrostatic pressure.2. These inter-membrane interactions depend on the membrane lipid composition and the nature of anesthetic agents. Development of high-resolution imaging techniques that can resolve real-time changes at nanometer scales (Chen et al. The cellular changes of the anesthetic-induced inter-postsynaptic membrane functional LINK are a spectrum of changes, ranging from direct membrane contact to reversible, inter-postsynaptic membrane hemifusion restricted to very small areas of approximately 10\u00a0nmStudies of the effect of anesthetic molecules on artificial membrane hemifusion process can be conducted. Role of membrane proteins and lipid composition on membrane interactions can also be studied.The relationship between neurodegeneration and the use of anesthetics with different octanol/water coefficients, their MACs, duration of use and lipid membrane composition can be examined both by clinical studies and by laboratory experiments using peripheral blood cells or by using artificial membranes.The following investigations can be undertaken to test whether the mechanism provided in the present work can explain how anesthetics work.The problem of understanding the mechanism of anesthesia has been persisted since the mechanism for consciousness remained unknown. Even though a framework for consciousness was put forward earlier Vadakkan , it was"}
{"text": "LMNA are responsible for an aggressive form of dilated cardiomyopathy due to a high rate of malignant ventricular arrhythmias. Inter-cellular communication is essential for proper cardiac function. Mechanical and electrical activities must synchronize so that the work of individual cardiomyocytes transforms into the pumping function of the heart. This well-coordinated excitation-contraction coupling of the heart relies on an efficient inter-cellular communication, which is under the regulation of the intercalated discs. We focused on the understanding of the molecular mechanisms of components of intercalated disc re-localization in pathological context. For this, we investigated disease mechanisms and identify novel therapeutic targets, using an integrated series of models in cultured cells, mice and humans. Positive results will break new ground for future work towards developing novel treatment for malignant arrhythmias.Mutations in"}
{"text": "Evidence of guest migration in \u03b1-cyclodextrin-octylamine (\u03b1-CD-OA) inclusion compound (IC) generated via plasmonic heating of gold nanoparticles (AuNPs) has been studied. In this report, we demonstrate local effects generated by laser-mediated irradiation of a sample of AuNPs covered with inclusion compounds on surface-derivatized glass under liquid conditions by atomic force microscopy (AFM). Functionalized AuNPs on the glass and covered by the ICs were monitored by recording images by AFM during 5\u00a0h of irradiation, and images showed that after irradiation, a drastic decrease in the height of the AuNPs occurred. The absorption spectrum of the irradiated sample showed a hypsochromic shift from 542 to 536\u00a0nm, evidence suggesting that much of the population of nanoparticles lost all of the parts of the overlay of ICs due to the plasmonic heat generated by the irradiation. Mass spectrometry matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) performed on a sample containing a collection of drops obtained from the surface of the functionalized glass provided evidence that the irradiation lead to disintegration of the ICs and therefore exit of the octylamine molecule (the guest) from the cyclodextrin cavity (the matrix).The online version of this article (doi:10.1186/s11671-016-1322-z) contains supplementary material, which is available to authorized users. Due to the strong electric fields at the surface, absorption and scattering of electromagnetic radiation by noble metal nanoparticles is enhanced robustly. These unique properties provide the potential for designing novel optically active reagents. The use of nanoparticles in medicine is one of the important directions being taken by current research in nanotechnology. Their applications in drug delivery, cancer cell diagnostics and therapeutics have been the active fields of research \u20136. PlasmOn the other hand, in the nanoscience field, cyclodextrins (CDs) have been used to prepare AuNPs capped with thiolated \u03b1- and \u03b2-CDs  for the 2) are available to interact with the particles thus stabilizing them + and [M\u2009+\u2009K]+, respectively. The presence of cyclodextrin and the absence of OA in the aqueous phase corroborate the disintegration of ICs. This finding is consistent with the absence of the corresponding signal of dimmer IC  or fragmented IC .It was possible to confirm the release of ICs from the AuNPs surface, due to the plasmonic heat of the irradiated nanoparticles, by observing a decrease in the height of the AuNPs using AFM and by observing one hypsochromic shift of the plasmon band using UV-Vis spectrophotometry.Analysis of the water drop on the surface of the irradiated glass using MALDI-TOF verified that the plasmonic heat led to the loss of the guest because the nominal mass corresponded only to \u03b1-CD and traces of OA.This study provides the first evidence of the disintegration of an inclusion compound due to local heating of AuNPs by laser irradiation at a wavelength tunable with the plasmon, thus separating ICs from the AuNPs surface. By using other methodologies as NMR is difficult to set up the irradiation and the observation at the same time which could lead to the reversion of the process forming the IC and or the AuNP-IC system. The release of the guest molecule may be relevant in the field of drug delivery where spatial and temporal control of the release of a guest from an inclusion complex is desired. Moreover, we designed a methodology that could serve as a screening method to test the release of drugs based on the photothermal effect."}
{"text": "Non-invasive ablation and hyperthermia treatments of abdominal organs using High Intensity Focused Ultrasound (HIFU) still impose severe challenges. Especially for liver and kidney treatments, the target motion and accessibility over the entire respiratory cycle make the application of HIFU difficult. To allow for a safe, effective, and efficient treatment, detailed planning and monitoring of the intervention is needed. Current general-purpose physics simulation software cannot fulfill the real-time requirements of the therapy-monitoring application. Our goal is to improve this by numerical simulation to allow for fast and accurate treatment planning and real-time detection of motion-induced risks during HIFU-therapy.We developed a method to numerically simulate HIFU using patient-specific motion information in real time. The bio-heat equation describing the temperature distribution in the patient is mathematically transformed to a static reference anatomy. The numerical solution can then be performed in the reference anatomy on a static computational domain. Patient-specific respiratory motion information is provided by an abdominal motion model that can be fed with sparse tracking data in the clinical setting. The respiratory motion is modelled allowing sliding motion of the inner organs along the abdominal wall.Motion information is fed into the simulation by an unstructured moving point cloud. On top of this point cloud a tetrahedral mesh is build to interpolate the motion information. The mesh is split at the abdominal wall into individually moving parts to allow the sliding motion of the liver along the abdominal wall. The numerical simulation thereby resolves the sliding boundary and allows the prediction of the temperature rise also in the beam path between transducer and target. Fast US beam steering is simulated using ultrasound pressure field pre-computations for key states over the respiratory cycle. Any remaining location mismatch between closest pre-computation and actual target location is compensated using an additional transformation. The numerical simulation method is integrated into a HIFU-therapy planning tool. Based on image data the target volume, anatomical and risk structures are defined. Treatment planning is then performed guided by direct feedback from the numerical simulation including respiratory motion of the domain. Using the feedback from the simulation, the user can manually optimize transducer and target location and HIFU parameters.The method accounts for patient-specific anatomy and motion information in real time. Sliding motion of the inner organs along the abdominal wall is accounted for by the simulation. The transformation to the static reference frame results in an accurate scheme for long simulation durations. The developed method can be a possible important building block for HIFU-therapy planning and conduction in moving organs."}
{"text": "The access of high-technology medicines in Russia is restricted for such reasons as pricing and reimbursement policy, medical indications and many others. Most difficulties are presented in children because of a lack of clinical data about effectiveness and safety.The objective of the study was to evaluate acceptability, affordability and availability of high technology medicines and provide the practical recommendations for optimization of their access in Russia ).A retrospective non-interventional study of JIA patients  for assessment of clinical and economical effectiveness of biologics and disease-modifying therapy[Availability: six biologics  were available for patients with JIA in Russia. Two of them (Infliximab and Rituximab) were used off-label. Affordability: direct medical costs for therapy including biologics were nine times higher than for disease-modifying drugs. Price nAcceptability: expert survey has shown that there is a very long patient journey for administration of biologics for advanced forms of JIA in patients with proved disability. There is a restriction of access to biologics on a regional level.There is an improvement of affordability of high-technology medicines in Russia thanks to development of the methods of health technology assessment."}
{"text": "To our knowledge, the use of point-of-care ultrasound for detecting a fish bone in the cervical esophagus has never previously been reported in the English literature.We herein report the case of the accidental ingestion of a fish bone which was detected in the cervical esophagus by means of point-of-care ultrasound. A-70-year-old woman presented at the emergency department of our hospital with odynophagia in the neck after eating a slice of grunt (a type of fish) simmered in broth. Prior to this presentation she had already undergone direct laryngoscopy without any fish bone being identified at an otorhinolaryngology clinic. Point-of-care ultrasound was thereafter performed. As a result, a linear and hyperechoic structure was thus identified in the cervical esophagus. The structure did not seem to penetrate the wall of the esophagus. Computed tomography confirmed the same finding without any penetration. An endoscopic examination revealed a fish bone stuck in the cervical esophagus. The bone measured 17 mm in length, and was safely removed under endoscopic guidance. Subsequently the patient demonstrated a good recovery without any complications.We describe the identification of a fish bone in the cervical esophagus using point-of-care ultrasound. Point-of-care ultrasound may therefore be a useful modality for both detecting the presence of fish bones in the cervical esophagus and also for confirming the existence of any complications.The study was conducted in accordance with the ethical standards dictated by applicable law. Informed consent was obtained from each owner to enrolment in the study and to the inclusion in this article of information that could potentially lead to their identification."}
{"text": "Men who have sex with men (MSM) are at increased risk of HIV and other STI infections in Nigeria. This is because MSM are afraid to seek medical help because the healthcare workers in various facilities are afraid of the consequences if they provide services for MSM citing the law as a reason not to intervene. MSM in northern states of Nigeria are facing double-jeopardy because the few international partners working in MSM in Nigeria are pulling out of these volatile areas because of the fear of attacks by the Boko Haram and the Nigerian law enforcement agencies.The intervention was conducted to promote affordable and sustainable HIV care and treatment for MSM in Nigeria.This intervention was conducted in the Boko Haram ravaged cities of Kano and Maiduguri (North-East Nigeria). Twenty MSM-key influencers from the two cities were identified and trained on HIV counselling and testing, caregivers, case managers and on initiation process for ARV treatment for new HIV+MSM as well as ethical considerations.The mean age of the key influencers was 24 years +/\u2212SD. Each of the trained 20 key influencers reached 20 MSM-peer with condom promotion, HCT, referral to identified MSM-community health centers and follow-up/caregiving within the space of one month. The project was able to reach 400 MSM in the two cities. 89% of the peers consented to HCT. HIV prevalence among the participants was at 18%. The project recorded ARV-successful referral to healthcare facilities for the respondents that tested positive. The key influencers have been following up for ARV-adherence.Use of community members should be promoted for sustainability and ownership. It also helps in eradicating socio-cultural barrier to HIV intervention for MSM. Moreover, this proves to be one of the safest and affordable methods of reaching MSM in Nigeria in this ugly time of legalization of homophobia in the country's constitution."}
{"text": "This article studies the viscous flow and heat transfer over a plane horizontal surface stretched non-linearly in two lateral directions. Appropriate wall conditions characterizing the non-linear variation in the velocity and temperature of the sheet are employed for the first time. A new set of similarity variables is introduced to reduce the boundary layer equations into self-similar forms. The velocity and temperature distributions are determined by two methods, namely (i) optimal homotopy analysis method (OHAM) and (ii) fourth-fifth-order Runge-Kutta integration based shooting technique. The analytic and numerical solutions are compared and these are found in excellent agreement. Influences of embedded parameters on momentum and thermal boundary layers are sketched and discussed. The fundamental problem of two-dimensional flow due to stretching plane surface, initially discussed by Crane The literature cited above deals only with the case of either linearly or exponentially driven velocity of the sheet. Vajravelu To our knowledge, the three-dimensional flow due to non-linearly stretching sheet has not been yet reported. It is obvious that three-dimensional flows can be appropriate in giving more clear physical insights of the real world problem when compared with the two-dimensional flows. The present work is therefore undertaken to fill such a void. The study also assumes that the temperature across the sheet is non-linearly distributed. Introducing a new set of similarity variables the boundary layer equations are first reduced into self-similar forms and then solved both analytically and numerically. It is pertinent to mention that computation of either approximate analytic or numerical solutions of the boundary layer equations governing the flow and heat transfer is often challenging  and (12) in Eq. (11), one obtainsvely see . The verThe non-linear differential and the auxiliary linear operators are selected as belowIf By Taylor's series expansion one obtainsmth-order deformation equations corresponding to Eqs. (7)\u2013(10) are as belowSubstituting In order to determine the optimal values of Minimize of the software MATHEMATICA (see Liao Such kind of error has been considered in other works st order ODEs by substituting Eqs. (7)\u2013(9) subject to the boundary conditions (10) have been solved numerically by shooting method with fifth order Runge-Kutta integration procedure. First, we reduce the original ODEs into a system of 1and the corresponding initial conditions areSuitable values of the unknown initial conditions th-order OHAM solutions for temperature This section contains the physical interpretations of the behavior of the interesting parameters entering into the problem. We compare the 15For the first time, the flow and heat transfer over a plane surface stretched non-linearly in two lateral directions have been investigated. The simulation in this study assumes that the temperature across the sheet is non-linearly distributed. Both analytic and numerical solutions are obtained and found in excellent agreement. Following are the major results of this study.I. It is seen that shear stress at the wall increase when the stretching rates ratio is increased. The entrainment velocity is negative, representing a downward flow in the vertical direction, which is a consequence of the bi-directional stretching sheet.II. The increased intensity of the cold fluid at the ambient towards the stretching sheet with an increase in stretching rates ratio III. The temperature decreases and thermal boundary layer thins when the power-law index IV. The results for the case of two-dimensional and axisymmetric flows can be obtained as special cases of present study when"}
{"text": "Despite more than a century of dedicated research, the etiology and pathogenesis of AIS remain unclear. By definition, 'idiopathic' implies an unknown cause. Nevertheless, many abnormalities concomitant to AIS have been described, often with the suggestion that these abnormalities are related to etio-pathogenesis. Insight in the concomitant abnormalities may assist in improving the understanding of the etiological pathways of AIS. For understanding of the etiology of adolescent idiopathic scoliosis (AIS), this systematic review gives as complete an overview as possible of abnormalities that have been implicated to be concomitant with AIS.Original studies comparing untreated AIS patients with healthy adolescents on abnormalities other than the deformity of the spine were retrieved from PubMed and Embase. We followed PRISMA guidelines and to quantify the relationship between each abnormality and AIS we used a best-evidence-syntheses for relating risk-of-bias to consistency of effect sizes.We identified 88 relevant citations, forty-seven carried high risk-of-bias and twenty studies did not report quantitative data in a sufficient manner. The remaining twenty-one publications failed to report data from before initiation of the deformity and blind assessments. These cross-sectional studies provided data on fourteen abnormalities concomitant to AIS. With our best-evidence-syntheses we were unable to find both strong evidence and a consistent pattern of occurrence for AIS and any of these abnormalities. From moderate risk-of-bias studies a relatively consistent pattern of occurrence for AIS and impaired gait control  and decreased bone mineral density  was found. For nine abnormalities a consistent pattern of occurrence with AIS was found, but the evidence for these was weak.Based on the available literature, strong evidence is lacking for a consistent pattern of occurrence of AIS and any abnormality. In addition, abnormalities were never studied before the onset of the deformity. The relevance for understanding the multifactorial etiology of AIS is very limited."}
{"text": "Spontaneous activity as recorded by fMRI has often been used to infer active connections  in the human brain through correlations of activity measures. Some serious questions have been raised about the interpretation of these correlations, which are often apparent only on time scales of tens of seconds. Confirmation of correlations in measures of activity on shorter time-scales closer to those of neural activity would be very desirable.Numerous mechanisms have been proposed for various rhythms but in the past half-century little consensus has been reached on the mechanism of any major rhythm. The recent development of high-throughput imaging methods enable us for the first time to rigorously and quantitatively test ideas about the dynamics of brain rhythms.We have generated high-resolution data on neural activity over most of one hemisphere of mouse cortex by voltage-sensitive dyes, in both anesthetized and awake animals. In previous work  we have Our results suggest that similar methods can be used with data generated by the new high-throughput technologies anticipated by the BRAIN initiative, to understand communication between brain regions at time scales of neural computation."}
{"text": "There is not any evidence of previous publications about the matter in our country.To observe if a sample of 4The students completed a questionnaire before and after a 2-hour practical lesson about ultrasound. The surveys were divided in three parts: a) questions about theoretical and practical knowledge about ultrasound using a 5-point Likert scale of perceived importance ; b) list of structures and pathologies that the students were able to detect by using the ultrasound; c) open-ended questions and comments. The statisitics are presented as percent means or proportions with p-values from t-testing.Significant improvements in knowledge about ultrasound were observed, comparing the pre- and post-practical tests (the number of structures and pathologies detected increased). The intervention also increased their perceived importance of this diagnostic tool.The students increased their level of knowledge about ultrasound, as well as the level of the perceived importance of its use in medical practice. It would be interesting to conduct more educational sessions on this diagnostic tool, including the introduction of ultrasound in different subjects, including anatomy and physiology during the pre-clinical years of training, in our country as it is done in other countries."}
{"text": "The evaluation of innovation from early to late phase studies requires appropriate selection and reporting of outcomes. These are well defined for pharmaceutical interventions, but much less well considered for non-pharmaceutical interventions such as surgery. We report a new method - an evolution review - to understand and document the evolution of outcomes reported at each stage of evaluation of novel surgery from first in human to pragmatic multi-centre RCTs.A search strategy identified all search terms for precursors and derivatives of a novel surgical intervention and was run in Embase and Medline. Abstracts with primary data were included and ordered chronologically, sequentially numbered and then grouped by year. We identified the year of publication of the first-in-human study and used that year to begin the sampling. Three publications were sampled from each year after randomly ordering. An additional sample equal in size to the previous sample was randomly sampled from the remainder. This methodology was chosen as the initial sample ensured representation of each year studied and the second sample added weight to years where there was a higher frequency of studies published.This new methodology - which we have termed an \u2018evolution review\u2019 - aims to use this information to inform guidelines for outcome reporting during the evolution of surgical interventions."}
{"text": "There are two errors in the RP-1164 row and Nucleotide Change and Protein Change columns of"}
{"text": "The Stimulus-Response (S-R) theory and Tolman's Cognitive Theory of behavior control both issued from behaviorism in the early 20th century still provide a relevant general framework to account for animal reward-based adaptive behavior. In this paper, we propose a new paradigm for representing and implementing both the cognitive strategy and the S-R habit strategy within a unitary coding frame. Based on a parallel learning of both strategies, the model explains how the fast learning cognitive strategy can supervise and accelerate the slow learning S-R habit strategy; and also how. In late learning stages, the habit strategy can overcome the cognitive. This parallel representation is inspired by the cortico-basal functional loops  and the The implementation of S-R habit strategy is based on a neural modified version of the classical Q-learning and is based on the model of , emulatiThe model exploits this speed difference in its parallel learning. The fast acquisition of the cognitive map allows the robot to quickly choose correct paths to the goal, and thus the time convergence of the Q-learning algorithm is optimized. The cooperation is based on the biasing of the selected transition by the cognitive map and the Q-learning in parallel (see Figure"}
{"text": "There is an error in the fifth sentence of the Abstract. The correct sentence is: In total, 288 up-regulated DEGs and 106 down-regulated DEGs were identified.There is an error in the third sentence of the Results section under the heading \u201cGO and pathway enrichment analyses of DEGs.\u201d The correct sentence is: Specifically, the DEG distribution in the pathway of Metabolism of xenobiotics by cytochrome P450 was shown in Fig 2."}
{"text": "Stem cells are undifferentiated cells with the ability to self-renew and the potential to differentiate into all body cell types. Stem cells follow a developmental genetic program and are able to respond to alterations in the environment through various signaling pathways. The mechanisms that control these processes involve the activation of transcription followed by a series of post-transcriptional events. These post-transcriptional steps are mediated by the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs creating a regulatory gene network. Characterizing these RNA-protein networks is essential to understanding the regulatory mechanisms underlying the control of stem cell fate. Ribonomics is the combination of classical biochemical purification protocols with the high-throughput identification of transcripts applied to the functional characterization of RNA-protein complexes. Here, we describe the different approaches that can be used in a ribonomic approach and how they have contributed to understanding the function of several RBPs with central roles in stem cell biology. Stem cells are undifferentiated cells that are found in multicellular organisms both throughout embryonic development and in adult tissues. These cells have the ability to self-renew and the potential to differentiate into all body cell types. This plasticity makes stem cells especially attractive for use in cell therapies.Embryonic stem cells respond to and follow a developmental genetic program that is triggered by a complex cascade of regulatory molecules. Adult stem cells remain in small amounts in adult tissues, where they are responsible for tissue repair and homeostasis  method involves the fusion of a double-tag either at the amino or carboxy terminus of the protein followed by transfection of the studied cell type Figure . In vivoRNA targets of RBPs have been identified by immunoprecipitation assays, followed by genomic analysis using microarrays, known as RIP-Chip (RNA ImmunoPrecipitation and microchip hybridization), or more recently using next-generation sequencing methods, RIP-Seq Figure  Tenenba, 2014. TOne major unwanted output of these techniques is the co-purification of non-specific and usually abundant transcripts. To isolate only specific transcripts that are bound by RBPs, different strategies have been developed to improve the RIP analysis. The refinement of this technique involves the cross-linking of RNA-protein complexes prior to purification (CLIP) Figure . UltraviTo map the binding site, RNA is digested up to a length of ~50 nt, reverse transcribed after RNA adapter ligation, and amplified to prior sequencing. One limitation is represented by the low efficiency of crosslinking using UV light. PAR-CLIP (PhotoActivatable Ribonucleoside-enhanced CrossLinking and ImmunoPrecipitation)  protein is essential for the maintenance of viable stem cells. This protein is expressed in human embryonic stem cells, where the population of associated mRNAs was identified  is responsible for fragile X syndrome. FMRP contains multiple domains that directly interact with RNA  mechanisms with alternative splicing regulation. In mouse embryonic stem cells, a stringent purification method was used when iCLIP libraries were generated by sequential Flag and HA tag immunoprecipitation . The Musashi proteins are found in stem and progenitor cells and are overexpressed in several cancer cells, with a well-defined role in the regulation of the undifferentiated state. A pulldown assay (RNA bind and seq) using RNA from mouse neural stem cells identified the population of MSI1-bound transcripts  proteins are mRNA regulators with a conserved role in the maintenance of mitotic division, resulting in the self-renewal of stem cells  of their respective transcriptomes  (Galgano et al., Our group was able to identify approximately 300 putative PUM2 targets in adipose-derived stem cells using RIP-Chip Figures  Shiguno. CellulaIn another study from our group, we evaluated the total RNAs and polysome-associated mRNAs in adipose-derived stem cells using polysome profiling (Spangenberg et al., The identification of which RNAs are associated with post-transcriptional regulatory proteins and the genetic network that they form is important to understand the essential steps in stem cell differentiation and the mechanisms that are responsible for the maintenance of the undifferentiated state. The combination of affinity purification methods and large-scale identification of transcripts, plus the development of powerful bioinformatics tools will lead to a systematic characterization of these networks. Though much effort has been devoted to this challenge, there is still much work in the future that is needed to understand the complex mechanisms underlying post-transcriptional regulation.The authors contributed equally to write the mini review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Exposure to the trauma memory is the common denominator of most evidence-based interventions for posttraumatic stress disorder (PTSD). Although exposure-based therapies aim to change associative learning networks and negative cognitions related to the trauma memory, emotional interactions between patient and therapist have not been thoroughly considered in past evaluations of exposure-based therapy. This work focuses on recent discoveries of the mirror-neuron system and the theory of embodied simulation (ES). These conceptualizations may add a new perspective to our understanding of change processes in exposure-based treatments for PTSD patients. It is proposed that during exposure to trauma memories, emotional responses of the patient are transferred to the therapist through ES and then mirrored back to the patient in a modulated way. This process helps to alleviate the patient's sense of loneliness and enhances his or her ability to exert control over painful, trauma-related emotional responses. ES processes may enhance the integration of clinical insights originating in psychoanalytic theories\u2014such as holding, containment, projective identification, and emotional attunement\u2014with cognitive behavioral theories of learning processes in the alleviation of painful emotional responses aroused by trauma memories. These processes are demonstrated through a clinical vignette from an exposure-based therapy with a trauma survivor. Possible clinical implications for the importance of face-to-face relationships during exposure-based therapy are discussed. Exposure to the memory of the traumatic event is the common denominator of most evidence-based interventions for posttraumatic stress disorder (PTSD) and is included in the guidelines for the treatment of PTSD set by the International Society for Traumatic Stress Studies and by the Veterans Health Administration and Department of Defense  emotions are shared thus creating a sense of \u201cwe-ness\u201d in the therapy; and 2) emotions are modulated in a way that simultaneously reduces fear as well as enhances regulation of a wider range of feelings. The interpersonal aspects of exposure therapy, as discussed above, may require an additional skill set for the therapist to further enhance the practice of exposure in psychotherapy for PTSD."}
{"text": "Increasingly, health policy-makers and managers all over the world look for alternative forms of organisation and governance in order to add more value and quality to their health systems. In recent years, the central government in England mandated several cross-sector health initiatives based on collaborative governance arrangements. However, there is little empirical evidence that examines local implementation responses to such centrally-mandated collaborations.Data from the national study of Health Innovation and Education Clusters (HIECs) are used to provide the first comprehensive empirical evidence about the implementation of collaborative governance arrangements in cross-sector health networks in England. The study employed a mixed-methods approach, integrating both quantitative and qualitative data from a national survey of the entire population of HIEC directors , a group discussion with 7 HIEC directors, and 15 in-depth interviews with HIEC directors and chairs.The study provides a description and analysis of local implementation responses to the central government mandate to establish HIECs. The latter exemplify cross-sector health networks characterized by a vague mandate with the provision of a small amount of new resources. Our findings indicate that in the case of HIECs such a mandate resulted in the creation of rather fluid and informal partnerships, which over the period of three years made partial-to-full progress on governance activities and, in most cases, did not manage to become self-sustaining without government funding.This study has produced valuable insights into the implementation responses in HIECs and possibly other cross-sector collaborations characterised by a vague mandate with the provision of a small amount of new resources. There is little evidence that local dominant coalitions appropriated the central HIEC mandate to their own ends. On the other hand, there is evidence of interpretation and implementation of the central mandate by HIEC leaders to serve their local needs. These findings augur well for Academic Health Science Networks, which pick up the mantle of large-scale, cross-sector collaborations for health and innovation. This study also highlights that a supportive policy environment and sufficient time would be crucial to the successful implementation of new cross-sector health collaborations."}
{"text": "Selenium (Se) is an important trace element for human physiology. It has anti-inflammatory, anti-neoplastic and anti-aging properties and protects from oxidative stress . It is pLow concentrations of Se were shown in patients with Graves' disease . Higher The influence of Se on goitrogenesis and carcinogenesis in the thyroid gland is still unclear. The data on effect of low Se levels in patients with goiter and thyroid nodules are divergent ,10. In vConclusive results about the undisputable role of Se in the treatment of thyroid related diseases, including hyperthyroidism or thyroid orbitopathy, on a wider scale are still unavailable and further research is both required and recommended."}
{"text": "With the launch of our journal, we aim to fill this gap and provide a forum for interdisciplinary research articles that specifically address computational approaches in drug-design and multi-scale analysis of bioactive substances from the cellular up to behavioral level."}
{"text": "Femtosecond X-ray irradiation of solids excites energetic photoelectrons that thermalize on a timescale of a few hundred femtoseconds. The thermalized electrons exchange energy with the lattice and heat it up. Experiments with X-ray free-electron lasers have unveiled so far the details of the electronic thermalization. In this work we show that the data on transient optical reflectivity measured in GaAs irradiated with femtosecond X-ray pulses can be used to follow electron-lattice relaxation up to a few tens of picoseconds. With a dedicated theoretical framework, we explain the so far unexplained reflectivity overshooting as a result of band-gap shrinking. We also obtain predictions for a timescale of electron-lattice thermalization, initiated by conduction band electrons in the temperature regime of a few eVs. The conduction and valence band carriers were then strongly non-isothermal. The presented scheme is of general applicability and can stimulate further studies of relaxation within X-ray excited narrow band-gap semiconductors. Intense ultrashort radiation available at the free-electron-laser (FEL) facilities all over the world12346810111213However, this experimental scheme also opens possibilities to extract information about the physical processes following the relaxation of the laser-excited materials. Similar techniques have been used in two-color experiments with optical lasers to extract information on the electron-phonon coupling coefficient1617In this study we revisit the results of the experiments measuring the transient optical reflectivity in GaAs irradiated with femtosecond pulses of soft and hard X-ray radiation8Electronic excitation and relaxation processes following the FEL irradiation of solids are well understood2324However, thermalization between the valence and conduction band may take longer time than the carrier thermalization within the conduction band. The relation between these two timescales depends on the ratio of the effective masses of holes and electrons. In GaAs holes are almost Already after the appearance of first photoelectrons within the conduction band, the energy exchange between free carriers and lattice starts. In semiconductors the timescale of this process In this work we show that the experimental data on the transient reflectivity allow to follow in time the relaxation of FEL excited GaAs on timescales up to a few tens of picoseconds. We follow the ideas from the optical measurements described in refs 17Our proposed theoretical framework uses rate equations to describe the evolution of electron distribution as a function of time. The rate equations are coupled with the two-temperature modelet al.et al.In experiments with X-ray FELs8Both experiments observed a centeracteristic shape of transient reflectivity curve, ectivity . These cectivity . In whatWith our modeling tool we performed simulations of the transient reflectivity changes within GaAs for the experimental conditions as described in refs First, we estimated the final electron-hole density after FEL irradiation, knowing the pulse fluence and the photoabsorption cross section at a given photon energy. We then followed the increase of the electron-hole density until the maximal density was reached. Such behaviour is typical for FEL irradiated semiconductors as described, e.g., in24After the maximal electron-hole density is reached, the system starts to relax. Electron-lattice thermalization and electron-hole recombination are the predominant relaxation channels. In GaAs the latter one contributes less significantly, as the typical recombination timescales are of the order of The extended Drude model including the interband contribution is used to calculate the transient reflectivity change from the dielectric function, where The average electron collision time Rate equations describe the changes of electron-hole density due to ionization and recombination processes. Heat capacities of the free-electron gas from ref.  . Plots  show theThe ultrafast drop and rise of optical reflectivity is due to the production of electron-hole pairs in the irradiated semiconductors as described in ref. et al. that lead to an overcritical electron density. However, at the pulse fluences close and larger than the one leading to the critical electron density, the minimum of The theoretical calculations shown in At a 400\u2009nm probe-pulse the interband absorption coefficient is about 100 times larger than at 800\u2009nm2121As we have discussed above, the centeracteristic time of the overshooting directly follows the timescale of the band-gap shrinking. The experimental data on reflectivity change can then be used to determine the electron-lattice thermalization time. Experimental studies of electron-phonon coupling and electron-lattice thermalization time have been extensively performed in metals1541424344171848493843515253545657N is the number of the available experimental points. The values of thermalization time and electron temperature presented in Here, we apply our model to the experimental data to extract information on the electron-lattice thermalization time in GaAs. In et al.) at the pulse fluence of 2 are The values of The estimated electron temperature at the end of the electron thermalization ."}
{"text": "The structure of synaptic connectivity plays an important role in information processing and dynamics of neuronal microcircuits. Previous work has shown that cortical microcircuits contain non-random features of the network structure , and thaA subpopulation of connected hubs can be analyzed using common mean-field methods. This analysis reveals two stable fixed points of the spiking activity, one at a low firing rate and another one at a high firing rate.We first model a single layer of a column of rodent barrel cortex. The subpopulation of connected hubs switches between the two fixed points and generates up-state/down-state oscillations (see Figure"}
{"text": "The concept of specificity of exercise prescription and training is a longstanding and widely accepted foundation of the exercise sciences. Simply, the principle holds that training adaptations are achieved relative to the stimulus applied. That is, the manipulation of training variables  directly influences the acute training stimulus, and so the long-term adaptive response (Young et al., one-size-fits-all approach to post-exercise recovery is likely to contribute to contrasting reports of the efficacy of many techniques. While these concerns could indicate the need for greater understanding of the mechanistic demands of specific exercise tasks and post-exercise recovery protocols so to be suitably matched, they are of great consequence in applied settings where maladaptation may be the result of inappropriate recovery practices (Kentt\u00e4 and Hassm\u00e9n, Despite the emphasis that is placed on specificity in the application of the desired training stimulus, it is noteworthy that this concept receives less attention within the post-exercise recovery literature. Indeed, most recovery strategies are intended to treat only symptoms of exercise-induced muscle damage by blunting inflammatory responses associated with disturbances to the structural integrity of the exercised musculature (Minett and Duffield, The research narrative surrounding post-exercise cooling for recovery reflects this point. A derivative of the use of ice as a therapeutic treatment of soft tissue injuries, the proposed benefits of acute cooling interventions on recovery after exercise relate to peripheral vasoconstriction centralizing blood volume away from exercised musculature (Bleakley and Davison, Irrespective of whether post-exercise cooling benefits recovery through the treatment of exercise-induced muscle damage or through other means, the specificity of administration of this intervention becomes key. Most pertinent, changes in circulatory dynamics and muscle metabolism as a result of post-exercise cooling (Vaile et al., The topic of post-exercise recovery from training has been the focus of recent attention in both narrative (e.g., N\u00e9d\u00e9lec et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This data article presents the differences observed between the myristoylated and non-myristoylated forms of the neuronal calcium sensor protein, neurocalcin delta (NCALD). Analysis of the myristoylated and non-myristoylated versions of the protein by mass spectrometry provided difference in mass values consistent with addition of myristoyl group. In the presence of calcium, mobility retardation was observed upon electrophoresis of the protein in native gels. The retardation was dose-dependent and was exhibited by both the myristoylated and non-myristoylated forms of the protein. Value of the data\u2022The relevance of myristoylation to the biological functions of Neuronal Calcium Sensor (NCS) proteins remains to be elucidated.\u2022Data is presented on the myristoylated and non-myristoylated forms of NCALD assessed by calcium-induced mobility shift assay.\u2022The calcium-induced mobility shift assay may be useful in assessing the contribution of myristoylation and other post-translational modifications to response of all NCS proteins to calcium.1Bacterially expressed NCALD was purified in its myristoylated and non-myristoylated forms independently. Mass spectrometric analyses was carried out to determine the mass of each form and to determine if the myristoylated form also contained the non-myristoylated form. A table of the mass values of the two forms is provided, along with those documented in an earlier report by other investigators. Based on the analyses, there is little non-myristoylated NCALD in the myristoylated preparations. The two preparations were subjected to electrophoresis in native gels in the presence of incremental concentrations of calcium. A dose-dependent mobility retardation is observed with both forms. However, the myristoylated form exhibits a greater amplitude and increased sensitivity to change in calcium concentrations.2E. coli ER2566 as described in N-Myristoyl Transferase were used and myristic acid was supplemented. Cells without the transferase were used to generate the non-myristoylated form; the supplementation was also skipped. Cells were collected 2.5\u00a0h after induction, sonicated and the protein was purified on phenyl sepharose columns as described previously NCALD was expressed in \u2212) or myristoylated (Myr+) NCALD. Protein was incubated in the presence of indicated concentration of calcium using calibration buffers and electrophoresed in native gels as described Mobility Retardation of NCALD (and other NCS proteins) in native gels has been documented. The retardation was directly dependent on the concentration of calcium. In order to determine if myristoylation of NCALD was essential for the calcium-dependent mobility shift, analyses were carried out with the non-myristoylated (Myr"}
{"text": "The original article \"Cost-Effectiveness of High, Moderate and Low-Dose Statins in thePrevention of Vascular Events in the Brazilian Public Health System\" published in theJanuary 2015 issue of the Brazilian Archives of Cardiology , was published in the Portuguese version as \"Effectiveness of High,Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian PublicHealth System\". A correction was made in the Portuguese version."}
{"text": "It is generally acknowledged that the 17-segment AHA model provides a suitable approximation for mapping the results of X-ray angiography onto myocardial anatomy in a consistent way in the absence of a more exact method. In practice, coronary anatomy varies from patient to patient which is acknowledged as the main limitation of the AHA model. The aim of this study was to establish whether the generation of a patient-specific coronary artery to perfusion segment map improved diagnosis of myocardial ischaemia.In this retrospective sub-study with the data from the CE-MARC trial  an 18-patient sample was selected where the image quality of the magnetic resonance angiography (MRA) data allowed for a reliable manual coronary tree annotation. Mediated spatiotemporal registration was used to compute the deformation fields between the MRA and perfusion data. The deformation fields were applied to the annotated coronary trees in order to warp them into the spatiotemporal coordinate space of the corresponding perfusion series. Three patient-specific coronary supply territories  were computed on the basis of the physical proximity of the major coronary arteries to the epicardial surface of the basal, medial and apical slices in the given perfusion series. Quantitative perfusion analysis using Fermi-constrained deconvolution was performed after manual motion correction and contour delineation in the perfusion series. Myocardial perfusion reserve (MPR) ratios were calculated from the ratio of stress to rest myocardial blood flow (MBF) estimates. A comparison between the diagnoses made using the AHA map and the patient-specific map was performed for each of the 18 patients. The presence of myocardial ischaemia was assessed using the consensus diagnosis of invasive, quantitative X-ray angiography and myocardial Single Photon Computed Tomography (SPECT) imaging.The patient-specific territories were markedly different from the AHA Figure . For a tThe use of patient-specific blood supply territories derived from the actual coronary anatomy has the potential of enhancing the diagnostic accuracy of quantitative perfusion analysis by providing a mechanism for computing perfusion parameters for the artery-specific regions of the myocardium. An improvement on the allocation of coronary artery to myocardial region over the AHA recommendation has been shown.This work was funded by the Top Achiever Doctoral scholarship awarded by the Tertiary Education Commission of New Zealand."}
{"text": "Intracranial branch atheromatous disease is a type of ischemic stroke that is caused by narrowing or occlusion of the orifice of the penetrating artery by atheromatous plaque. Pontine branch atheromatous disease is usually diagnosed using indirect findings such as the extension of a lesion to the basal surface of the pons because of the difficulty of demonstrating plaque in the basilar artery.A 72-year-old Japanese man developed sudden dysarthria and left hemiparesis, and his symptoms deteriorated thereafter. Brain magnetic resonance imaging revealed an acute infarction in the territory of the right paramedian pontine artery extending to the basal surface. Non-contrast-enhanced three-dimensional fast spin-echo T1 imaging with variable flip angles and three-dimensional fast imaging with steady-state acquisition revealed a plaque in the dorsal wall of the basilar artery that spread to the origin of the paramedian pontine artery that branched toward the infarction. Although antithrombotic agents were started, the left hemiparesis got worse and became flaccid on the following day.This is the first report to confirm the pathological basis of branch atheromatous disease by three-dimensional images using the new modalities of 3-Tesla magnetic resonance imaging. The use of these techniques will foster better understanding of the clinicopathological mechanisms of branch atheromatous disease. Intracranial branch atheromatous disease (BAD) is a type of ischemic stroke that is caused by narrowing or occlusion of the orifice of the penetrating artery by atheromatous plaque. Pontine BAD is usually diagnosed using indirect magnetic resonance imaging (MRI) findings such as the extension of a lesion to the basal surface of the pons. Here we report a case of pontine BAD diagnosed directly by the radiographic demonstration of BAD pathophysiology using 3-Tesla MRI.A 72-year-old Japanese man with hypertension, diabetes mellitus, and dyslipidemia presented with sudden left hemiparesis in the early afternoon. He developed dysarthria and choked on food and drink in the evening. By the next morning, the left hemiparesis had progressed and he could not stand up. He was taken by ambulance and admitted to our hospital; on admission a neurological examination revealed dysarthria and left hemiparesis involving his face, arm, and leg. MRI  revealed an acute infarction in the territory of the right paramedian pontine artery (PPA) extending to the basal surface Figure\u00a0A. MR angCaplan described BAD as cerebral infarction caused by narrowing or occlusion of the mouth of the branching artery by an atheromatous process that is different from lipohyalinosis causing lacunar infarction . RecentlCube T1 is a volumetric imaging technique with isotropic voxels that enables reformation of black-blood images into any plane and allows detection of atherosclerotic plaques with high resolution. In addition, we depicted the outer contour of the PPA using 3D-FIESTA, which detects small amounts of fluid based on the long T2 relaxation. These new reconstructive modalities of MRI clearly and three-dimensionally demonstrated the presence of atherosclerotic plaque in the major artery at the origin of the penetrating artery, which is the pathological basis of BAD.We reported the case of a patient with a typical clinical course of BAD and demonstrated the pathological basis of BAD using 3-Tesla Cube T1 and 3D-FIESTA MRI techniques. At present, the recognition of BAD is insufficient and the use of these high-resolution MRI modalities will foster better understanding of the clinicopathological mechanisms of BAD.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
{"text": "Pre-eclampsia is a major cause of maternal and fetal mortality in pregnancy. The identification of genetic variants which predispose to pre-eclampsia demands large DNA collections from affected mothers and babies and controls, with reliable supporting phenotypic data. The InterPregGen study has assembled a consortium of researchers from Europe, Central Asia and South America with the aim of elucidating the genetic architecture of pre-eclampsia. The MoBa collection is playing a vital role in this collaborative venture, which has the potential to provide new insights into the causes of pre-eclampsia, and provide a rational basis for novel approaches to prevention and treatment. The InterPregGen consortium, a multinational collaboration between research groups from Europe, Central Asia and South America, is seeking to identify genetic factors which predispose to pre-eclampsia, a quest which has proved challenging to investigators from around the world for decades. Pre-eclampsia is the most serious of the hypertensive disorders of pregnancy, with an incidence ranging from 2-5% of pregnancies in Western Europe and North America to as high as 18% in parts of Africa . Exact fth week of gestation; these are manifestations of widespread vascular endothelial dysfunction. It is possible that this is a common end point to diverse pathogenetic mechanisms, but the two-stage theory is a useful model, supported by observational and experimental evidence [The clinical features of pre-eclampsia are maternal hypertension and proteinuria developing after the 20evidence . In the evidence . For theEpidemiological studies over the past five decades have provided robust and consistent support for the clinical observation that pre-eclampsia runs in families. First degree relatives of affected women have a 2- to 3-fold increase in risk of pre-eclampsia -10. FurtThese observations justify the search for genetic variants in mothers and babies which confer susceptibility to pre-eclampsia. Genetic studies offer an important advantage in the identification of novel pathogenetic mechanisms in diseases of pregnancy, as they circumvent the practical and ethical challenges of obtaining suitable maternal and fetal tissue early in pregnancy, when trophoblastic invasion of maternal tissues occurs; investigation of genetic variation in mother and offspring can be conducted on DNA obtained at any time. Furthermore, in a disorder such as pre-eclampsia with a rapidly progressive pathophysiology it is often difficult to distinguish between causal factors and secondary phenomena resulting from disease processes. Genetic variation which proves to be associated with disease is guaranteed to predate the disease process.Genome-wide linkage studies of pre-eclampsia, analysing families with two or more affected women from Australasia, Iceland, Finland and Holland, have each identified loci which appear to show linkage with pre-eclampsia in their populations, but these results have not been independently replicated -18. ManyA major cause of the lack of success in identifying susceptibility genes has been the limited statistical power of the majority of studies performed to date. It is now apparent that many common genetic variants which predispose to complex disorders have individually small effect sizes. These variants are therefore difficult to detect by linkage analysis but can be detected with much higher power using genetic association study designs . InteresThe InterPregGen consortium was formed to address these deficiencies, aiming firstly to include a sufficiently large number of subjects with rigorously defined pre-eclampsia to provide adequate statistical power for association studies to detect genetic variants with small effect sizes; secondly, to use genome-wide association screening (GWAS) to scan both the maternal and fetal genomes for variants that predispose to pre-eclampsia. Also, the majority of larger published genetic studies in pre-eclampsia have been conducted in women of European ancestry, where the incidence of pre-eclampsia is amongst the lowest in the world. Therefore a further objective of the InterPregGen study was the inclusion of populations from different ethnic backgrounds in Europe, Central Asia and South America.InterPregGen is making use of several large biobanked DNA collections for studies of pre-eclampsia in Western Europe. These include the Norwegian Mother and Child Cohort Study (MoBa) ,25; the th week of gestation [The diagnosis of pre-eclampsia is based on an international definition, requiring new-onset hypertension , associated with proteinuria (\u2265 300 mg/L) after the 20estation . RecruitThe majority of control subjects are women with no history of hypertension (blood pressure <140/90 mm Hg) recruited during pregnancy. For Icelandic and UK subjects control data is provided by extensive existing GWAS data from population cohorts of respectively 36000 and 6000 individuals. Population control data have been used successfully for the identification of genetic associations with many complex disorders ; providiAll participants in the study have provided informed consent for the use of their samples, or those of their babies, in genetic studies. Approval for use of the samples and associated clinical data has been obtained from Research Ethics Committees in their country of origin, and over-arching approval for the InterPregGen study has been provided by the University of Nottingham Research Ethics Committee.The study is using genome-wide association screening as the primary strategy for discovery of genetic variants which are associated with pre-eclampsia. The principles of GWAS have been well-described elsewhere : case anTo maximise the statistical power of the study in a cost-effective way, InterPregGen is making use of GWAS data generated in the course of earlier studies in maternal and control samples from Iceland, the UK and Colombia. Additional GWAS is being undertaken using Illumina genome-wide arrays on offspring of pre-eclamptic pregnancies from Iceland and the UK, and also on newly collected maternal-fetal cases and controls from Central Asia. GWAS data is therefore available from a total of 7600 maternal cases and 4000 fetal cases .\u22128 is applied for genome-wide significance . For each study population with GWAS genotypes from pre-eclamptic mother-baby pairs, SNPs are also tested for evidence that maternal-fetal genotype interaction increases susceptibility to pre-eclampsia. Allelic odds ratios (OR) provided for each population by logistic regression analysis are combined in a meta-analysis to generate an overall OR for each SNP. The selection of SNPs for subsequent replication genotyping is based on the results of meta-analysis, with priority given to those with the lowest p-values. To adjust for the multiple statistical tests conducted in the course of GWAS, a meta-analytic p-value below 5\u00d710nce  effects. The approach for examining parent-of-origin effects in Icelandic data will differ, due to the richness of existing Icelandic whole-genome data, providing two independent approaches to test for imprinting effects. Through whole-genome sequencing of Icelandic individuals, long-range haplotype phasing and parental-origin determination the deCODE dataset provides complete information of the parental-origin of each allele, without additional genotyping of paternal samples.We anticipate that the research effort will identify functional DNA variants, or their proxies, which pre-dispose to pre-eclampsia and its complications, leading to enhanced understanding of the underlying disease process. InterPregGen will explore the potential for translating this information into clinical benefits through risk-profiling and the development of novel predictive markers. Currently the prediction of women at high risk of pre-eclampsia depends on clinical criteria, including the identification of risk factors at antenatal booking . These iMoBa is a unique collection of samples and data gathered prospectively at the time of pregnancy. For researchers into the genetics of complex disorders of pregnancy such as pre-eclampsia MoBa offers the advantages of a searchable database of reliable clinical information which can be used to identify cases and controls which fulfil the inclusion criteria of the study with a high degree of confidence. The well-managed biobanking facility ensures that DNA of dependable quality is available for genotyping studies from large numbers of cases and controls, a vital requirement for adequately powered genetic association studies. In contrast to many case-control collections, MoBa includes data and DNA samples from the partners and babies of pregnant women, which will enable InterPregGen to explore both maternal and fetal genomes, the interactions between maternal and fetal gene variants, and the contribution of paternal genes to pre-eclampsia. The biobanking expertise of MoBa partners in the InterPregGen study is proving invaluable in the discussion of ethical policies, and in the development of procedures for the newly formed biobanks in Uzbekistan and Kazakhstan.The identification of genetic factors which predispose to pre-eclampsia is a large undertaking, in which MoBa has a key role. InterPregGen is conducting the largest ever genome-wide association screen of maternal and fetal genes and their interactions in this disorder, and is also the first with adequate power to investigate the role of genetic imprinting (parent-of-origin effect). The ability to compare the genetic architecture of pre-eclampsia in subjects from three continents may give insights into the source of variation in the frequency of the condition across different ethnic groups. The prospects are good for novel findings which will ultimately translate into a better understanding and management of a condition which remains one of the major killers of pregnant women and their babies throughout the world."}
{"text": "We launched the special research topic of cortico-cortical communication dynamics to invite contributions that would cast light on such evolution of spatio-temporal action potential and membrane potential dynamics in the cerebral cortex.A considerable number of axons from neurons in one cortical area end up on other cortical areas. When one neuron in one cortical area sends an action potential to target neurons in other cortical areas, this is a realization of a cortico-cortical communication. Sensory perception, thinking, and planning of a specific behavior, all rely on the evolution of cortico-cortical communications. The action potentials change the membrane potentials in the target neurons and, in turn, may excite these neurons to produce action potentials and complex patterns of excitation and inhibition in in vivo experimental data from animals accounting for specific aspects of cortico-cortical communication dynamics.The contributions were theoretical models, human EEG, and MEG data and data-driven models, and in vitro experiment, Branco et al. (2+ influx when their depolarization progresses toward the soma, than when depolarization progresses away from the soma. Kiebel and Friston (in vivo. In vivo, the neurons and their dendrites are in a high conductance state (Destexhe et al., In a recent o et al.  show tha Friston  construc Friston  if the sAs pointed out in a critical review of cortico-cortical communication dynamics, there are many obstacles precluding the tracing the ms by ms evolution of the spatio-temporal dynamics of the cortex (Roland et al., Facing the obstacles of tracing the spatio-temporal dynamics of cortico-cortical communications at the cellular scale, many scientists choose to study membrane electrical activity at the scale of large neuron populations, and from EEG and MEG signals try to infer putative routes of communication. Banerjee et al.  discuss At the mesoscopic scale one can observe changes in the membrane potentials with voltage sensitive dyes, local field potentials and combine this with recordings of action potentials from a few neurons or single neurons in experimental animals. Harvey and Roland  demonstrIf one wants to understand how the cerebral cortex works one must be able to trace the evolution of the spatio-temporal transmission of action potentials and membrane conductances down to the cellular scale. As the critical review concludes, this is not possible yet. Assume that a full connectome of the mouse cerebral cortex exists (Bohland et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Multi-parameter gene expression assays (MPA) to aid selection of chemotherapy in hormone-sensitive early breast cancer have not been prospectively validated. This field of personalised medicine is rapidly evolving. There is currently no \u201cbest test\u201d. OPTIMA is an adaptive trial of MPA-based chemotherapy assignment in a largely node-positive breast cancer population.OPTIMA prelim, the feasibility phase, recruited 302 patients to establish acceptability of the trial to patients and clinicians and evaluate the performance of MPAs to identify a suitable test(s) to be used in the main efficacy trial. Ethical approval was also gained for an additional 200 patient roll through before the opening of the main trial. The logistics of this design and practicalities of rolling through will be discussed. Whilst this design was efficient and minimises bureaucracy, the delays encountered with this type of design stem from the need to produce pilot results quickly and for funding bodies to make quick decisions about the feasibility of the main trial.The success of OPTIMA not only relies on the integration of a multi-disciplinary team of methodologists, clinical experts and patients at all stages of the trial, but on its adaptive design. The complexities of using such methodology and decision-making to roll forward into a main trial are challenging but provide the most efficient use of patients and costs.Project funded by the NIHR HTA Programme (10/34/01). Views expressed are those of the authors and not those of the HTA programme, NIHR, NHS or the DoH."}
{"text": "The short allelic variant has been shown to reduce 5-HTT transcription resulting in diminished 5-HTT levels and reduced serotonin (5-HTT) reuptake into human platelets. We speculate the possibility of altered hormone levels (Melatonin and Serotonin) in individuals with ASD.Autism Spectrum Disorder (ASD) is a developmental disorder that affects the behavior and social communication of the child. In India, awareness about Autism coupled with shortage of skilled professionals poses severe constraints in management of children with ASD. There arises a need to explore the avenues of alternate therapy in the form of Group Therapy. A 44-bp insertion/deletion polymorphism in the promoter region of the serotonin receptor gene As per earlier reports an association between 5-HTT gene polymorphism and autism has been indicated. Recent evidences from clinical and neuroscience research suggests an approach based on yogic principles and meditative tools is worth experimenting in children with autism.The same could be addressed in ASD individuals to ameliorate the drastic effect of these hormones on ASD individuals.5-HTT) is to be analyzed to correlate the endocrine findings.A single group pre-/ post- test study design was employed. With the aid of a social and behavioral assessment scale for ASD, fifteen children with ASD between the age group of 7 - 14 years were evaluated for assessing the effect of the Vedic Chants Intervention Program recruited from special schools in and around Chennai. Chanting of select Sanskrit Mantras by an experienced meditator were given as an auditory stimulus in a closed room to the children for a period of 20 min daily at a fixed time. Alterations in the endocrine profile (Melatonin and Serotonin) were measured using ELISA Kits. Polymorphism in serotonin transporter (Study shows that there is a difference in the pre & post-test mean achievement scores due to the Vedic Chants Intervention Program. Some of the qualitative changes observed by the special educators were a reduction in the hyper activity, self-biting and other common traits of ASD like head nodding, hand flapping etc. This reflected in their class room sitting as well. Some of the children were remembering certain lines of the mantras and imitating the sound \u2018Om\u2019 and responding to the \u2018Namaste\u2019 gesture. Most of the children including those with ADHD sat throughout the entire session. The endocrine profile of the subjects was altered.The auditory stimulus has the potential to provoke the cognitive abilities of the children. Vedic Chants therapy might be one of the efficient Group therapies for the management of children with ASD."}
{"text": "Part of the innate host defense against microbial infection is nutritional restriction of access to sources of host nutrients  that is ER-derived and evades lysosomal fusion   results in varying degrees of failure in intra-vacuolar proliferation and attenuation in the mouse model of Legionnaires' disease  family of membrane proteins (Cedernaes et al., in vivo is essential for our understanding of host-microbe interaction, and nutrient retrieval strategies by intracellular pathogens are potential targets for therapy.Remarkably, pyruvate or citrate supplementation is as effective as amino acids in rescuing the intra-vacuolar growth defect of the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "We will report the design and performance of a MR-compatible SPECT system that utilizes a dual-FOV aperture design for microscopic SPECT imaging of small animals inside an pre-existing MR scanner. The MRC-SPECT-DF system consists of a full ring of high resolution CdTe detectors and an aperture that consists of dual-FOV aperture system design that has two sets of aperture rings along the axis, one providing a large FOV and the other one allowing an ultrahigh resolution microscopic imaging of a selected target region in the object. The switching between apertures does not require mechanical shifting of either the aperture or the CdTe detector ring. This is critical for integrating the SPECT system with the MR scanner, and minimizing the interference between both sub-system while operation."}
{"text": "Being the first second messenger described  is a second messenger of paramount biological importance, involved in the regulation of a significant number of cellular functions To our belief, this aim has been successfully fulfilled. The present collection of articles highlights, in a representative (but certainly not exhaustive) way, the research activity and emerging concepts in the field, while it also reveals the therapeutic potential that targeted pharmacological manipulation of intracellular cAMP levels could exert on a number of pathological conditions. We organized the papers of this Research Topic/e-Book into three sections (A\u2013C).Frontiers in the role of cAMP in cellular function, homeostasis and disease\u201d) opens with a very informative review article on the reciprocal regulation between cAMP signaling and the ubiquitin-proteasome system, as well as its relevance to certain human diseases . A more focused perspective on the importance of cAMP in cardiac physiology and pathophysiology is presented by the review article of Boularan and Gales and the mini review article of Froese and Nikolaev; both articles provide an up-to-date account of recent developments in the field and should be considered by readers as complementary to each other. Later in section A, readers will discover an elegant mini review on the role of cAMP signaling in neural plasticity, learning and memory (Lee), that summarizes findings generated by research on the fruit fly Drosophila melanogaster and briefly highlights implications of this signaling pathway to potential therapeutic applications. Section A concludes with an original article on the role of cAMP signaling in human trophoblast fusion , and with a perspective article on the spatiotemporal regulation of cAMP signaling in blood platelets .The first section  includes an informative review article on state-of-the-art methodologies which can be utilized toward the study of cAMP-mediated signal transduction via G-protein coupled receptors , as well as two excellent review articles on the pharmacological manipulation of intracellular cAMP levels through interference of the molecular interactions between the A-kinase anchoring proteins and other signaling protein intermediates . This section also accommodates a contribution by R\u00f6ck et al. with an original research article in which analysis of protein kinase A (PKA) dynamics following the integration of patient mutations into its catalytic (PKAc) and regulatory (RIa) subunits is presented. The section is completed with two analytical review articles that present recent developments in the utilization of genetically encoded tools for cAMP measurement in health and disease .The second section  is introduced with a perspective article on the role of patients' sex toward a more targeted (cAMP pathway-regulated) therapeutic approach to brain tumors , followed by two original research articles on the role of cAMP signaling in the context of hematological malignancies and the potential therapeutic applications that could arise through its pharmacological manipulation . The current Research Topic / e-Book is concluded with a well-written review article on cAMP signaling in trypanosomatids that provides an overview of the complex functions of cAMP in these protozoan parasites, as well as a fine perspective on how potential targets for the trypanosomatid-specific cAMP pathway could provide efficient therapeutics for serious human diseases such as the sleeping sickness and other trypanosomatid-induced pathological entities .The third section (C: \u201cThe recruited articles cover multiple aspects of the ongoing research in the cAMP field and allow an appreciation of the difficult task ahead in fully-understanding the complexity of this ubiquitous signaling cascade and taming it to develop efficient therapeutic applications. Hopefully, readers will consider this collection of papers as a small step toward these goals.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "It is currently one of the most active areas of research in diagnostic imaging. The characterisation of an incidental renal lesion can be difficult. In particular, the differentiation of an oncocytoma from other solid renal lesions such as renal cell carcinoma (RCC) represents a diagnostic challenge. We describe the detection of an incidental renal oncocytoma in a 79-year gentleman who underwent a re-staging"}
{"text": "Sensitivity to temporal contingencies appears early in life and plays a key role in the ontogeny of socio-cognitive abilities in humans  quantifying how interactions with the environment and others have a causal role at the intra-individual level and non-additive consequences at the inter-individual level, and (2) deciphering the different factors of coupling across neural, behavioral and cultural scales. A last challenge is to embrace the ongoing change of paradigm that shall bridge the gap between the lived and the observed experience of social coordination in ecological contexts. Taken together, integrating first-, second- and third-person perspectives is a required move to accurately study natural human coordination phenomena.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The generation of engineered tissues and organs has entered into the clinical practice in response to the chronic lack of organ donors. In particular, for the skeletal and cardiac muscles the translational potential of tissue engineering approaches has clearly been shown, even though the construction of these tissues lags behind others given the hierarchical, highly organized architecture of striated muscles. Failure of the cardiac tissue leads to cardiovascular diseases, which are the leading cause of death in the developed world  structures able to induce stem cell differentiation and which may be used in pre-clinical and clinical studies.Of the two bio-artificial systems described, one is a silicon chamber system for the generation of skeletal muscle constructs described by Snyman et al. . This inin vivo implantation. Pagliari et al.  from skeletal muscle. Perniconi et al.  demonstrThe same authors also contributed a review article on the usefulness of the MAS as a scaffolding platform able to re-create the natural structure of the muscle. MAS is naturally embedded with active native molecules which remain active after the decellularization process and help the implanted proto-tissue to integrate in the host organ. Tissue-derived ECM helps in structuring niches rich in adhesive and signaling molecules supporting stem cells self-renewal and differentiation  applies. In this case the muscle should be replaced by devices able to re-establish the function of the musculature and which preserve force transmission and continuity of the architecture within the host tissues. Hence, Cittadella Vigodarzere and Mantero  describeA clinical example of the latter is described in an interesting review discussing the importance of angiogenesis and the pro-angiogenic and pro-myogenic effects of the vascular endothelial growth factor (VEGF)/VEGF receptor pathway as a therapeutic strategy to cure muscle weakness and cardiomyopathy in Duchenne muscular dystrophy (DMD) patients .Apart from the structures of ECM and vasculature, also growth factors, cytokines, pleiotropic signaling pathways, and cell-specific regulators play an important role in the differentiation and self-renewal of cardiac as well as skeletal muscle stem cells. Pagliari et al.  describeThis book provides a comprehensive up-to-date review on cardiac and skeletal muscle tissue engineering and highlights the several elements which have to be taken into consideration when engineering a functional proto-tissue.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "There are errors in the Results, PEST-NLS and yEVenus-NLS when expressed by the constitutive promoter ADH1 .There is an error in the penultimate sentence of the third paragraph of the \u201cConstruction of Yeast Gateway Vectors for One-step Gene Assembly\u201d subsection of the Results. The correct sentence is: We compared the fluorescence produced by yEVenus-Cln2There is an error in There is an error in"}
{"text": "The main challenge for understanding motion processing in the visual system is that local motion signals do not accurately represent the direction of the whole object. This is known as the \"aperture problem\". The small receptive fields of individual neurons can only measure motion components orthogonal to their preferred direction. Neuro-physiological studies show that neurons in brain area MT (V5) have a major role in dealing with this problem . We deveThe model contains two levels of rate-based neuron. The first level is a model of V1 with two sets of neurons: complex neurons and hyper-complex end-stopped neurons. End-stopped neurons respond to the end-points of the stimulus , thereby representing an unambiguous estimation of the direction of motion . The resExcitatory recurrent connections between integration neurons propagate end-stopped information from the object terminators. As each spatial location contains neurons selective to different directions, inhibitory connections are added between the neurons such that there will be only one neuron active at each spatial location. Long-range inhibitory connections are also added between more distant MT neurons selective to other directions. Segmentation neurons send inhibitory connections to integration neurons to prevent the propagation of motion signals outside the border of the input stimulus. Inhibitory connections between segmentation neurons are defined based on center-surround interactions; this suppresses activity when the motion signals in the center and surround are in the same directions; ensuring that their activity will not prevent the propagation of motion signals when there is no discontinuity.The results of simulations show that the activity of V1 neurons along the edges is much stronger than the activity of the neurons at the end-points. Activation of end-stopped neurons in V1 suppresses ambiguous motion signals along the edges of the stimulus. Therefore, unambiguous information at the end-points wins the competition over the neurons with ambiguous motion signals. The final output of the model shows that MT neurons achieve an accurate estimation of motion using the information provided by the end-stopped neurons.We developed a model of MT neurons for motion perception based on the available neuro-physiological data. These neurons receive their input from neurons in V1. The results show the successful function of these neurons in the perception of motion of a single moving bar. In this model, we also investigated the role of end-stopped neurons in overcoming the aperture problem. The results suggest that MT neurons are not able to solve the aperture problem without the vital role played by end-stopped cells."}
{"text": "Kangaroo mother care has been highlighted as an effective intervention package to address high neonatal mortality pertaining to preterm births and low birth weight. However, KMC uptake and service coverage have not progressed well in many countries. The aim of this case study was to understand the institutionalisation processes of facility-based KMC services in three Asian countries  and the reasons for the slow uptake of KMC in these countries.Three main data sources were available: background documents providing insight in the state of implementation of KMC in the three countries; visits to a selection of health facilities to gauge their progress with KMC implementation; and data from interviews and meetings with key stakeholders.The establishment of KMC services at individual facilities began many years before official prioritisation for scale-up. Three major themes were identified: pioneers of facility-based KMC; patterns of KMC knowledge and skills dissemination; and uptake and expansion of KMC services in relation to global trends and national policies.Pioneers of facility-based KMC were introduced to the concept in the 1990s and established the practice in a few individual tertiary or teaching hospitals, without further spread. A training method beneficial to the initial establishment of KMC services in a country was to send institutional health-professional teams to learn abroad, notably in Colombia. Further in-country cascading took place afterwards and still later on KMC was integrated into newborn and obstetric care programs.The patchy uptake and expansion of KMC services took place in three phases aligned with global trends of the time: the pioneer phase with individual champions while the global focus was on child survival (1998\u20132006); the newborn-care phase (2007\u20132012); and lastly the current phase where small babies are also included in action plans.This paper illustrates the complexities of implementing a new healthcare intervention. Although preterm care is currently in the limelight, clear and concerted country-led KMC scale-up strategies with associated operational plans and budgets are essential for successful scale-up. Babies with a birth weight of <2500\u00a0g are the most vulnerable newborns at higher risk of mortality , 2. Low Three-quarters of deaths from preterm birth complications are preventable without intensive care units . AccordiKangaroo mother care is a \u2018total health-care strategy\u2019 , which iBorn Too Soon report \u2019 \u2019 ) and of phasis]\u2019 ) should Responses in the bottleneck investigation that was part of the Every Newborn Action Plan included the absence of an investment plan for scale-up of KMC, with no funding allocation to KMC implementation, resulting in high dependency on external funding . In all The focus of this study was limited to the provision of facility-based KMC services. It is acknowledged that almost half the preterm babies in middle- and low-income countries are born at home . AlthougThis paper illustrated the complexities of the implementation of a new healthcare intervention. Professional resistance and the lack of political priority for newborn and LBW care within the political and healthcare structures at the time when early adopters introduced KMC into their health facilities explain why the vast majority of institutions were left behind. Only now that KMC has been included in the global health agenda as one of the key interventions for the reduction of newborn morbidity and mortality can we expect the majority to follow suit. However, this expectation might not materialise without a country-led clear and concerted KMC scale-up strategy with an associated operational plan and budget.Enabling mothers and their families to practice kangaroo mother care entails a complex interplay between health-system requirements, organisational culture, human behaviour and community networks. Scaling up KMC is not an easy process and it takes time for services to become institutionalised and integrated into the total newborn care package. Leadership reflecting an understanding of the necessity of prioritising the provision of facility-based KMC services and good governance at all levels throughout the implementation process is essential. Scale-up processes should be driven by strategies to ensure appropriate quality of care."}
{"text": "The dynamics of intense twin beams in pump-depleted parametric down-conversion is studied. A generalized parametric approximation is suggested to solve the quantum model. Its comparison with a semiclassical model valid for larger twin-beam intensities confirms its applicability. The experimentally observed maxima in the spectral and spatial intensity auto- and cross- correlation functions depending on pump power are explained in terms of different speeds of the (back-) flow of energy between the individual down-converted modes and the corresponding pump modes. This effect is also responsible for the gradual replacement of the initial exponential growth of the down-converted fields by the linear one. Furthermore, it forms a minimum in the curve giving the effective number of twin-beam modes. These effects manifest a tight relation between the twin-beam coherence and its internal structure, as clearly visible in the model. Multiple maxima in the intensity correlation functions originating in the oscillations of energy flow between the pump and down-converted modes are theoretically predicted. Nowadays, parametric down-conversion (PDC) describing three mutually interacting optical fields68910141518192022We note that the model developed here for twin beams may be useful also for other three-mode nonlinear interactions found, e.g., in acousto-opticsIn the process of PDC, pump, signal and idler fields mutually interact in a nonlinear medium with an effective nonlinear susceptibility \u03bb giving the quantum probability amplitudes of finding a given paired mode in the state are obtained  proportional to the squared product In a classical nonlinear problem. The Schmidt decomposition provides the signal and idler modes in pairs in which they share a common Schmidt coefficient \u03bb. As a consequence, the signal and idler field amplitudes (expressed in photon numbers) belonging to one pair are the same. Using this symmetry, the classical counterpart of the Heisenberg equations written for mean values of the symmetrically-ordered signal To include the quantum statistical character of the signal and idler fields in multi-thermal PDC, we first propose The solution of defining We note that the second term on the r.h.s. of a semiclassical model (SCM) that preserves the overall energy. In this model, we build the operator solution from the classical one written in To verify the validity of GPA, we develop in parallel We recall that P for which an exponential growth of the number N of emitted photon pairs is observedN slows down as the pump power P increases and finally a linear increase is reached  become completely depleted and begin to take their energy back from the signal and idler modes with whose they share the common modes\u2019 triplets. This reflects the most important feature of the nonlinear dynamics of individual modes\u2019 triplets in PDC: the larger the mode\u2019s incident pump power, the faster the nonlinear dynamics of the corresponding triplet. Detailed insight into the dynamics is provided in P forming an increasing succession. For high powers P, the pump modes with the largest Schmidt coefficients \u03bb  are completely depleted inside the crystal and they even take some energy back from their signal and idler modes contrary to the rest of pump modes (with lower Schmidt coefficients \u03bb), which are only losing their energy during the propagation in the crystal. This results in the slower-than-exponential growth of the signal- and idler-field intensities. The observed nearly-linear character of this growth is a consequence of the large number of modes with different evolution that constitute the TWB  crystal cut for a nearly collinear spectrally degenerate type-I interaction  of spatial and spectral coherence accompanied by a decrease (increase) of the number of modes observed in different regimes of pump powers. The comparison of the results with the experimental data and with the results of semiclassical model confirms the validity of the suggested \u03bcm wide (FWHM) at the lowest pump power. A half-wave plate followed by a polarizing-cube beam splitter was used to change the pump power. Phase-matching in the crystal for frequency degenerate down-converted beams was reached in a slightly non-collinear configuration. The down-converted light was collected by a lens with 60-mm focal length and then focused in the plane of the vertical slit of an imaging spectrometer . The angularly dispersed far-field radiation was recorded, shot by shot, by a synchronized EMCCD camera  operated at full-frame resolution . We note that for the detection of intense TWBs EMCCD cameras are more convenient compared to iCCD cameras, which have been often exploited in this area383940The experimentThe intensity auto- and cross-correlation functions characterizing the TWB coherence are obtained as correlation coefficients between a single pixel (In 12), ,  standsThe number of TWB modes in the radial direction was determined by the Fedorov ratioHow to cite this article: Pe\u0159ina, J. et al. Internal dynamics of intense twin beams and their coherence. Sci. Rep.6, 22320; doi: 10.1038/srep22320 (2016)."}
{"text": "EGFR gene.Multiplex ligation-dependent probe amplification (MLPA) is a multiplex copy number analysis method that is routinely used to identify large mutations in many clinical and research labs. One of the most important drawbacks of the standard MLPA setup is a complicated, and therefore expensive, procedure of generating long MLPA probes. This drawback substantially limits the applicability of MLPA to those genomic regions for which ready-to-use commercial kits are available. Here we present a simple protocol for designing MLPA probe sets that are composed entirely of short oligonucleotide half-probes generated through chemical synthesis. As an example, we present the design and generation of an MLPA assay for parallel copy number and small-mutation analysis of the"}
{"text": "Solar magnetism displays a host of variational timescales of which the enigmatic 11-year sunspot cycle is most prominent. Recent work has demonstrated that the sunspot cycle can be explained in terms of the intra- and extra-hemispheric interaction between the overlapping activity bands of the 22-year magnetic polarity cycle. Those activity bands appear to be driven by the rotation of the Sun's deep interior. Here we deduce that activity band interaction can qualitatively explain the \u2018Gnevyshev Gap'\u2014a well-established feature of flare and sunspot occurrence. Strong quasi-annual variability in the number of flares, coronal mass ejections, the radiative and particulate environment of the heliosphere is also observed. We infer that this secondary variability is driven by surges of magnetism from the activity bands. Understanding the formation, interaction and instability of these activity bands will considerably improve forecast capability in space weather and solar activity over a range of timescales. The origins of the Sun's periodic activity, such as sunspot cycles, are poorly understood. McIntosh et al. posit that the rotational forcing of the activity bands comprising the 22-year magnetic cycle undergoes shorter-term variations, driving magnetic flux surges that impact solar output on those timescales. The obvious hemispheric asymmetry of the solar atmosphere over the past several years 2009\u20132014) has generated a significant amount of interest in the heliophysics community4 has genet al.et al.McIntosh Rotating atmospheres, like that of the Earth and the giant planets of our solar system, often exhibit shorter-timescale global-scale phenomena such as Kelvin and Rossby waves47Variations of significantly shorter period than the canonical 11-year) envelope of solar variability are visible in the Sun's flaring activity . The fig9-year envStudying the last solar cycle in more detail, 13We see that the peaks in the total sunspot number have corresponding peaks in the CME rate. The surges in the daily sunspot number can be as large as 30% and they can lead to a 100% increase in the daily CME rate. The same strong correspondence is visible for the flare rate. The relationship between the disk-integrated CME rate and the hemispheric rates of sunspot and flare formation highlight a critical property in disk-integrated quantities\u2014they will typically exhibit shorter period variations than hemispherically resolved ones. The phase offset between the two hemispheres will determine the resulting \u2018hybrid' period observed. In this case, we see that marked increases in surface magnetism lead to a profound increase in the rate of eruptive phenomena.\u22122\u2014equivalent to the variation over the whole solar cycle . The seasonal variation of the latter modulates the visible area of the solar diskThese periodic changes in the morphology of the coronal (and heliospheric) magnetic field can be inferred from Magnetic fields on smaller spatial scales than coronal holes and sunspots display similar periodicities to their larger brethren throughout the solar cycle. 225The physical origin of these strong quasi-periodic surges in the Sun's magnetism is not known. However, their effect on the outer solar atmosphere and on the geospace environment is profound. Their existence has been documented extensively since the start of the space-age. For example, strong quasi-periodicities that are longer than the Sun's rotation rate have been amply documented in the literature for sunspot areas29et al.As we have noted above, it is unlikely that a strong modulation in the number of sunspots can be easily explained by processes in the near-surface layers of the Sun. However, considering a spatio-temporal decomposition of solar surface magnetismet al.We infer that the interaction of the oppositely signed, long-lived activity bands in each hemisphere as discussed by McIntosh In addition to the decadal envelope of solar activity, there is a clear, strong, variability of the magnetic flux in each solar hemisphere of approximately 1  year. We propose that the process at the root of the short-term propagating pattern shown in 910112526272829So, what are the poleward-propagating excursions seen in et al.et al. indicate that there are global-scale waves and instabilities that propagate in the shear layer known as the tachocline38One possible explanation follows from the deliberations of Howe What could these perturbations to the magneto-convective system be? The Earth's mantle, ocean and thermosphere/stratosphere exhibit global-scale waves that are driven by the rotation of the planet at shear interfaces, or Rossby waves4042To summarize, we have inferred that the interaction of the activity bands belonging to the Sun's relentless 22-year magnetic polarity cycle shape the decadal-scale variability of solar activity1The growing dependence of our civilization on technology susceptible to space weather should motivate investigations into the rotational forcing of the Sun's deep convection zone by the radiative zone. Specifically, challenging simulations of activity band formation, intra- and extra-hemispheric activity band interaction and the zoo of rotational-gravity-buoyancy waves that interact with those activity bands are required. These factors appear to be key drivers of solar variability on decadal and annual timescales. A better understanding of the processes responsible for modulating the decadal variability and the (quasi-)annual \u2018seasons' of solar activity will yield a significantly increased forecast skill for solar activity in parallel with continued observational monitoring.Using the Morlet wavelet as a model representation of the oscillatory signals observed, we construct the wavelet power spectra of each timeseries. In the most general sense a wavelet power spectrum can be thought of as an image that indicates the strength and the duration that an oscillation of a particular period is present in the timeseries. It is a particularly powerful tool for the analysis of timeseries that exhibit mixed periods and quasi-periodicities as is often the case in many solar phenomena.For the wavelet power spectra shown in N up to the next-higher power of two\u2014this limits any edge effects and speeds up the Fourier transform at the core of the computation.The cross-hatched areas in the wavelet power spectrum define the \u2018cone of influence.' The interpretation of the cone of influence is relatively straightforward\u2014the signal in the cross-hatched area may not be entirely reliable because of the influence of edge effects of the timeseries. Because these are finite-length timeseries, errors will occur at the beginning and end of the wavelet power spectrum, as the Fourier transform used in the Wavelet method assumes that the data are cyclichttp://virtualsolar.org) data archives.The data used in this paper are openly available from the NGDC, SOHO, SDO and the Virtual Solar Observatory .Supplementary Figures 1-3"}
{"text": "Inverse synthetic aperture radar (ISAR) imaging of a maneuvering target is a challenging task in the field of radar signal processing. The azimuth echo can be characterized as a multi-component polynomial phase signal (PPS) after the translational compensation, and the high quality ISAR images can be obtained by the parameters estimation of it combined with the Range-Instantaneous-Doppler (RID) technique. In this paper, a novel parameters estimation algorithm of the multi-component PPS with order three  based on the modified discrete polynomial-phase transform (MDPT) is proposed, and the corresponding new ISAR imaging algorithm is presented consequently. This algorithm is efficient and accurate to generate a focused ISAR image, and the results of real data demonstrate the effectiveness of it. In this paper, a novel algorithm for the parameters estimation of multi-component CPS by the MDPT method is proposed. This algorithm has better performance than the traditional DPT algorithm in the case of similar amplitudes of each component. Then, the corresponding ISAR imaging algorithm based on MDPT is presented. The ISAR imaging results of real data demonstrate the validity of the novel algorithm proposed in this paper."}
{"text": "The establishment of the Cancer Drugs Fund (CDF), which removed the necessity for cost-effectiveness as a criterion for drugs access and expedited access to non-NICE appraised drugs, has significantly changed prescribing of cancer drugs for terminally ill cancer patients in the NHS. Neither clinicians nor the public have a preference for spending money on cancer over other disease states. The most effective and efficient way to spend resource within cancer care is hotly debated.Audio-recorded, semi-structured interviews with oncology and palliative care consultants (n=16) took place in the South West region (March-October 2013). Transcripts were analyzed iteratively using constant comparison to identify and understand common themes. Matrices were developed to explore and compare derived themes and highlight dissonant views.The complex dynamic of personal, familial, media and political influence on palliative chemotherapy decision-making were described by participants. Decision-making around palliative chemotherapies was improved by the CDF according to all oncology participants. The main benefit of the CDF was thought to be access to treatments not previously available to patients. However, the improved availability of high cost drugs caused conflict for clinicians reconciling the apparent benefits for the patient and the cost for the population. The disadvantages of the CDF included a potential reduction in clinician discretion in chemotherapy decision-making since the National CDF Cohort List and a delay in advanced care planning conversations. The appropriateness of \u2018weighting\u2019 the value of life more at the end of life (as defined by NICE) was felt to be artificial by 5/6 palliative care and 5/10 oncology consultants. The majority of consultants described an uncomfortable compromise between the importance of that time to some individuals offset by the lessened quality of life for the majority (13/16). Professional opinion clashed most over the role of Multi-Disciplinary Team meetings (MDTs) in accessing CDF drugs. MDTs were felt to be a cause for delay and \u2018a tick-box\u2019 exercise (oncologists) and a missed opportunity for patient advocacy .Clinicians indicated that they mostly approved of the CDF in enabling patient access to new palliative chemotherapy. However; clinicians sometimes struggled with judging the balance between potential gains and losses in length and quality of life for individual patients and the level of financial cost incurred by the NHS. The views of patients accessing drugs through the CDF are currently being sought in order to improve understanding of the impact of the CDF."}
{"text": "In patients with idiopathic normal pressure hydrocephalus (iNPH) with features of Disproportionately Enlarged Subarachnoid-space Hydrocephalus (DESH), ventriculomegaly and the tight high-convexity and medial subarachnoid spaces appear in magnetic resonance (MR) images before the occurrence of objective symptoms. There are few reports of longitudinal observation of clinical course in DESH-type iNPH patients with no objective symptom.We longitudinally observed 4 patients  with features of DESH who visited the neuropsychological clinic in our hospital, whose symptoms were not apparent in the first visit. We evaluated the triad symptoms with iNPHGS and conducted the cognitive and gait examinations once a year. We also evaluated quantitative rCBF of those patients by 123I-IMP single photon emission computed tomography (SPECT) using the autoradiography (ARG) method.Based on the scores of iNPHGS, we classified 4 patients into two groups; two stable patients and two deteriorated patients. In one patient of the stable group, the score of the Mini-mental State Examination (MMSE) did not change and the score of the Frontal Assessment Battery (FAB) and the Timed Up & Go Test (TUG) improved, however, in the other patient, the score of MMSE, FAB and TUG worsened. In the deteriorated group, one patient expressed the gait disturbance and the other patient did the gate disturbance and the cognitive impairment. In the former patient, the score of MMSE and FAB worsened and a wide-based gate and the disturbance of the dynamic equilibrium appeared, although the score of TUG did not change. In the latter patient, the score of FAB and TUG worsened but the score of MMSE did not change. The changes of quantitative rCBF of 4 patients were various.The different clinical courses and changes of quantitative rCBF were observed in each patient."}
{"text": "Realities remote from the objective value of molecular allergology / component-resolved diagnosis may explain the gap in clinical implementation between Europe and North America. If the latter is to assert a dominant role in the field of allergy, its professionals will have to embrace change and provide leadership in molecular allergology. As for sublingual immunotherapy, inaction on the part of allergy professionals will leave to commercial and industrial interests the definition of the business model and ultimately the patients' health care options.Was America sleeping on its laurels or just snubbing molecular allergology / component-resolved diagnosis? The clinical implementation of molecular allergology testing in Europe dates back to the early 2000's. Although the importance of major allergens seems to have been readily recognized by allergy professionals in North America, more exhaustive exploration and clinical use of molecular allergology is still waiting. In this day and age of instant communication and worldwide professional collaboration, it is surprising that such a gap could have developed. A review of factors that may have led to this situation represents an opportunity to identify important dynamics that sometimes hinders the introduction of valuable science and/or technologies to our patient care. In France, the model of physician remuneration may have set up the opportunity for the professional cooperation that developed the science and its integration to government-sponsored healthcare services. In Canada, the lack of expertise and demand for molecular allergology services has hindered the country-specific certification process of laboratory technology otherwise widely recognized. In the US, the FDA is still restricting its endorsement to the \"Peanut-You-Know\" portion of Thermofisher's line of molecular allergy testing products. All the while and until recently, pioneering US-based research in oral immunotherapy (OIT) neglected basic data concerning peanut allergy molecular profiles at a time when comprehensive protocols were routine clinical practice in some French centers. Whereas"}
{"text": "The use of the extra-vertebral balloon osteoplasty is increasing and in the meanwhile it has become a safe surgical technique in the treatment of tibial head, distal radius and calcaneus fractures. In addition, we already could show in a biomechanical setup that the balloon osteoplasty might be a safe tool for reduction in the treatment of Hill-Sachs lesions, but clinical application has not been performed so far.We report the case of a 53\u00a0year- old male patient who was referred to our Trauma department (level I trauma center) after the first manifestation of a posterior shoulder dislocation due to an epileptic seizure, originated in a- up to this date unknown -glioblastoma. After closed reduction of the dislocated shoulder the X-ray showed a subcapital fracture of the proximal humerus with a large reversed Hill-Sachs lesion. We performed an open surgery via a deltoideopectoral approach and balloon osteoplasty was used to reduce the impression fracture (Hill-Sachs lesion) before fixing the fracture with a locking plate. In the post-operative CT scan we could show an anatomical reduction of the Hill-Sachs lesion. At the follow-up examination one year after surgery the patient reached full range of motion and stated no re-dislocation of the shoulder nor instability or pain.The reduction of an impressed humeral head fracture by use of balloon osteoplasty is a safe technique. This technique could be a new option in the treatment of Hill-Sachs lesions and might be an alternative to well known standard procedures like the remplissage or tendon transfers without affecting rotation. The use of the balloon-guided kyphoplasty is a safe and reliable operative technique  and in tA 53- year- old male patient who sustained a posterior shoulder dislocation with combined subcapital fracture and reversed Hill-Sachs lesion see Fig.\u00a0 was refeIn a first step the reverse Hill-Sachs lesion was reduced using an inflatable balloon as used in kyphoplasty. In contrast to our experimental set-up  were we The patient recovered well from this surgical intervention, achieved a free range of motion and had no re-dislocation at the one year follow-up. No technique-related complications occured. Unfortunately, we are not able to report about the long-term follow-up as the patient died of complications caused by his glioblastoma 22\u00a0months after surgical intervention.Posterior dislocation of the shoulder is a rare entity and therefore often misdiagnosed . Once diAs an alternative technique Keppler et al.  describeThe presented case describes the reduction of the reverse Hill-Sachs lesion using a regular kyphoplasty balloon  in a firSome questions are left unanswered and remain for future research. Though we used a open deltoideo-pectoral approach due to the accompanying subcapital fracture and the need of additional plating we are convinced that this technique is suitable under arthroscopic conditions thereby further reducing the surgical trauma and remaining minimal-invasive. From our own experience the Hill-Sachs lesions has then to be treated as close to the accident as possible. To enable exact arthroscopic intervention a guiding instrument as we know it from ACL reconstruction might be helpful as well as a fenestrated cannula likewise we used in tibial head reconstruction as an abutment and lesion indicator . In addiThe other remaining point is the matter of defect filling after reduction of the reverse Hill-Sachs lesion. In our case we were able to save the reduction by positioning of the locking plate. In those cases where you would have an isolated impaction fracture it might be sufficient to limit range of motion to leave the defect unaffected for the first 6\u00a0weeks. As an alternative, defect filling would be possible either with cancellous bone or bone substitues and would probably be superior to filling of the emerging hollow with bone cement as described by Jacquot et al.  in the tDespite all positive reports on the inflation osteoplasty, this new surgical technique is not free from complications and as in all emerging techniques there is always the risk of potentially harm patients until the technique is well established and validated . In thisHowever, this is a first report on the described technique in the reduction of a reversed Hill-Sachs lesion and further studies are needed with special remark on complications and their management.In our described case the reduction of the reverse Hill-Sachs lesion by use of inflation osteoplasty enabled us to achieve an almost anatomical reduction in the humeral head without limitation of external rotation as commonly found in patients after remplissage or tendon transfers and there we see the great advantage of the presented technique. In cases with isolated reverse Hill-Sachs lesions the application of the balloon osteoplasty might be even performed arthroscopically and thereby further reducing the comorbidity of the open surgical approach.Written informed consent has been obtained from the patient for the publication of this case report and any accompanying images.A copy of the written consent is available for review for the editor-in-chief of this journal."}
{"text": "Since the discovery of the structure of the DNA double helix in 1953 by Watson and Crick . It tookHans-Achim WagenknechtKarlsruhe, November 2014"}
{"text": "The cell's fate is largely governed by the dynamics of cellular events, brought about by the interplay of various proteins, in which post-translational modifications (PTMs) play a key role. Therefore, a better understanding of post-translational modification is of utmost importance to a biochemist. Over the years much work in this regard has been achieved through mass spectrometry, however, the \u201con-off\u201d nature of PTMs, which accounts for cell's dynamics, has posed a serious challenge in quantitating them, especially with regards to measuring the occupancy of PTMs on a particular site. Protein phosphorylation has served as the best model for which measurement of occupancy has been attempted by employing stable isotope labeling and label-free approaches. But the reliability of these methods has mainly been limited to the relative quantitation between samples. Although the fractional occupancy/absolute quantitation of phosphorylation has been determined by grossly applying these methods, but overall they fall short of testability. Moreover, the field demands a broad approach which can even encompass a more challenging task of absolute quantitation of Cys-based PTMs.For quantitation, differential labeling of samples with stable isotopes or in the label-free approach the peak intensity of a peptide ion or identification frequency of the peptides of a particular protein is used for measurement. Stable isotope labeling is achieved through metabolic labeling in cell culture or by chemical labeling in post-metabolic stage. For the metabolic labeling of proteins, the cell cultures are grown in the presence of naturally abundant amino acids (light version), and amino acids  labeled with heavy isotopes , this method is known as stable isotope labeling with amino acids in cell culture (SILAC). The ratio of the ion intensities of the peptide (light vs. heavy) in the MS scan is used for quantitation (Ong et al., per se. These standards are the pre-selected synthetic peptides from the protein of interest that gets labeled with an isotope. A known amount of the isotope labeled peptides are mixed with the sample and then introduced into the mass spectrometer. Absolute abundance of the PTM can be obtained by measuring the relative abundance of the modified and unmodified peptides and comparing it with the amount of standard used. Notably, stable isotope labeling and synthetic peptide standards were used in absolute quantitation of phosphorylation on Ser1526 in human separase (Stemmann et al., Stable isotope labeling for absolute quantitation requires internal standards that are used to measure protein abundance Interestingly, an integrated phosphatase treatment and stable isotope labeling approach was adapted for determining the absolute phosphorylation occupancy in the yeast proteome. This approach did not make use of any standard, instead equal amounts of protein lysates after protease-digestion were either mock- or phosphatase treated, differentially labeled with stable isotope and subsequently mixed. The absolute phosphorylation site occupancy was represented by the single ratio between the non-phosphorylated peptides with and without phosphatase treatment (Wu et al., per se is very low. Thus, looking at the fast pace of the field and the continuous out-flux of ideas from the think-tank, the doorway for site occupancy measurement of Cys-based PTMs is already open but to come up with a foolproof method, would require some sound strategizing.With the present day, state-of-the-art technology and improved methodology we have made significant progress in characterizing phosphorylation and the databank is increasing every day. Nonetheless, another segment of the field; Cys-based PTMs considerably lags behind! The mechanistic insight of Cys-based modifications, in particular, S-nitrosylation and S-palmitoylation, is ever growing, and their involvement in regulating various cellular events is quite plausible. There are few remarkable methods developed over the years to identify the Cys-sites of these modifications with mass spectrometry, like the biotin-switch technique and SNO-Rac for S-nitrosylation (Jaffrey et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The term onco-nephrology has been coined in an attempt to highlight the evolution of an increasingly complex and important sub-specialty in the practice of renal medicine.The term onco-nephrology has been coined in an attempt to highlight the evolution of an increasingly complex and important sub-specialty in the practice of renal medicine. Given the improved survival and aging population, the prevalence of comorbidities is ever expanding and chronic kidney disease (CKD) is a major constituent. Between 2005 and 2009 >75% of cancer diagnoses occurred in individuals aged \u226565 years . When thMMA is the single author of the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the author.None."}
{"text": "Neural cell adhesion molecule (NCAM) plays important roles in the regulation of the brain plasticity during its development and in adulthood. NCAM functions may be regulated by the addition of long linear homopolymers of alpha 2-8-linked sialic acid (PSA). PSA is attached to NCAM via either of two specific sialyltransferases: ST8SiaII and ST8SiaIV. PSA-NCAM is expressed abundantly in the retina and optic nerve during development and adulthood. In the retina PSA-NCAM is expressed in the glial cells in close proximity to retinal ganglion cell (RGC). The functions of the PSA-NCAM in the retina remain unknown. The aim of this study was to investigate the roles of PSA-NCAM in the survival of RGCs after administration of the exitotoxin kainic acid (KA). Intraocular administration of KA induced reduction in the density of RGCs approximately by 60%. Administration of endoneuraminidase (Endo-N) an enzyme, which removes PSA residues from the surface of NCAM, enhanced the toxic effect of KA on RGC. In knockout mice with constitutive deficiency of either ST8SiaII or ST8SiaIV genes, the levels of PSA-NCAM did not differ from those in wild type mice. The toxicity of KA on RGC in these animals also did not differ from control. It should be noted, however, that in knockout ST8SiaII-/- adult mice a reduced number of RGCs was found despite the presence of high levels of PSA-NCAM. These data suggest that during development ST8SiaII ensures high levels of PSA-NCAM, which necessary for the developmental survival of RGCs. The PSA-NCAM in the adult retina ensures the resistance of RGCs to injury."}
{"text": "Recognition of systemic autoinflammatory diseases (SAIDs) in the last decade is growing rapidly. About 250 children is under care with suspicion or diagnosis of SAIDs in our centre and monitoring of inflammatory markers is fundamental in their diagnosis and monitoring of treatment.To check the practical usefulness of home CRP monitoring in patients during diagnosis or monitoring of autoinflammatory diseases.Ten patients with genetically confirmed or suspicion of AIDs  were monitored at home with both use of diary of symptoms/treatment and regular CRP measurement.CRP levels were checked by parents at home using ready-to-use system on a finger-prick blood sample of their child.Ready-to-use system provided patients with very fast, easy to perform and safe CRP measurement, having obtained reliable results.Children and their parents found avoidance of frequent outpatient clinic visits and painful collection of blood from veins extremely important. Parents were able to use the system properly just after 2-3 hours of practical training.Regular, up to twice a day measurement of CRP greatly facilitated the diagnosis and monitoring of patients' treatment. It proved to be extremely useful in an appropriate modification of treatment with the use of steroids in PFAPA or IL1-blockers in TRAPS.The results of introductory pilot study of home measurement of CRP levels in children with autoinflammatory diseases are encouraging. The opportunity of fast, regular monitoring of inflammatory marker in home conditions improved both diagnostic-therapeuthical process as well as quality of children's life."}
{"text": "The considerable pressure on healthcare systems, exerted by increasing expenditures for new drugs, urges specific initiatives, including the development of new models, to optimize the managed entry of new medicines and guarantee their sustainability.To develop a forecasting model for drug utilization and expenditure of emerging medicines identified, prioritized and critically assessed by the Italian Horizon Scanning Project (IHSP), integrating a cellular automata (CA) model describing the diffusion process on the market with the budget impact analysis (BIA), performed before the market entry of a new drug.Selection and critical evaluation of high-impact emerging medicines. Development of CA and BIA models for emerging drugs, using medical prescription data from the administrative ARNO-CINECA databases.The first-in-class emerging anti-diabetic dapagliflozin was selected and critically evaluated by the IHSP about 12 months before the European Marketing Authorization (MA). Other competitors already on the market were identified. A CA model describing the diffusion process of more than 200 Italian specialties of oral antidiabetic drugs (ATC A10B), sold between 2000 and 2014 has been developed and validated.A protocol for the identification of the real-world target population in the ARNO-CINECA database was set up on the grounds of the expected indication for dapaglifozin. The estimation of the budget impact of dapagliflozin is ongoing based on the estimation of market shares, through the application of the CA model, the analysis of the identified target population and the analysis of the potential variations in related healthcare costs for the treatment of type 2 diabetes, after the introduction of dapagliflozin.The proposed forecasting model (C-ToBIA model) predicts the impact of emerging drugs on the National Health System (NHS), under the sufficient conditions for estimability. The originality of the C-ToBIA model is basically related to the assessment of emerging drugs 12 months before the MA date, and the estimation of the diffusion process and the potential financial impact before market entry.The C-ToBIA model will help to timely estimate the possible utilization pattern of new medicines and their potential impact on the NHS before their market entry."}
{"text": "We examined the extent to which the two generic health- related quality of life (HRQL) measures recommended for use in adult, general critical care  - the SFA patient-based conceptual framework for survivors' HRQL was built using: a systematic review of the literature; secondary analysis of 40 in-depth interviews with adult critical care survivors; and primary analysis of in-depth interviews with a maximum variation sample of 25 white critical care survivors in England. Two methods were then used to assess the extent to which the SF-36 and EQ-5D captured their HRQL, as detailed in the framework: the content of both instruments was examined, alongside data collected from the in-depth interviews; and the opinions that survivors expressed about how accurately the SF-36 and EQ-5D reflected their ideas on health and HRQL were analysed and taken into account.The patient-based framework was in two parts: the first covered survivors' personal status which consisted of their physical status, emotional/psychological status and cognitive status; and the second comprised nine subdomains affected by their personal status. The latter were: activities and behaviours; physical zone of comfort and/or activity; interactions and relationships with others; perception of, interpretation of, and responses to life; personality; external appearance; suitability and availability of clothes; place of residence; and finances. The current generic measures recommended on the basis of expert consensus for use with survivors of adult, general critical care have substantial gaps in their coverage of this conceptual framework for survivors' HRQL, particularly in relation to their cognitive status and its subsequent impact.The two most commonly used generic HRQL measures in adult, general critical care have significant gaps in their coverage of survivors' HRQL. Any (new) critical care-specific HRQL measure should be designed specifically to capture the impact of critical illness on survivors' cognitive status and its subsequent effects."}
{"text": "In recent years, small-world graphs have gained considerable interest as models of real-world systems, which often display features residing between regularity and randomness. The most notable of these models is the Watts-Strogatz graph , though Theoretical investigations of small-world graph models have generally applied asymptotic evaluations in the limit of large system size  or the cWe then utilize the exact nonasymptotic expression for the clustering coefficient in order to assess the small-worldness of structural brain networks in an analytic setting. Using the number of nodes and edges of the given brain networks to construct the equivalent small-world network, we observe that a significant edge rewiring of at least 20% up to 60% is required to produce the small-worldness indices observed in these networks. Importantly, the maximum of the small-worldness index however occurs in all cases at one order of magnitude lower than the required rewiring found. This result suggests that neural graphs reside far away from the small-world regime of the Watts-Strogatz model."}
{"text": "In recent years the study of age-related derangements of the gonadotropin releasing hormone (GnRH) synthesis and secretion resulting from both the GnRH gene expression changes and interaction of glia with GnRH-ergic neurons of the hypothalamus is a focus of attention. It was demonstrated earlier that this could result from the decreased activity of monoaminergic and peptidergic systems that control the GnRH preovulatory secretion surge initiation, specifically from the loss of the signal coming from the suprachiasmatic nuclei (SCN) of the hypothalamus. This signal is critical for the emerging of the GnRH regular cyclic secretion, which is mediated prominently by vasoactive intestinal peptide (VIP). We have studied age-related changes in the biogenic amines and VIP content in the hypothalamic structures responsible for the GnRH synthesis and secretion. It has been shown by us that the GnRH level in the median eminence with the arcuate nuclei (ME-Arc) of the hypothalamus of 22-month-old rats is half as high compared to that of 7-8-month-old animals. Beside that, the VIP level in the SCN tended to decrease, with the norepinephrine, dopamine, and 5-hydroxyindoleacetic acid levels decreased significantly in the median preoptic area of the hypothalamus responsible for the GnRH synthesis and in the ME-Arc exercising its secretion into the portal vein of the pituitary. It has been shown that the initial phase of the reproductive failure with 13-14-month-old animals having irregular estrous cycles is characterized by gradual disappearance of the normal biogenic amine diurnal dynamics in the studied hypothalamic structures, which could be due to the loss of regulatory signals coming from the SCN."}
{"text": "There is growing evidence of an accumulation of mutations and mechanisms of resistance to targeted therapies in cancer. Non-small-cell lung cancer (NSCLC) is still an untreatable disease and is the leading cause of cancer related deaths worldwide . Various"}
{"text": "The nonlinear mean-field dynamics of spiking neuronal networks with non-homogeneous connectivity is studied numerically and analyzed mathematically. The network under study is comprised of three subnetworks of either excitatory or inhibitory leaky integrate-and-fire neurons, two of which are of the same type. The excitatory and inhibitory weights are arranged to establish and maintain a balance between excitation and inhibition for a constant external drive. Each subnetwork has random connectivity with fixed in-degree and fixed out-degree for all neurons belonging to a particular population (configuration model). Neurons are also randomly connected with the same probability across different subnetworks; however, depending on their identity, the connection weight is scaled by a common factor. We observed that for a certain regime of ratios of the \"within\" versus \"between\" connection weights (bifurcation parameter), network activation spontaneously switches between the two subnetworks of the same identity. In the mean-field model, this phenomenon is explained by a set of coupled stochastic differential equations of Lotka-Volterra type ,2 that eThe deterministic phase portrait is characterized by two attractors and a saddle node, its stochastic component is essentially given by the multiplicative inherent noise of the system . We obse"}
{"text": "The control and scaling of the input-output behavior of neural networks, or gain control, is one of the main strategies used by neural systems for the processing and gating of information. This input-output behavior is often described by the so-called f-I curve, which shows the output firing rate as a function of the input current to the neuron or neural circuit . In partSeveral gain control behaviors have been found to be particularly relevant for the gating and transformation of information in neural circuits. For instance, common biological mechanisms have been found to produce subtractive effects in the f-I curve , while ain vivo in weakly electric fish.We present here (see  for furtin vitro experimental recordings in the electric fish [Our work illustrates how subtractive, divisive and non-monotonic gain control may be obtained in inhibitory feedforward neural circuits. In addition, the analysis of the conditions in which the f-I response curve of superficial pyramidal neurons becomes non-monotonic reveals a novel nonlinear gain control mechanism which agrees with ric fish ."}
{"text": "The activator\u2019s principle action is based on application of light of powerful light-emitting diodes with the big intensity of a luminescence of monochrome color without a thermal component.Several techniques are used for detection of dental caries including a fiber-optic light (FOL), the method of optical coherence tomography (OCT), the method of fiber optic transillumination and the infrared tomography. For an assessment of light-induced fluorescence of hard dental tissues and primary dental caries diagnosis, we propose to use the domestic light-emitting-diode activator \u201cLED active\u201d, , with a wavelength of 530 nanometers and illumination of 10 000 meter-candle, and also wavelength of 625 nanometers at the 140 MWt/cmThe present study employed 150 18-45 years old subjects. For the diagnosis and severity of initial caries we used \u2013 light-induced fluorescence and electrometric diagnostic tools. Caries prevention was attempted by daily applications of remineralized preparation \u2013 \"Radogel-GAMK\" with amino acids and hyaluronic acid for the caries precaution at the early stages for 15 days.Under the influence of a \"Radogel-GAMK\"\u2019s preparation parameters of electrometry at group of surveyed patients with initial caries have decreased by one third on hillocks, in fissures and on seal border. On fragment enamel and vestibular surfaces - in half, accordingly.Under the influence of green light (530 nm) on the demineralized enamel area, zone of increased opacity was identified and, confirmed by the presence of microbial contamination and degradation products. The extent of opacity of demineralized enamel correlated with the process of demineralization and the index of fluorescence signal (+). The use of red light (625 nm) allows identifying secondary caries on borders of abutment filling, which is manifested as a center of brown pigmentation of varying intensity. Reducing opacity of demineralized tooth enamel under the green light impact, allowed assessment of the remineralization effect of dental hard tissues and restoration of its organic and mineral components.As a result of research special parameters confirming the enamel changes after the impregnation by organic components that make up the protein matrix of the tooth have been identified. Remineralizing effect was proved by a reduction of electrometry parameters and opacity of demineralized tooth areas.Thus, studies of light-induced fluorescence can offer an actual and effective method of early detection of initial carious lesions."}
{"text": "Over a half-century ago, the scientist Vannevar Bush explored the conundrum of how to tap the exponentially rising sea of human knowledge for the betterment of humanity. In his description of a hypothetical electronic library he dubbed the memex, he anticipated internet search and online encyclopedias Bush, . By blurShould we achieve such BCI integration, we would come up against the attentional, multi-tasking and global processing limitations of the brain. Both in terms of overall spatial architecture and in moment-to-moment engagement of the world, we appear to have a limited amount of real-estate or bandwidth to work with (M\u00fcller et al., While we can learn to pay attention to multiple things simultaneously, there appears to be an upper limit to our moment-to-moment information processing capacity after which performance on any given sub-task breaks down (Busse et al., If we can identify the neural signatures of meditative states then we can, both with traditional techniques of breathing and posture ubiquitous to prayer and meditation the world over, and with neurofeedback facilitated by neural modules designed to allow the conscious mind to gain unprecedented perception of the power spectral and ensemble unit firing activity patterns of the brain itself, move our brains into meditative states with improved attentional and integrative capacity (Dickenson et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Bioactive peptides within original food-derived proteins are inactive but can be activated by being released during food processing (by enzymatic hydrolysis or fermentation) or during gastrointestinal digestion. Hence, the utilization of computer-aided techniques as screening tools may be helpful in predicting the potential of food proteins as precursors of DPP-IV inhibitory peptides. This paper reviews the current literature on DPP-IV inhibitory peptides, focusing on their in vitro activity and in vivo antidiabetic effects. In addition, the feasibility of various in silico approaches is also summarized in this review.One of the new approaches to the management of type 2 diabetes mellitus (T2DM) consists of orally administered dipeptidyl peptidase-IV (DPP-IV) inhibitors. These synthetic drug inhibitors are reported to have some side effects and that subsequently limits their applications. There is a growing interest to develop natural DPP-IV inhibitors that will be potent without undesirable side effects. Many  Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder that is characterized by insulin insensitivity as a result of impaired insulin secretion, insulin resistance, and eventual pancreatic beta-cell failure , 2. T2DMOne of the novel strategies for the treatment of T2DM consists of orally administered dipeptidyl peptidase-IV  inhibitors. The enzyme DPP-IV, a serine protease, has a specificity to remove dipeptides from the N-terminus of substrate poly-peptides by cleaving postproline or alanine residues . It is pin vitro DPP-IV inhibitory activity. Research on some DPP-IV inhibitory peptides has shown that they are effective at stimulating insulin secretion and improving glycemic control in animal models and subjects with T2DM . The authors of the study suggested that the peptide may not bind to the active site of DPP- IV as assumed in the docking prediction. Their results revealed that there is no clear relationship between the docking affinity and the DPP-IV inhibitory activities of the peptides. In addition, they showed that the utilization of molecular docking can be a predictive tool for the competitive inhibitors. Thus, docking can be used as a preliminary tool to help focus experimental screening efforts on a smaller number of candidate peptides.Additionally, a docking analysis has also been used as an in vitro or in vivo hydrolysis. Further effort is therefore needed on the development of an in silico approach capable of being used as a screening tool for the evaluation of the potential of dietary proteins for the generation of in vitro and in vivo DPP-IV inhibitors.Since the studies relied entirely on the currently available data on DPP-IV inhibitory peptide sequences, it is possible that other fragments presenting even better DPP-IV inhibitory activity are presently unknown or have not yet been reported in the literature. Furthermore, the putative peptide sequences have to be released from their parent proteins to become active, and the final conclusions on the potential of dietary proteins for DPP-IV inhibitors can be drawn only after experimentally assessing the release of these bioactive peptides upon in vivo antidiabetic effect needs to be built in more animal and clinical studies. The \"BIOPEP\" database is responsible for collecting all of the information about bioactive peptides from academic literature, and 707 protein sequences are also available. Further research into the establishment of in silico approaches to efficiently predict the potential of proteins as the precursors of DPP-IV inhibitory peptides is necessary.The importance and scientific understanding of DPP-IV inhibitors that may improve glycemic control in T2DM patients has increased in the last few decades. Much work has been done with food protein-derived DPP-IV inhibitory peptides; however, the evidence of their in vivo antidiabetic activity. Albeit the simulated GI digestion is a kind of model mimicking the actions of human GI enzymes, the antidi- abetic effect of the peptides released from the DPP-IV inhibitory peptides through simulated GI digestion is not guaranteed to be similar to that through the GI tract in vivo. So the possible strategies for increasing the resistance to digestive enzymes as well as the cellular permeability of the peptides are two factors that also need to be investigated.The most challenging task in the DPP-IV inhibitory peptide research is the establishment of a detection model for identification of possible mechanisms by which they can exert"}
{"text": "Modern medicine cannot avoid the understanding of the fine-tuned communication between the many, seemingly distinct systems in the body. An excellent example of this is the challenge to understand the bi-directional communication between the brain and the immune system. Brain-immune interactions take place in different organs, involving a wide range of cells and mediators, coordinated through sensory and effector pathways in the central nervous system , a mouse model of multiple sclerosis  shape the responses of macrophages, mast cells and other immune cells throughout the body and how these interactions contribute to immune defense and diverse inflammatory conditions (Assas et al., Neuro-immune abnormalities not only affect adults and the elderly, but also play a role in diverse diseases that manifest in children. D'Angiulli et al. show that children in the Mexico City Metropolitan Area, who are chronically exposed to high concentrations of air pollutants, present with increased amounts of inflammatory mediators along with accumulation of misfolded proteins in the cerebrospinal fluid (Calderon-Garciduenas et al., Paul Ashwood and colleagues report that the behavioral characteristics, including social deficits, repetitive grooming behavior and atypical vocalizations, observed in BTBR T+tf/J mice are associated with the development of an inflammatory macrophage phenotype in this strain (Onore et al., We hope that the articles presented in this research topic give thought-provoking and valuable insight into some of the important aspects of brain-immune interactions. Neuro-immune processes are likely to contribute to diverse pathologies in both the periphery and the brain leading to complex human diseases that affect millions of people worldwide. Understanding mechanisms of neuro-immune interactions could help to find appropriate therapies to some of these conditions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The analysis of dynamic volume-dependent compliance provides the rationale basis for PEEP titration during mechanical ventilation. Due to its volume dependence, the compliance of the respiratory system is nonlinear within each single breath , which is reflected in the compliance-volume curve (CV curve). The shape of the CV curve is determined by the PEEP level. The mechanical stress for the mechanically ventilated lung is expected to be minimal when the lung is ventilated within the volume range of maximal compliance. We present a new graphical user interface (GUI) that supports the clinician to titrate the PEEP level by means of a shape category analysis of the CV curve.A decision support system in the form of a computer-based GUI was developed and tested using respiratory data obtained from patients of the University Medical Center Freiburg. The new clinician- oriented approach provides a breath-by-breath visualization of the patient's individual intratidal CV curve. The dynamic compliance was analyzed using the gliding-SLICE method . The resThe GUI provided a breath-by-breath visualization of the intratidal CV curve and the intuitive individual compliance shape category. Based on the compliance shape category, different guidelines of PEEP titration were applied with the objective of ventilating the patient mechanically within the range of maximal compliance.The newly developed GUI allows a breath-by-breath visualization of the intratidal CV curve with high reliability. Automated classification of the intratidal CV curve into compliance shape categories provides the rationale basis for patient-individual PEEP titration."}
{"text": "Unexpectedly, we find that the mass enhancement of itinerant charge carriers in the strongly correlated band is dramatically reduced near the \u0393 point and attribute this effect to orbital mixing induced by pronounced spin-orbit coupling. Embracing the true band structure allows us to describe all low-energy electronic properties obtained in our experiments with remarkable consistency and demonstrate that superconductivity in this material is rather weak and mediated by spin fluctuations.Iron-based superconductors have been found to exhibit an intimate interplay of orbital, spin, and lattice degrees of freedom, dramatically affecting their low-energy electronic properties, including superconductivity. Albeit the precise pairing mechanism remains unidentified, several candidate interactions have been suggested to mediate the superconducting pairing, both in the orbital and in the spin channel. Here, we employ optical spectroscopy (OS), angle-resolved photoemission spectroscopy (ARPES),  The outer hole band of Fe-3dxy orbital character in The effect of electronic correlations on the low-energy electronic structure of uin zone  reveals k\u2014quasiparticle wave vector, and E\u2014quasiparticle energy. For a parabolic dispersion Quite surprisingly, the outer hole band\u2019s dispersion reveals a departure from a parabolic shape , the dispersion of the hole bands at low energies shows a pronounced departure from that obtained in the non-relativistic calculation presented in The aforementioned reduction of the effective mass due to orbital mixing does not rely on the existence of strong electronic correlations and should be observable already at the level of quasiparticle band masses. Indeed, effective electronic subsystems: one with a large and the other one with a small scattering rate  from an intermediate boson. This conclusion is consistent with the association of the broad Drude component with electronic correlations based on the doping dependence of the optical conductivity in various iron-based compounds24It is tempting to assign the narrow Drude component to the combined response of charge carriers on the electron sheets of the Fermi surface  n is the electron density, e and me are the bare electron charge and mass, respectively. Quite similarly, the itinerant spectral weight  is also constant, with me substituted by the quasiparticle band mass including renormalization at energies larger than the plasma frequency. Any low-energy mass renormalization due to, e.g., coupling to phonons or other bosonic excitations will not affect this spectral weight as long as its characteristic energy is smaller than the plasma frequency of free charge carriers. On the other hand, the low-energy band structure and the plasma frequency extracted from it will be affected by such renormalization. Therefore, the comparison of the total itinerant plasma frequency obtained from OS and ARPES data provides access to purely boson-exchange\u2013induced effective mass renormalization even when it is not immediately apparent in the experimental band structure. In the present case of \u03bb via Fortunately, even in such complicated cases the spectral-weight analysis of the itinerant optical response bears fruit. It is well-known that the total spectral weight of any system  is constant and does not depend on the details of the band structure:  to  see . This isHaving established that only three out of five electronic bands predicted theoretically actually contribute to the itinerant carrier response of in  ref. . Our anaThe vanishing of the optical conductivity in the superconducting state  are in a very good agreement with the properties of the two effective itinerant electronic subsystems extracted in the Drude analysis of the conductivity data in Our theoretical analysis of the optical conductivity in the framework of an effective two-band Eliashberg model thus reconciles all of the characteristic energy scales and spectral features observed in trum see , below wThe remarkable agreement between different experimental probes and theoretical tools employed in this work demonstrates the importance of employing a realistic electronic band structure to interpret the low-energy electronic properties in such complex multiband systems as iron-based superconductors, if complete and consistent understanding of their properties is to be achieved. Our observation of a dramatic reduction of the effective mass in one of the electronic bands of 3\u2013ARPES\u201d end-station at BESSY) within the range of photon energies 20\u201390\u2009eV and various polarizations on cleaved surfaces of high-quality single crystals of Angle-resolved photoemission measurements were performed using synchrotron radiation ."}
{"text": "The North Western Mental Health Eating Disorder Program at The Royal Melbourne Hospital provides treatment for adults 18 years and over since 1994. The eating disorder program provides an in-patient and day-patient treatment program and comprehensive out-patient services.Family members have been an effective and vital support for clients with eating disorders in their treatment and recovery in our day patient program. This pilot trial is to explore the family dynamics and confidence of family members in supporting in-patient clients with anorexia nervosa during a meal. Family members would be empowered with evidence based knowledge and strategies to support their loved ones through a meal prior to discharge as part of the discharge planning.The theoretical framework for this trial is based on a modification of the Family-Based Therapy (FBT). In several controlled studies, it has proven that Family-Based Treatment to be successful in an out-patient setting especially for adolescent in helping individual in weight restoration."}
{"text": "The goal of public health interventions is to move the distribution of life style risk factors in a healthier direction to decrease disability-causing disease and improve quality of life in the population. We recently presented a novel method to estimate the population-level impact of a public health intervention, using changes in the distribution curve of the outcome of interest. This method makes it possible to calculate the proportion of the target population that benefited from an intervention. The objective of this study is to demonstrate the potential of the new method to estimate not only the effect, but also the cost-effectiveness of public health interventions.A population-based model called Risk factors, Health and Societal Costs (RHS) was developed to simulate changes in incidence and related societal costs of several chronic diseases, following assumed changes in four life style risk factors: obesity, tobacco smoking, physical inactivity, and risky consumption of alcohol. The RHS model is based on relative risks and simulates changes in disease incidence due the reduction of the prevalence of a risk factor that can be attributed to diverse interventions. The health gains are calculated as decreased incidence of the disease, increased health-related quality of life years (QALYs) and decreases in disability-adjusted life years (DALYs). Swedish national registers were used to retrieve disease-specific medical care costs, while local authority costs for care and sickness insurance expenses were estimated via a Swedish study. The changes in the distribution of physical inactivity as a result of a hypothetical mass-media campaign targeting the adult population in Uppsala County was used as the input parameter for the model.The hypothetical intervention was estimated to improve the distribution of physical inactivity and the overlapping area between the distribution curves at baseline and follow-up was calculated as two percent, i.e. a 2% reduction in the prevalence of physical inactivity. This reduction among the Uppsala County population under five years is estimated to lead to a health gain of 14 QALYs and societal savings  of 6 million SEK . The intervention is estimated as cost-effective if the intervention costs are less than 900,000 GBP with ICER<30,000 GBP/QALY.This study opens a new avenue to calculate the cost-effectiveness of public health interventions by using changes in the distribution curve of health-related outcomes combined with population-based modeling of risk reductions and costs."}
{"text": "There is controversy regarding needle aspiration for primary spontaneous pneumothorax (PSP), with contradictory recommendations between the American College of Chest Physicians consensus statement (2001) which suggests that needle aspiration has little place in the management of PSP, and the British Thoracic Society guidelines (2010) which recommend that needle aspiration be attempted first for all cases of PSP where drainage is deemed necessary. Studies have shown that there is no significant difference between needle aspiration and tube thoracostomy with regard to safety, rates of immediate success and early failure and has the advantages of decreasing pain, reducing rates of hospital admission and duration of hospital stay compared to tube thoracostomy. Point-of-care ultrasound can facilitate needle aspiration by decreasing the risk of complications and detect pneumothorax resolution during or reexpansion after the procedure.This is a case series where the sonographic finding of the \"lung point\" on point-of-care ultrasound was used to facilitate needle aspiration to monitor pneumothorax resolution during or reexpansion after the procedure.We report three cases of PSP in adolescents presenting to the pediatric ED, where needle aspiration was safely performed by using ultrasound to track the sonographic finding of the \"lung point.\" This technique allows the determination of pneumothorax resolution or reexpansion in real-time.Point-of-care ultrasound may assist in the evaluation and management of spontaneous pneumothorax in the pediatric ED. Ultrasound assisted needle aspiration may be a safe and less painful option for pediatric ED patients with PSP."}
{"text": "Attention represents one of the main mechanisms of modulation of pain  of gamma oscillations increased  while alpha decreased (750 ms) during stimulation of the attended compared to the unattended finger. Conversely, the increase of stimulus intensity was associated with power increase in delta (300 ms) and gamma bands, and power decrease in alpha and beta bands (600 ms). Source analysis identified the contralateral insula as generator of gamma activity during top-down attentional control, and the sensory-motor and mid-cingulate regions as gamma activity generators during bottom-up capture of attention. The activation found in the sensory-motor areas during bottom-up attention is not surprising as previous studies reported the association between activity in the primary somatosensory cortex and selective nociceptive laser stimulation (Timmermann et al., A relevant aspect of Hauck et al.'s study (Hauck et al., Tiemann et al.  found thOther studies reported a gamma-band modulation by top-down attention during different sensory modalities (Fries et al., Despite differences in stimuli and methodology, altogether these studies indicate the gamma-band oscillatory activity may not only index bottom-up salience of the sensory event but also top-down relevance of the sensory representation for the ongoing behavioral goals. However, further methodological and analytical efforts will be needed to clarify the role of the gamma activity across different types of top-down attention manipulations.VN has developed most of the content of the article. EV has supervised her during the writing and he has edited the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Current Challenging Medical Image Analysis\". This issue consists of two selected papers presented at the 35th IEEE-EMBC Workshop on Current Challenging Image Analysis and Information Processing in Life Science, which was held on 03 July 2013, Osaka, Japan; and one invited paper to reflect the theme of this issue. All three papers were accepted based on the peer-review process of BioMedical Engineering Online journal.The theme of this special issue (supplement) is \"Deformable part models for object detection in medical images\" by Klaus Toennies, et al., presents a novel application of a deformable model of the finite element method for the detection of objects in medical images. This proposed approach is promising for context-based detection, model-based segmentation, and shape analysis of medical objects.The first paper entitled \"Motion correction of whole-body PET data with a joint PET-MRI registration functional\" by Michael Fieseler, et al., makes use of the multi-modal information simultaneously provided by both PET (position emission tomography) and MRI (magnetic resonance imaging) data for the registration and correction of respiratory motion, whereas current methods for PET-MRI-based motion correction do not utilize the valuable sources of information provided by PETdata.The second paper entitled \"Automated CT detection of intestinal abnormalities and ischemia for decision making in emergency medicine\" by Taichiro Tsunoyama, et al., reports an original work on automated image analysis of bowel ischemia and abnormality patterns, which is important for the urgent treatment of patients in emergency departments. The combination of the sources of knowledge from medicine and imaging science offers a computer-aided tool that can be essential to surgeons to gain insights into this complex disease.The last paper entitled \"BioMedical Engineering Online for his approval of the proposal of the publication of this special issue. It was a great pleasure to work with Ms. Sarah Headley of BioMed Central, who kindly and frequently communicated with the Guest Editor in all editorial aspects to help ensure the editing quality and timely publication of this special issue.Many thanks are to Professor Kenneth R. Foster, the Editor-in-Chief of December 2013Tuan D. PhamGuest EditorThe Supplement Editors declare that they have no competing interests."}
{"text": "Indigenous populations around the world have consistently been shown to bear a greater burden of disease, death and disability than their non-Indigenous counterparts. Despite this, little is known about what constitutes cost-effective interventions in these groups. The objective of this paper was to assess the global cost-effectiveness literature in Indigenous health to identify characteristics of successful and unsuccessful interventions and highlight areas for further research.A systematic review of the published literature was carried out. MEDLINE, PSYCINFO, ECONLIT, EMBASE and CINAHL were searched with terms to identify cost-effectiveness evaluations of interventions in Indigenous populations around the world. The WHO definition was followed in identifying Indigenous populations. 19 studies reporting on 27 interventions were included in the review. The majority of studies came from high-income nations with only two studies of interventions in low and middle-income nations. 22 of the 27 interventions included in the analysis were found to be cost-effective or cost-saving by the respective studies. There were only two studies that focused on Indigenous communities in urban areas, neither of which was found to be cost-effective. There was little attention paid to Indigenous conceptions of health in included studies. Of the 27 included studies, 23 were interventions that specifically targeted Indigenous populations. Outreach programs were shown to be consistently cost-effective.The comprehensive review found only a small number of studies examining the cost-effectiveness of interventions into Indigenous communities around the world. Given the persistent disparities in health outcomes faced by these populations and commitments from governments around the world to improving these outcomes, it is an area where the health economics and public health fields can play an important role in improving the health of millions of people. There are almost 400 million Indigenous people living in countries around the world Economic evaluation of health care programs has become an important area of applied economics over the last 30 years The objective of this review is to systematically search the literature to pull together existing evaluations that estimate the cost-effectiveness of health interventions into Indigenous populations around the world. This review allows for an exploration of the type of interventions that have been shown to be effective in these unique population groups, the specific resource requirements needed to deliver programs to these populations and the aspects of these programs that are deemed to be of value by the populations to whom they are targeted.There is an increasing recognition of the shortcomings of traditional methods of measuring health benefits in economic evaluations of healthcare programs To provide a basis for further evaluating these arguments, this review also highlights any explicit attempts by included studies to incorporate these concerns into cost-effectiveness evaluations.A systematic review of the literature was conducted to find articles that provide an economic evaluation of interventions targeting or reporting on an Indigenous population. No protocol has been previously published for this review.The inclusion criteria for this review specified three characteristics for studies. First, the studies had to examine interventions that were primarily aimed at improving the health of target populations. Second, included papers had to be economic-evaluations of an intervention that met the definition of one of the types outlined in A search was conducted of CINAHL, MEDLINE, EMBASE, PSYCINFO and ECONLIT (from inception to May 2014) using variations of the search string contained in Study review, selection and data extraction were independently undertaken by two authors (BA and JM). Abstracts, titles and keywords of the studies returned from the search were screened for compatibility with the inclusion criteria. Once studies were identified for potential inclusion, full texts were reviewed. Data were extracted from the studies using a form developed for the review based on standard techniques used in the literature and included the following items: country of origin, methodology including type of evaluation, comparators used, outcome measures, settings and participants, results and evidence of inclusion of Indigenous conceptions of health The search yielded 559 abstracts see . One furSeven studies were conducted in Australia (covering eleven interventions) Two studies evaluated interventions in urban areas, one looking at a midwifery program The majority of the studies focused on Indigenous populations with known health conditions including diabetes  Of the 27 interventions included in the study, two were carried out in infants Studies were broadly grouped into two groups. The first included group included studies where authors collected effectiveness data within the study itself (twelve studies and sixteen interventions) The types of economic evaluation are outlined in Costs were the primary outcome measure reported in eight of the studies Each included paper made some judgment as to the cost-effectiveness or cost-impact of the interventions being studied. In total, only five of the 27 interventions were deemed to be strictly not cost-effective or cost-saving The choice of comparator against which the cost-effectiveness of the intervention is assessed plays a large part in determining whether a particular intervention is cost-effective or not. Included studies could be grouped into two main categories in this regard. Fourteen of the studies assessed the cost-effectiveness of their intervention against so-called \u2018business as usual\u2019 cases where they were compared to a situation with no intervention, either through the use of a control group Only one study that met the inclusion criteria explicitly set out to capture wider benefits of culturally appropriate service provision This systematic review has found that very few cost-effectiveness studies are available in the published global Indigenous health literature. This has implications for generating investment into Indigenous health programs since the lack of such evidence limits our ability to assess the investment-case of interventions based on the criteria of cost-effectiveness, rather than solely for equity reasons or broader policy objectives. This is concerning given the significant disparities in health and access to health care that exist between Indigenous and non-Indigenous populations worldwide. Nonetheless, the evidence-base that does exist in the literature provides some isolated insights into the potential cost-effectiveness of specific types of interventions. There is potential for further work to both increase the use of economic evaluation in this area and methodological work to ensure that health economic methodologies are relevant to Indigenous populations.A total of nineteen studies met the inclusion criteria for this review. Given the broad scope of the research question and search strategy, this depicts a very limited evidence-base from which to draw insights on the potential cost-effectiveness of interventions into Indigenous populations. This finding implies that investment into the area is largely being undertaken blind, based on assumptions rather than evidence of the cost and effectiveness of particular policies and interventions.Three main reasons are offered here as potential factors explaining the lack of research in the field. First, there is a general lack of effectiveness studies in the field of Indigenous health, with the majority of research carried out in the field being observational rather than interventional in nature While the evidence-base identified in this review demonstrates that traditional health economic approaches can ostensibly be used to show the cost-effectiveness (or otherwise) of interventions aimed at improving Indigenous health, there has rarely been much attempt to incorporate Indigenous valuations of the potential gains from such programs.Examples do exist in the literature of attempts to incorporate these values into economic evaluations of health interventions. The study of the Daruk-controlled midwifery service included above attempted to do so by taking a broader cost-consequence approach rather than restricting the analysis to narrowly defined health outcomes While there was a limited amount of cost-effectiveness research of interventions to improve the health of Indigenous population groups, a number of conclusions can be drawn from the studies that were identified.First, this review highlights that interventions into Indigenous populations, in particular rural and remote Indigenous communities, can be cost-effective, a broad but important finding given the often isolated and small populations of these groups when compared to non-Indigenous populations. Of the 27 interventions examined by included studies, 21 were deemed to be cost-effective or cost-saving while of the twelve interventions targeted solely to rural and remote populations, ten were found to be cost-effective or cost-saving by the respective studies. Being able to point to a body of evidence highlighting the cost-effectiveness of such interventions is important to justify widespread implementation of such programs on more than solely equity grounds and ensure that domestic debates on service provision are informed and based on the best available evidence.The evidence-base drawn together by this review provides insights into particular interventions. Outreach programs were shown to be consistently cost-effective or cost-saving in all six interventions studied. These interventions were assessed relative to populations obtaining the services from alternative service providers. Thus they were found to be cost-saving or cost-effective despite often representing relatively high-costs for the health gains that occurred. They may be prohibitively costly in low-income environments outside of donor provision and it is also unclear how sustainable or community appropriate such models of service provision are. Explicit decisions need to be made by policy-makers in assessing the appropriateness of these services to local conditions.The four injury prevention interventions were all found to be cost-effective as was the study of telehealth. Conversely, neither of two midwifery programs studied was found to be strictly cost-effective (one found non-significant cost-savings). Nor were the two studies focused solely on interventions in urban areas, highlighting the need for further work in this area. The majority of the interventions were targeted specifically at Indigenous groups (twenty-three interventions) and most were delivered through culturally specific medical providers, such as Aboriginal Medical Services in Australia and Canada. This is in line with findings from the literature that culturally specific services are more effective in reaching these populations While the strength of the review lies in the broad search strategy and research question, the heterogeneity of included studies limited the policy implications that could be drawn from the identified literature. The studies were of varied scope and included different notions of what constituted a cost-effective intervention. There are inherent difficulties in comparing the outcome of the studies when the notion of what constituted a cost-effective intervention varied so greatly between them.The studies identified were largely drawn from high-income nations and focused at a primary-care level in rural or remote populations. There is a large gap in the literature for Indigenous populations of low and middle-income nations. Similarly, urban Indigenous communities have been largely overlooked in the literature despite these communities often representing the bulk of Indigenous populations within countries. In Australia, for example, it is estimated that the 60% of the \u2018gap\u2019 in health outcomes between the Indigenous and non-Indigenous populations is a result of the health of urban Indigenous communities Despite global commitments to reducing Indigenous health disadvantage, relatively little is known about what constitutes cost-effective investments into Indigenous populations around the world. Furthermore, the evidence that exists has often relied on pivotal evidence extrapolated from non-Indigenous settings and been based on methods that have not allowed for the values that such communities place on health to be included. Nevertheless, in light of the limited available evidence, this review suggests that interventions into these often hard to reach populations can be cost-effective. Further economic research has the potential to provide much needed guidance to policy-makers on resource allocation decisions and help improve the health of Indigenous people around the world but it needs to be based on the development of methods that incorporate values specific to the communities in question.\u2003.Checklist S1PRISMA checklist.(DOC)Click here for additional data file."}
{"text": "Acetylcholine (ACh) signaling underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. Alterations in ACh signaling are involved in the pathophysiology of multiple neuropsychiatric disorders. In the central nervous system, ACh transmission is mainly guaranteed by dense innervation of select cortical and subcortical regions from disperse groups of cholinergic neurons within the basal forebrain  and the pontine-mesencephalic nuclei, respectively. Despite the fundamental role of cholinergic signaling in the CNS and the long standing knowledge of the organization of cholinergic circuitry, remarkably little is known about precisely how ACh release modulates cortical and subcortical neural activity and the behaviors these circuits subserve. Growing interest in cholinergic signaling in the CNS focuses on the mechanism(s) of action by which endogenously released ACh regulates cognitive functions, acting as a neuromodulator and/or as a direct transmitter via nicotinic and muscarinic receptors. The development of optogenetic techniques has provided a valuable toolbox with which we can address these questions, as it allows the selective manipulation of the excitability of cholinergic inputs to the diverse array of cholinergic target fields within cortical and subcortical domains. Here, we review recent papers that use the light-sensitive opsins in the cholinergic system to elucidate the role of ACh in circuits related to attention and emotionally salient behaviors. In particular, we highlight recent optogenetic studies which have tried to disentangle the precise role of ACh in the modulation of cortical-, hippocampal- and striatal-dependent functions. Acetylcholine (ACh) is essential to normal CNS function, modulating cognitive, emotional and behavioral functions, including learning and memory  or both  physiology. The role of ACh in specific behaviors has been addressed using lesions of cholinergic projections or pharmacological interventions with ACh receptor activation. Such approaches, though informative, are confounded by issues of bioavailability, lack of complete reversibility and the fact that such interventions act on time scales of unknown relevance for cholinergic driven changes in excitability With the exponential rise in the number and type of optogenetic tools developed over the last decade it is now possible to selectively stimulate or inhibit specific populations of CNS cholinergic neurons and/or their axonal terminal fields through the activation of light-sensitive opsins  reported a long-lasting ACh increase during attention-related performance tasks  to CA1 synapses  projections to the hippocampus with whole-cell patch clamp recordings and voltage sensitive dye (VSD) imaging it has been shown that inhibitory interneurons in the hippocampus receive cholinergic EPSPs in response to light stimulation of septal cholinergic fibers that are sensitive to Dh\u03b2E, but not MLA  and endogenous opioid systems may participate in the generation of ACh-dependent modulation of hippocampal oscillatory activity  and the nucleus accumbens (NAc), is strongly modulated by ACh. The main source of ACh to the VTA neurons in the midbrain arises from the brainstem structures LDTg and PPTg, which play a role in acquisition of reward, and reward-related locomotor activity  and muscarinic receptors, together with the activation of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in the enhancement of striatal DA release. Thus, a synergy exists between ACh and glutamate in modulating the activity of the striatal network. The source of glutamate may be the striatal cholinergic interneurons themselves  to striatal cells (Dautan et al., The application of optogenetic tools has accelerated the acquisition of precise information about the varied modulatory and direct synaptic signaling by ACh in an array of brain regions and behaviors. Selective expression of optogenetic probes in ChAT+ neurons allows studies of the connectivity, functionality and anatomy of cholinergic neurons and circuits throughout the rodent brain (Atasoy et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Processing of time intervals in short temporal ranges, typically in sub- and supra-second intervals, is vital for the survival of primates and humans. Research evidence has already shown that the processing of sub- and supra-second intervals is subserved by different neural mechanisms (Buhusi and Meck, The concept of the building block for \u201cneural oscillators\u201d in Gupta  in essenMovement is the expressed time (Teki et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Headaches and other cranio-oro-facial pains are widely distributed in the general population. Unfortunately, there is very little evidence regarding the impact of these conditions in patients admitted to rehabilitation units, regardless of the disease or syndrome requiring rehabilitation. The availability of diagnostic and therapeutic guidelines, as well as the increasing number of data coming from controlled clinical trials, should be implemented in these patients to reduce the burden of pain and improve their global outcome.http://www.doloreinneuroriabilitazione.it/).The Italian Society for Neurorehabiltation, in collaboration with the Italian Society of Physical Medicine and Rehabilitation, has promoted the Consensus Conference on Pain with the aim to foster attention on pain also in the rehabilitative field ;- Standard methods exist to evaluate migraine in terms of disability (A);- It is important to evaluate the impact of cephalic and cranio-facial pain in neurorehabilitation (D);- Standard methods or criteria exist to diagnose head and cranio-facial pain (GL);- It is important to identify predictive factors associated with the development of cephalic and cranio-facial pain in association with a condition requiring neurorehabilitation (D);- Effective pharmacological treatment exists for primary headaches and for trigeminal neuralgia (GL);- Manual therapy is indicated in the management of migraine and tension-type headache (GL);- Manual therapy may be effective in TMD-associated pain (D);- Botulinum toxin A is effective in the treatment of idiopathic trigeminal neuralgia (B);- Botulinum toxin A is effective in the treatment of hemifacial spasm (B);- Topical capsaicin is effective in chronic neuropathic pain (B);- Evidence is needed to evaluate the impact of treating cephalic and cranio-facial pain on the outcome of patients undergoing neurorehabilitation (D).The recommendations are presently under evaluation by the Consensus Conference panel."}
{"text": "The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer's disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory  substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed. Notably, oxidative damage to RNA -verapamil to study the function of the P-glycoprotein (Pgp) transporter at the blood-brain barrier (BBB) with PET [ in vivo and in vitro preclinical models may be particularly useful to test whether lithium and other medications commonly used in the treatment of BD can reverse and/or prevent BBB damage. If a link between BD and BBB disruption is established, this would not only advance the knowledge on the neurobiology of BD but also open numerous possibilities to investigate new treatment pathways  as a method for studying BBB disruption in vivo . Anotherwith PET . Finallyhibitors , ROS scahibitors ) for thi"}
{"text": "We describe the treatment of a patient with BN  who completed stage one and stage two of CBT-E at a specialist eating disorders outpatient clinic. Despite good compliance with all components of the treatment, the patient did not achieve an early rapid reduction in binge-eating and purging by the stage two progress review and was considered to be at-risk of suboptimal treatment outcome. Her repetitive negative thinking (worry and rumination) was identified as significantly interfering with progress, and the primary trigger for episodes of binge-eating and vomiting. In light of this, it was decided to evaluate the usefulness of abandoning CBT-E and switching to metacognitive therapy (MCT) for repetitive negative thinking (RNT). RNT is defined as cognitive perseveration on negative themes. MCT has been shown to demonstrate excellent outcomes in patients with anxiety and depressive disorders at the same clinic. Switching to a transdiagnostic meta-cognitive was associated with achieving optimal outcomes at the end of treatment. It is recommended that clinicians routinely assess the degree to which patients have achieved an early response to CBT-E and systematically evaluate the effectiveness of switching or pursuing CBT-E in this patient group.Treatment in Community and Inpatient Settings stream of the 2014 ANZAED Conference.This abstract was presented in the"}
{"text": "In most cases, hands of caregivers are the vehicle for the transmission of germs to the patient. Therefore, it is crucial to help medical staff and healthcare workers acquiring the skills necessary for optimal hand hygiene (HH) in order to ensure quality of care and patient safety.To give the caregivers a training tool well adapted to their needs and integrated into a blended learning (class and distance).The Hygiene Prevention and Infection Control (HPCI) Unit - Vaud, the Preventive Medicine Service of Center Hospital Universitary of Vaud (SMPH) in partnership with the collective of the Federation of Vaud Hospital, the Commission e-learning of University to Lausanne, the Center for Education and Audiovisual Communication, have developed an interactive training module of HH in 3 steps.- Identification of the academic content- Development of a teaching strategy fitted to any learning styles- Selection of the interactive teaching resources- Development of academic learning content- Development of practical content (care situations cut out in various interactive e-lessons)- Tutorial construction (integration of multimedia elements and interactivity)- Module overview by infection control professionals in Vaud institutions- Module provision through training platforms - The Module is freely accessible on the InternetAfter a brief theoretical reminder , the module content covers aspects of skills through simulation exercises. Care situations are specific for each category of professionals . Throughout the course, a knowledge assessment evaluates the benefits of training.The training module meets the predefined goals. This e-learning module broadens infection control class offer and is part of the five areas of the WHO multimodal HH strategy. The educational effectiveness will be evaluated after 9-12 months by a query filled up by the caregivers, by the participation rate, and by reality in practice (assessed during audits).None declared."}
{"text": "Trypanosoma cruzi causes Chagas' disease in humans  when compared to patients with heart damage, suggesting an important role for Tregs in Chagas' disease  was first identified as a growth and differentiation factor produced and utilized by T cells (Liao et al., T. cruzi, allows the elucidation of the mechanisms and conditions that may be targeted to reprogram the host immune system by using tools that interfere with components of the regulatory arm of the immune system machinery. This knowledge would certainly result in a better understanding of the necessary balance to achieve or reestablish the health of the host during T. cruzi infection, thus providing new strategies to treat Chagas' disease. In this regard, the in vivo biological activity of nondepleting antibodies to CD25 seems to reinforce rather than inhibit the function of regulatory T cells either in mice or humans (Nihei et al., in vivo administration of IL-2 or complexes of IL-2/anti-IL-2 to increase the numbers and functional activity of regulatory T cells would also be a valuable approach to be used in Chagas' disease (Letourneau et al., The study of acute and chronic phases of infection with intracellular pathogens, such as T. cruzi in combination with distinct strains of mice should be performed in order to better establish these conceptual clinical interventions, perhaps in addition to more acquiescent schemes of benznidazole treatment (Bustamante et al., The notion concerning the manipulation of Treg cells either by antibodies to CD25, IL-2, and/or IL-10 might open up a new avenue for therapeutic strategies in Chagas' disease. It should be noted that more pre-clinical studies, using different strains of JM Design the paper hypothesis, wrote the first draft. FC Design the paper hypothesis, wrote the first draft. LP Design the paper hypothesis, wrote the first draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Changes in the transmission properties of synapses may influence actively the processing of information. This is in particular the case for the working memory, viz the temporary storage of information, which is thought to be mediated via short-term or transient synaptic plasticity effects . The staWe implement a slightly modified version of the Tsodyks-Markram model for cyclic networks characterized by Mexican-hat type connectivity profiles for the synaptic weights. The system shows a surprisingly rich set of dynamical states, even for rings of only four neurons , such as transient state dynamics [4]. In this case one observes extended plateaus in the time series of the population firing rates, indicating well defined transient states (see left panel of Figure Going beyond the simple mean-field analysis, we present an in-depth study of the bifurcation diagram, as a function of several bifurcation parameters, such as the strength I of the external current or the integration time 1/\u0393 of the neural activity. Four classes of distinct limit cycles are found (see right panel of Figure"}
{"text": "Suliman et al.  have perMuch of the research regarding a potential role for BDNF in the mechanisms underlying psychiatric disorders has been conducted in the context of animal-models of depressive disorders. Mice with a knock-in of the human loss-of-function Val66Met BDNF gene polymorphism have decreased dendrite length, as well as decreased spine-synapse density, maturity and function in the hippocampus and the prefrontal cortex , with characteristics that are thought to reproduce the phenotype of humans with the Val66Met polymorphism, has increased anxiety-related behavior in the open field and elevated plus maze (Chen et al., The evidence linking BDNF with anxiety-like behaviors in animal models is not as abundant or clear. Foot-shock stress leads to reductions of BDNF levels, arguing for a link between BDNF and anxiety disorders such as post-traumatic stress disorder (Rasmusson et al., The meta-analysis by Suliman et al.  raises nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Objective: This presentation aims to leverage the experience gained from making a projection of the impact of pandemic mitigation strategies on longevity in the early advent of the COVID-19 pandemic.Before the COVID-19 pandemic, the literature on psychosocial stressors and psycho-social protective factors already clearly indicated that the two were linked in a multitude of ways to longevity. These ways include 1) directly through increased risk in suicides with respect to psycho-social stress or lack of connectivity 2) increased risk for psychopathologies such as depression, post-traumatic stress disorder and others, which in turn can decrease longevity in indirectly, and 3) a worse/healthier lifestyle that may be associated through decreased/improved social connectivity. With the advent of the COVID-19 pandemic, the ways in which these psychosocial factors could be impacted by policy came into focus. Attempting to quantify the potential future impact of such policies on longevity through psycho-social changes appeared necessary to allow better guidance of policy making. Discussion: This presentation will discuss issues concerning quantifications of the impact of COVID-19 related policy on psychosocial health. The assumptions necessary to arrive at projective models may be at odds with parts of the current culture in the field. The presentation will discuss potential strategies in order for the scientific community to be better prepared for similar events in the future.The authors model indicated the high need for measures that are protective of the general populations\u2019 psychosocial health in the face of a pandemic and associated mitigation strategies. No significant relationships."}
{"text": "This Research Topic explores some recent advances in the field of Aging and the Immune System. We asked our Editorial Board members for forward-looking contributions that describe the state of the art, outlining recent developments and accomplishments. Our goal was to shed light on some of the progress made in the past decade in the field of Aging and the Immune System and how this relates to age-related changes in the health of older adults. Collectively, these articles emphasize the point that aging of the immune system is associated with increased inflammation as well as dysregulation of both innate and adaptive immune responses, which can then contribute to the development of many age-associated diseases.Obesity Accelerates Age-Associated Defects in Human B Cells Through a Metabolic Reprogramming Induced by the Fatty Acid Palmitate, Frasca et al. examined the concept that obesity and aging may exert similar impacts on the immune system via induction of chronic inflammation. They focused on production of autoantibodies, which are increased with both obesity and aging. They found that fatty acids can reprogram the metabolism of B cells from young lean subjects to function like those from young obese or elderly lean subjects, thus linking the impact of fatty acid-induced inflammation to dysregulation of B cell responses. Duong et al., Aging Leads to Increased Monocytes and Macrophages with Altered CSF-1 Receptor Expression and Earlier Tumor-associated Macrophage Expansion in Murine Mesothelioma, examined the response to mesothelioma in young and aged mice in order to understand how aging impacts the response to tumors. They found that Ly6Chigh macrophages, which have increased proinflammatory responses, are increased in older mice with tumors and prior work has shown that these cells may contribute to diminished anti-tumor activity that occurs with aging.Two original research articles that were contributed examine how aging impacts autoimmunity and anti-tumor responses. In the article Growth Differentiation Factor-15 in Immunity and Aging by Pence examines the immunoregulatory and anti-inflammatory roles of growth differentiation factor-15 (GDF-15). GDF-15 can be a component of the senescence associated secretory phenotype (SASP) and its production is induced in response to proinflammatory conditions in order to dampen inflammation. Importantly, the plasma concentration of GDF-15 increases with aging, likely as a result of chronic age-associated inflammation. This age-related elevation of GDF-15 could also function to dampen immune responses, including those to infectious agents, which could explain why it is one of the proteins most strongly correlated with multimorbidity in older adults. The review article Inflammation, Immune Senescence, and Dysregulated Immune Regulation in the Elderly, by Shive and Pandiyan extends the analysis of inflammation and dysregulated responses in this Research Topic by providing an overview of age-related inflammation and how it impacts the immune response in older adults including an examination of inflammatory and anti-inflammatory cytokines and regulatory T cells. In the review article T Cell Aging-Associated Phenotypes in Autoimmune Disease, Zhao et al. and her colleagues focus on the adaptive arm of the immune system and discuss T cell aging associated phenotypes (TASP) and how they contribute to two age-related autoimmune diseases: rheumatoid arthritis (RA) and giant cell arteritis (GCA). RA results from premature aging of T cells, leading to excessive production of inflammatory mediators, while GCA results from age-associated loss of control of T cell induced inflammation, including loss of regulatory T cells. Finally, the review Proteolysis dysfunction in the process of aging and age-related diseases from Frankowska et al. presents current insights on how aging impacts proteolytic systems. Failure to appropriately regulate proteolysis can result in protein aggregation and chronic inflammation, which can then lead to age-related diseases.The mini-review We hope that this Research Topic provides readers with a glimpse of some of the exciting research that is happening in the field of aging and immunity and that it stimulates new ideas and future progress."}
{"text": "This cross-sectional study investigates sales of over-the-counter iodine-containing drugs in 20 European countries between January 2021 and March 2022. Two major concerns are the potential use of nuclear weapons and the environmental consequences of the capture of nuclear sites by the Russian army.1 A nuclear war would result in many immediate deaths and delayed deaths from chronic diseases and climate disruption. Although guidelines from the World Health Organization advocate the prudent prophylactic use of iodine,3 media outlets have reported panic buying of iodine-containing drugs in Europe and other regions of the world since the beginning of the Russia-Ukraine conflict.4 Given that, to our knowledge, there is no research on this topic yet, the present pharmacoepidemiological study aimed to investigate sales of over-the-counter iodine-containing drugs in 20 European countries between January 2021 and March 2022.In February 2022, Russia invaded Ukraine and aimed to control the country rapidly.This cross-sectional study used data from the OTCims database (IQVIA), which contains data on sales of over-the-counter drugs in Europe. The present study included sell-out data of drugs with iodine as the only active ingredient. The number of packages of iodine-containing drugs sold per month was analyzed in each country between January 2021 and March 2022. Differences in percentage were assessed between February 2022 and January 2022, and March 2022 and January 2022  observed in this study may be related to the fact that these countries are geographically close to Russia and Ukraine and may, therefore, be more likely to suffer from collateral nuclear damage than other European countries. Interestingly, this is not the first time panic buying of iodine-containing drugs has occurred, and this behavior has also been reported after the Fukushima crisis.5 Panic buying of iodine-containing drugs since the beginning of the war is likely explained by the fear of the use of nuclear weapons and the fear of radiation leaks from nuclear sites.2 Despite international efforts, the nuclear threat is real, and this threat has been found to have adverse effects on mental health.6 Moreover, lack of awareness of international recommendations on iodine prophylaxis following nuclear accidents and inaccurate information from the media may potentiate the effects of the war between Russia and Ukraine on panic buying of iodine-containing drugs.The findings of this cross-sectional study are in line with recent reports from the media.The major strengths of this study are the number of countries included in the analyses and the use of empirical data obtained every month. Two critical limitations are the absence of data on prescribed iodine-containing drugs and the lack of information on the sociodemographic and clinical characteristics of buyers of iodine-containing drugs.In conclusion, the war between Russia and Ukraine was associated with increased sales of over-the-counter iodine-containing drugs in 20 European countries in February and March 2022 compared with January 2022. On the basis of the findings of this study, there is an urgent need to better inform the general population about the international recommendations on iodine prophylaxis following exposure to radioiodine."}
{"text": "The COVID-19 pandemic has had an enormous impact on both physical and mental health of people around the world.The aim of the study was to evaluate the number and characteristics of people seeking emergency psychiatric help during combined psychosocial stressful events in March 2020.Data for 3927 patients seeking emergency psychiatric help were collected and analyzed for the months preceding, during and after lockdown due to COVID-19 pandemic and concomitant earthquake that took place on 22nd March 2020 in Zagreb, and compared with the same months of 2019.A significant decrease in both the number of visits and admissions to the hospital was found for the month of lockdown. There was a significant decrease in the number of out-patients visits and day hospital admissions. Compared with other months, more women and younger patients sought help. There was a significant rise in the number of patients presenting with suicidal thoughts, as well as a larger percentage of involuntary admissions.Overall less people sought psychiatric help in the face of an unpredictable acute threat, which was interpreted in the light of prioritizing fear of infection over mental health issues. Alternatively, it is possible that people threatened with immediate danger mobilize short- term compensatory psychological resources which help deal with or put off mental illness. This research was conducted as part of the project of the Croatian Science Foundation CORONA-04-2086 Life in the time of COVID-19-social implications on the security and well-being of vulnerable groups in the European context.No significant relationships."}
{"text": "The negative consequences of transfers are known as transfer trauma. Nursing home (NH)-to-NH transfers place long-term NH residents at risk for developing transfer trauma and this risk may have increased during the COVID-19 pandemic in the setting of a state policy that increased the number of residents who transferred between NHs. The objective of this cross-sectional cohort analysis was to assess the incidence of transfer trauma and major events  among long-term NH residents who transferred from one NH to another before and during the COVID-19 pandemic using a composite measure of transfer trauma based on validated scales from Minimum Data Set (MDS) assessments. A total of 750 residents transferred in the pre-COVID cohort and 795 in the COVID cohort were eligible for assessment of transfer trauma and major events. After adjusting for demographic characteristics, residents in the COVID cohort were almost twice more likely to die and almost three times more likely to discharge within 90 days compared to those in the pre-COVID cohort . Residents in the COVID cohort were less likely to experience transfer trauma compared to those in the pre-COVID cohort. In the during-COVID cohort, 26% of residents had a COVID-19 diagnosis and they were less likely to experience transfer trauma compared to residents without a COVID-19 diagnosis . It is important to note that some residents may have not stayed in the nursing home long enough to assess them for transfer trauma."}
{"text": "The Editors-in-Chief would like to alert readers that concerns have been raised regarding the data in this article . SpecifiNone of the authors have responded to any correspondence from the editor or publisher about this Editorial Expression of Concern."}
{"text": "The 2PASS-4Health project  was founded by the Erasmus+ Sport programme of the European Union to improve the participation in sport and physical activity (PA). This project aims at examining examples of PA promotion interventions in secondary school, identifying good practices as well as the main barriers and difficulties linked to the design, implementation and evaluation of such interventions in order to improve their quality and sustainability. This project targets both the scientific community and various stakeholders involved in school-based PA promotion for adolescents to provide them with clear knowledge and usable tools. The overall design of this project will be presented as well as the first results and deliverables created to implement the interventions.In order to fill the existing gap between theory and practice by identifying evidence-based practices that work we are translating recent scientific knowledge into accessible information and tools that meet the needs of the stakeholders in the field. Furthermore, using a co-design approach involving several internationally recognised experts, stakeholders, and end-users, we developed some adapted and ready-to-use contents and we designed an optimised multicomponent school-based intervention that has been implemented in France and Spain. We evaluated these interventions not only in terms of outcomes related to PA and sedentary time, but also in relation to other important domains like implementation or maintenance based on the RE-AIM framework.We are producing: (1) a white paper geared towards professionals and policy makers, and a consensus statement intended for the scientific community; (2) two handbooks on the implementation of the intervention and its evaluation, accompanied by two scientific publications; (3) an educational toolkit to support PA promotion in schools; and (4) articles on the evaluation of the interventions held in France and Spain.System approach seems needed to implement a sustainable multilevel whole-of-school intervention co-constructed with the different stakeholders and end-users involved."}
{"text": "To examine associations of self-care and the quality of life (QOL) in patients with Parkinson's disease (PD) and their caregivers dyads.Patients with PD engage in self-care with motor and non-motor symptom experiences. There is insufficient knowledge about associations of self-care and QOL in patients with PD and their caregivers though PD patients and family caregivers are interdependent. Method: A total of 73 PD patients and primary family caregivers from the Korean Parkinson's Disease Association or who visited outpatient clinics of the tertiary hospitals in Korea participated in this study. Dyad members completed the survey of the self-care (the Self-Care of Chronic Illness Inventory and Caregiver Contribution to Self-Care of Chronic Illness Inventory) and QOL . The comparisons of self-care and quality of life within two dyad members were conducted via paired t-test and Pearson's correlation using SPSS 26.0 Result: PD patients reported significantly higher levels of self-care maintenance  and management  than caregivers. Patients\u2019 self-efficacy was significantly correlated with their QOL . Caregiver contribution to self-care management was significantly correlated with their own QOL  and patients\u2019 QOL .The self-care efficacy of patients and the contribution of caregivers to self-care management can affect the QOL of both patients and caregivers. A dyadic approach for the intervention of self-care management is crucial to improve the QOL of patients with PD and caregivers."}
{"text": "A theoretical investigation on neutral excitons confined to a mono-layer (ML) semiconductor transition metal dichalcogenide (TMDC) materials under the influence of elliptically deformed gate induced confining potential is presented. It has been shown that the anisotropy of the confinement induces the anisotropy of linear response of the system on in-plane external electric field. The linear response is expressed in terms of principal moments of the static dipole polarizability tensor. In this manner the direction-dependent polarizability of the system can be fully controlled by tuning the parameters of gate-induced confining potential. The components of the polarizability tensor are determined using finite-field method based on the exact diagonalization of the electron-hole Hamiltonian including confining potential, Coulomb electron-hole interaction and an external electric field, within effective mass approximation, close to the K-points of the first Brillouin zone of a single-layer MX In the case of GNRs, the electronic states strongly depend on the width and on the edge structure of the ribbon. In the case of CNTs the electrical properties essentially depend on the diameter and on the shape of the edges. One of the most recognized examples of ballistic transport devices exhibiting correlation between geometry and electronic properties is the geometric diode. In the geomeric diode the electric current rectification is obtained due to geometrical asymmetry4. In many materials, energy bands posses a discrete number of inequivalent local minima or maxima for specific values of momenta. The minima usually known as valleys seem to be promising candidates for components of pseudospin or a binary variable6. The separation of charge current composed of electron states belonging to only one valley can be regarded to as valley polarization. For graphene in particular, several schemes have been proposed to achieve valley-current filtering depending on geometrical deformation. At the field of geometry-induced effects also strain-induced effects in graphene has been the topic of a large number of theoretical works aimed at understanding the impact of controlled geometrical deformations on electronic properties13.The correlation between geometry and electronic properties in two-dimensional semiconductor structures has recently become an active area of theoretical and experimental research due to its potential application for electronic purposes. The interplying between electronic properties and geometry appears as an efficient tool for manipulation of band structure or transport properties what allows for the design of electronic nano-devices with a desired functionality. In graphene systems, the coupling between geometry and the electronic band structure is the most visible for graphene nanoribbons (GNRs) and carbon nanotubes (CNTs)16. They are considered as ideal materials for next-generation electronics, photonic and opto-electronic devices, relying on ultimate atomic thicknesses18. The bandgap of semiconducting TMDCs can be sized by varying the number of layers, and it can be changed from indirect to direct approaching the single layer. This tunable bandgap in TMDCs is accompanied by a strong photoluminescence and large exciton binding energy, making them promising candidate for a variety of opto-electronic devices, including solar cells, photo-detectors, light-emitting diodes, and photo-transistors22. Similarly to traditional semiconductor heterostructures quantum dots (QDs) can be formed on atomically thin ML TMDCs materials by applying a gate voltage to tune the local band structure23. Gate-defined QDs, in addition provide an efficient tool to tune electrically the confinement geometry and the strength. The realization of a quantum dot device has been obtained from the nanosheet on a Si/SiO24. The fabrication of single quantum dots defined by gates has been reported recently for bilayer and monolayer WSe26. The Coulomb blockade in single and coupled dots in high quality single layer MoS24. Intrinsic exciton-state mixing and nonlinear optical properties, particulary the mechanism of second harmonic generation in TMDCs monolayers have been recently investigated on the basis of symmetry analysis27. Many other investigations based on several approaches including tight binding method, ab initio calculations, a many-body Bethe-Salpeter equation, 35. One should be also added that the Coulomb-exchange interaction, having an important influence on the energy structure of the 2D excitons, can be separated into the long-range and the short-range parts. In particular, the long-range exchange interaction has quantum electrodynamic nature, by the analogy to the exchange interaction in a positronium36. A theoretical study on the long-range exchange interaction in excitons has been performed treating the bright exciton as a microscopic dipole which produces an electric field and the backaction of this field on the exciton leads to the long-range electron-hole exchange interaction. Formally this treatment corresponds to the decomposition of the Coulomb interaction up to the dipole term and calculation of matrix element of the dipole term using the antisymmetrized Bloch functions28.Recent advances in the epitaxial growth of 2D crystals have opened up new opportunities towards novel devices based on van der Waals heterostructures in which TMDCs play a major role. Two-dimensional TMDC materials, such as MoS26. The electrodes generate the confining potential trapping additional electron added into conduction band (CB) as well as the hole in the valence band (VB). We model the confinement using non-centrosymmetric parabolic potential with the deformation of an elliptic type. In particular, we study the effect of the dot geometry on quantum properties of the Mott-Wannier exciton in terms of static dipole polarizability tensor and correlated probability distribution function of the electron-hole pair confined to the dot. Although obtained results can be directly linked with any ML TMDC system, due to relevant scalling relations derived in this paper, we explicitly demonstrate the dependence of static dipole polarizabilities on the dot geometry using material parameters appropriate for MoS32. Moreover, the dipole polarizability is related to the dielectric constant and the reflection coefficient. Thus, in order to determine these parameters theoretically, the excitonic contribution to the total dielectric polarization should also be taken into account37.The purpose of this paper is a theoretical investigation of anisotropic quantum confinement effect on the linear response on external electric field of a neutral Mott-Wannier exciton formed inside the gate-defined quantum dot, for different geometries of the dot. The dot shape can be controlled electrostatically by appropriate system of metallic electrodesThe system under study is sketched in Fig. m is supposed in the form of anisotropic parabolic potential,zero-point energy in the energy scale, relatively to which the energy bands edges s), due to the Coulomb interaction between the electron and a hole. The eigenvalue problem,38. The scaling  and y direction, with the same degree). We can see that in this case the polarizability is simply rotated by the angle x-extended quantum dot, that is a consequence of the symmetry transformation of the confining potential connecting the cases \u2019a\u2019 and \u20191/a\u2019. One can also see that the polarizability increases with decreasing confinement strength.Figure 38. We can note that, similarly to the effect of increasing atomic number Figure critical point, corresponding to the maximum of It is worth to note that contrary to the electron confined in the atom due to Coulomb interaction with a nucleus, the gate-defined confinement opens up the possibility of controlling the polarizability of the excitonic system by changing confinement strength and its geometry. More precisely, one can be observed the existence of a competition between the effective Coulomb interaction between electron and hole and the geometric confinement in producing polarizability. We note that pure Coulomb attraction between electron and hole is effectively modified by material parameters nt}\u03b5 see . This cont}\u03b5 see  and 15)\\document42x direction reduces the extension of y direction. The extension in the y direction reduces the electron-hole Coulomb attraction, relatively to the x direction, that leads in turn to increase of the linear response of the exciton on external electric field, stretching the electron-hole pair more effectively in the y direction (due to weaker confinement), that is expressed in the difference in magnitudes of principal moments of the polarizability tensor.In Fig. Figure In the paper, we have presented an realistic example of the interplaying between stable external system and the quantum system subject to it. The exact theoretical study on the influence of the geometry of external quantum confinement on static dipole polarizability of Mott-Wannier exciton, formed close to the K-points of the first Brillouin zone of the TMDC monolayer material, has been presented. The properties of the quantum system expressed in terms of the static dipole polarizability as a linear response on the external electric field and the electron-hole density function have been linked with geometry of the external confinement. In particular, we have shown how both the magnitude and the anisotropy of the dipole polarizability may be effectively defined by the proper chose of the confinement strength and its geometry. One should be also noted that results obtained in this paper are universal in the sense that they are applicable for any MXSupplementary Information."}
{"text": "Understanding the predictors of the willingness to get vaccinated against COVID-19 may aid in the resolution of current and future pandemics.Understanding the predictors of the willingness to get vaccinated against COVID-19 may aid in the resolution of current and future pandemics.We aim to investigate how the readiness to believe conspiracy theories and the three dimensions of health locus of control affect the attitude towards vaccination.A cross-sectional study was conducted based on data from an online survey of a sample of Czech university students (n=866) collected in January 2021, using multivariate linear regression models and moderation analysis.Sixty-six percent of Czech students wanted to get vaccinated against COVID-19. Forty percent of the variance of willingness to get vaccinated was explained by the belief in covid-related conspiracy theories and the powerful others dimension of health locus of control. One sixth of the variance of the willingness to get vaccinated was explained by health locus of control, cognitive reflection, and digital health literacy.Health locus of control and conspiracy mentality and its predictors are valid predictors of a hesitancy to get vaccinated against COVID-19. Campaigns promoting vaccination should target groups specifically vulnerable to conspiracy theories and lacking health locus of control related to powerful others.No significant relationships."}
{"text": "There was and still is much speculation about the COVID-19 pandemic impact on suicide rates. We aimed to assess the effect of the COVID-19 pandemic on suicide rates around the world.We sourced real-time suicide data from countries or countries areas through a systematic internet search , recourse to our networks (e.g. ICSPRC) and the published literature (a living systematic review). We used an interrupted time-series analysis to model the trend in monthly suicides before COVID-19 in each country or country area, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic . We have now updated this work to cover the first 15 months of the pandemic and stratified analyses by age and sex and method. We will present findings from the new updated data (35 countries) at the conference.Initially we sourced data from 21 countries (16 high-income and five upper-middle-income countries). Rate ratios (RRs) and 95% CIs based on the observed versus expected numbers of suicides showed no evidence of a significant increase in risk of suicide since the pandemic began in any country or area. There was statistical evidence of a decrease in suicide compared with the expected number in 12 countries or areas.This was the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. Early on high-income and upper-middle-income countries, suicide numbers remained largely unchanged or declined compared with the expected levels based on the pre-pandemic period. We need to remain vigilant and be poised to respond as the longer-term mental health and economic effects of the pandemic unfold. We will present updated findings with more recent data."}
{"text": "I read with great interest the article \u201cTelehealth-Based Psychoeducation for Caregivers: The Family Intervention in Recent-Onset Schizophrenia Treatment Study\u201d by Mueser et al .First, I would like to congratulate the authors for raising awareness of telehealth-based psychoeducation for informal caregivers of people with mental illness. The results of their study present important understandings and hope for continued progress in the web-based delivery of valuable family interventions within the field of psychiatry. Although this study did not show the family psychoeducation intervention to be advantageous at the level of exposure reached, explorations of future caregiver-focused, telehealth-based interventions in mental health are still needed.As we look toward future development in working with families and informal caregivers of people with mental illness, digital innovations, applications, and advancements in web-based interventions  suggest Compared to patient groups, telehealth-based interventions with family groups have been limited  despite In light of accelerating digital interventions within the field of psychiatry, I call on the research community to also draw more attention to the potential of telehealth-based psychoeducation for informal caregivers of people with mental illness. With the expected growth in the caregiver population coupled with significant caregiver needs and demands for help and support, notwithstanding those who are unable to join or have no access to these mental health services or best practices, taking advantage of the future potential of digital technologies and interventions for caregivers is inevitable."}
{"text": "When studying the multiple aspects of the problem of criminal offences of a sexual character committed by adult males towards teenage girls, the role of digital communication technologies is not taking into account.To reveal the negative aspects of social and family connections and the influence of digital communications on the formation of deviations in psycho-sexual development of teenage girls who had become victims of sexual delicts of a non-violent character.We have studied the specifics of psycho-sexual behavior of seventeen teenage girls, aged 12-16 and their Internet and SMS correspondence with adult males by analysis of semantics and pathos-psychological markers.Intellectually, all the teenage girls are within normal age limits. They were bringing up in full, materially well-off families. Most of the girls\u2019 parents experience a formal attitude towards them. The disrupted emotional ties of the teenage girls with mother or both parents leads to deviations in the development of normal teenage reactions, sexual attitudes. Their feeling of loneliness within the family, forces them to turn towards support to Internet-society or other adults of the opposite sex to their parents\u2019 acquaintances. The desire to ascertain perfectionist expectations and self-assertion leads the teenagers to the realization of various forms of auto-destructive sexual behavior. They actively demonstrate in the Internet obscene photos of their genitals. While trying out their sexual importance, they persistently urge adult males towards sexual contacts.Thus, the negative aspects of psycho-sexual development of teenage girls can disrupt their sexual behavior in adulthood.No significant relationships."}
{"text": "Owing to cognitive radar breaking the open-loop receiving\u2013transmitting mode of traditional radar, adaptive waveform design for cognitive radar has become a central issue in radar system research. In this paper, the method of radar transmitted waveform design in the presence of clutter is studied. Since exact characterizations of the target and clutter spectra are uncommon in practice, a single-robust transmitted waveform design method is introduced to solve the problem of the imprecise target spectrum or the imprecise clutter spectrum. Furthermore, considering that radar cannot simultaneously obtain precise target and clutter spectra, a novel double-robust transmitted waveform design method is proposed. In this method, the signal-to-interference-plus-noise ratio and mutual information are used as the objective functions, and the optimization models for the double-robust waveform are established under the transmitted energy constraint. The Lagrange multiplier method was used to solve the optimal double-robust transmitted waveform. The simulation results show that the double-robust transmitted waveform can maximize SINR and MI in the worst case; the performance of SINR and MI will degrade if other transmitted waveforms are employed in the radar system. The concept of cognitive radar, first introduced in 2006 , is a syHowever, the above research was based on a known target spectrum or clutter spectrum. Accurate target and clutter spectrums are difficult to obtain in complex electromagnetic environments due to a lack of prior knowledge of target and clutter. To address this problem, the joint optimization of the radar transmitted waveform and the receive filter was considered in ,28. An iThe design of a robust transmitted waveform only considers one of the cases of target spectrum fuzzy or clutter spectrum fuzzy. Our research team previously only considered single-robust radar waveform designs with an uncertain target spectrum . In 33]33], the The rest of this paper is organized as follows. In The model for the random target is given in The energy spectrum variance (ESV) of a random target is written as Equation (1), which describes the average energy of the target signal in a finite duration.To effectively improve the detection performance of the radar systems, the output SINR of the matched filter in the radar receiver is adopted as the criterion for designing the transmitted waveform. Maximization of SINR means the best radar detection performance. Thus, the expression for the SINR can be represented by (2)\u00a0SINRTo improve radar estimation performance on the target, the MI between the radar echo and the random target impulse response is utilized as the estimation criterion. The MI representation between the echo and the random target impulse response is (3)\u00a0MI, for the right side of the inequality, the optimal transmitted waveform is the maximin optimal transmitted waveform when eference . It is aWhen the clutter spectrum is fuzzy, the maximin single-robust waveform design method should satisfy ,38(8)maBased on the theory of maximin robust signal processing , the maxIn the above Formula (9), for the right side of the inequality, the optimal transmitted waveform is the maximin optimal transmitted waveform when When the radar transmitted waveform is designed under the condition of a fuzzy target spectrum, the lower bound of the uncertain range of the target spectrum is taken as the target spectrum in the optimization problem, and where The maximin single-robust transmitted waveform optimization problem based on SINR under the condition of a fuzzy target spectrum should satisfyThe maximin single-robust waveform of the optimization problem (10) isAs shown in Equation (11), The maximin single-robust transmitted waveform optimization problem based on MI under the condition of a fuzzy target spectrum should satisfyThe maximin single-robust waveform of the optimization problem (15) isThe above design method of a single-robust transmitted waveform based on SINR and MI is the same as that for single target spectrum uncertainty in reference . This isWhen the radar transmitted waveform is designed under the condition of a fuzzy clutter spectrum, the upper bound of the uncertain range of the clutter spectrum is taken as the clutter spectrum in the optimization problem, and where The maximin single-robust transmitted waveform optimization problem based on SINR under the condition of a fuzzy clutter spectrum should satisfy.The maximin single-robust waveform of the optimization problem (20) isIn Equation (21), The maximin single-robust transmitted waveform optimization problem based on MI under the condition of a fuzzy clutter spectrum should satisfyThe maximin single-robust waveform of the optimization problem (25) isIn this subsection, considering that radar cannot simultaneously obtain precise target and clutter spectra, the design method for the double-robust transmitted waveform based on the SINR and MI is proposed. The SINR and MI optimization criteria for waveform design can be represented by The double-robust transmitted waveform is designed under the condition that radar cannot simultaneously obtain precise target and clutter spectra. The lower bound of the uncertain range of the target spectrum is taken as the target spectrum, and the upper bound of the uncertain range of the clutter spectrum is denoted as the clutter spectrum in the optimization problem. The detailed design process is shown as follows.The maximin double-robust transmitted waveform optimization problem based on SINR should satisfyThe maximin double-robust waveform of the optimization problem (31) isIn the above result of the double-robust transmitted waveform design based on SINR, by analyzing Equations (32)\u2013(34), if we change the lower bound value of the target spectrum in the result to the value that can be accurately obtained, or if we change the upper bound value of the clutter spectrum in the result to the value that can be accurately obtained, then the double-robust transmitted waveform will degenerate into a single-robust transmitted waveform. The double-robust transmitted waveform design based on MI also has such characteristics.In order to prove the conclusion above, the optimal problem should satisfyAssume that the lower bound of the target spectrum and the upper bound of the clutter spectrum can be obtained. The uncertainty of the target and clutter spectra are considered under certain energy constraints. To maximize the output SINR of the matched filter in the worst-case scenario, the double-robust transmitted waveform based on SINR is designed. We use the Lagrange multiplier method to solve the optimization model of the double-robust transmitted waveform. The main idea is to introduce a new parameter  can also be written asTherefore, we obtain the following:Then, we approximate the integral computation by substituting the spectrum results into the output SINR expression:The maximin double-robust transmitted waveform optimization problem based on MI should satisfyThe maximin double-robust waveform of the optimization problem (48) isIn order to prove the conclusion above, the optimal problem should satisfyThe double-robust transmitted waveform based on MI is designed to maximize the MI between radar echo and random target impulse response in the worst-case scenario. The Lagrange multiplier method is also used to solve the optimization model.The Lagrange multiplier method is employed to construct the objective function based on MI:When the target and clutter spectra are uncertain simultaneously, the MI between radar echo and random target impulse response is a function of This is equivalent to maximizing Next, the first derivative of Let The expression (61) is further expressed asTherefore, we obtain the following:Then, we approximate the integral computation by substituting the spectrum results into the MI expression:From Equation (69), The simulation results in this section demonstrate the effectiveness and practicability of the double-robust transmitted waveforms based on SINR and MI criteria.The uncertain ranges of the target spectrum and clutter spectrum are shown in The results of the robust waveform designs (including single-robust waveforms and double-robust waveforms) based on SINR and MI criteria are depicted in (1) The amplitudes of the SRWs fluctuate around those of the OTWs. The two types of waveforms have the same energy allocation strategy. The SRWs with the worst CNR and the double-robust waveforms with the worst TCR also have the same characteristics see b,c, and (2) In the case of the worst TNR, the SRWs need to allocate more energy than the OTWs in the sub-frequency band where the target spectrum is strong. Since the radar cannot obtain the precise target spectrum in the worst TNR, it can only use the lower bound of the uncertain target spectrum to optimize the transmitted waveforms, which leads to the SRWs needing to allocate more energy than OTWs in the sub-frequency band with the strong target spectrum to ensure the improvement in MI and SINR, such as the energy allocation in the sub-frequency bands around the central frequencies of \u22120.2, 0, and 0.4 in (1) The SRWs allocate the most energy to the sub-frequency bands where the upper bound of the uncertain clutter spectrum (the blue line in (2) The energy allocation of SRWs is more than that of OTWs in the sub-frequency band where the upper bound of the uncertain clutter spectrum is less than the target spectrum. Since the precise clutter spectrum cannot be obtained by radar in an actual scene, radar can only use the data in the upper bound of the uncertain clutter spectrum in the worst case; thus, the result is worse than it actually is. Meanwhile, the target spectrum is greater than the upper bound of the uncertain clutter spectrum. SRWs must allocate more energy than OTWs to ensure the improvement in MI and SINR, such as the energy allocation in the sub-frequency band around the central frequency of 0.4 in (3) The energy allocation of the SRWs is less than that of the OTWs in the sub-frequency bands where the upper bound of the uncertain clutter spectrum is greater than the target spectrum. This energy allocation strategy of SRWs is still aimed at maximizing SINR and MI in the worst CNR, because when the upper bound of the uncertain clutter spectrum is much greater than the target spectrum in some sub-frequency bands, it means that the clutter echo interferes with the target echo more. Therefore, in these sub-frequency bands, the energy allocation of the SRWs is less than that of the OTWs to reduce the SINR and MI loss. Such as the energy allocation in the sub-frequency bands around the central frequency of \u22120.2 in (1) The DRWs also allocate the majority of energy to the sub-frequency bands with strong target spectrum features.(2) MI-based DRW allocates less energy than SINR-based DRW in the sub-frequency band where the upper bound of the uncertain clutter spectrum is less than the lower bound of the uncertain target spectrum. On the contrary, MI-based DRW allocates more energy than SINR-based DRW in the sub-frequency band where the upper bound of the uncertain clutter spectrum is greater than the lower bound of the uncertain target spectrum. This is because MI as an optimization criterion makes radar pay more attention to the acquisition of the target information than the influence of clutter on the radar.(3) Compared with the SRWs with the worst TNR, the DRWs allocate more energy than SRWs in the sub-frequency band where the upper bound of the uncertain clutter spectrum is less than the lower bound of the uncertain target spectrum. On the contrary, the DRWs allocate less energy than SRWs in the sub-frequency band where the upper bound of the uncertain clutter spectrum is greater than the lower bound of the uncertain target spectrum. Such as the energy allocation in the sub-frequency bands around the central frequencies of \u22120.2, 0, and 0.4 in (4) Compared with the SRWs with the worst CNR, the DRWs allocate more energy than the SRWs in the sub-frequency bands with strong target spectrum features regardless of whether the lower bound of the uncertain target spectrum is greater than the upper bound of the uncertain clutter spectrum, such as the energy allocation in the sub-frequency bands around the central frequencies of \u22120.2, 0, and 0.4 in Assume that the total energy of the transmitted waveform increases from 1 to 10 J. The MIs and SINRs corresponding to the several transmitted waveforms are compared in the case of the worst TCR in In this paper, the double-robust transmitted waveform design based on SINR and MI is proposed in the presence of clutter, respectively. First, the single-robust transmitted waveforms are designed for the worst TNR and CNR cases. The single-robust transmitted waveforms with the worst TRN allocate more energy than the optimal transmitted waveforms with the best case in the sub-frequency band where the target spectrum is strong. The single-robust waveforms with the worst CNR allocate more energy than the optimal transmitted waveforms with the best case when the target spectrum is greater than the upper bound of the uncertain clutter spectrum. On the contrary, they allocate less energy than the optimal transmitted waveforms with the best case when the target spectrum is less than the upper bound of the uncertain clutter spectrum. All single-robust waveforms allocate the majority of energy to the sub-frequency bands with strong target spectrum features. Since radar cannot obtain the precise target and clutter spectrum in an actual scene, the double-robust waveforms are proposed in the case of the worst TCR. The double-robust waveforms also allocate the majority of energy to the sub-frequency bands with strong target spectrum features. However, they can further improve the MI and SINR compared to the single-robust waveforms. Finally, the simulation results show that the double-robust transmitted waveforms can maximize SINR and MI. In the case of the worst TCR, the performance of SINR and MI will degrade if other transmitted waveforms are employed.The communication base station (BS) will be considered to be added to the existing model to form a joint radar and communication system. The orthogonal frequency division multiplexing (OFDM) waveforms with N subcarriers will be considered to be used for radar and communication base stations to design the radar transmitted waveform."}
{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader alerting the Editorial Board to duplicated panels of figure 4c between this article and an article by Zhao et al (2016) (https://doi.org/10.1186/s40659-016-0086-3). The authors have been contacted with regards to the retraction but have not responded to the Journal's queries or the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
{"text": "A project designed to examine, for the first time, the health records of adult prisoners in Northern Ireland and their linkage to other available health data: the test case of prisoner post-release mortality riskThe linkage of routinely collected administrative data for research purposes has the potential to improve knowledge and public benefit. We describe a novel data linkage study between the Northern Ireland (NI) Healthcare in Prisons and Business Services Organisation (BSO). This work is undertaken within the Administrative Data Research Centre-NI (ADRC-NI).This joint project between ADRC-NI Queen\u2019s University Belfast and NI Healthcare in Prisons  will test linkage of prisoner health records to health data held in the BSO and the potential to generate a population-based cohort for a retrospective analysis of prisoner health (2012-2021) that will attempt to characterise prisoners according to socio-demographic, health and committal factors, compare post-release mortality rates with a reference group from the NI population using indirect standardisation and estimate post-release mortality risk using Cox proportional hazards models.Using novel data-linkages, a dataset will be created to examine the health of prisoners (and former prisoners) in NI. Ethics and governance approvals are in place for this data-linkage. The linkage will be undertaken via the Honest Broker Service (HBS) in NI and the dataset will be accessed in the safe setting at the BSO. The processes involved, experiences including significant delays or difficulties, and recommendations for future data-linkage studies will be discussed. In addition, a key deliverable of this project will be an assessment of access and linkage capabilities of the prisoner health data, with metadata created and made available to future researchers. In addition, we plan to present preliminary results relating to the test research question.We will describe the processes involved and first-hand research experience in the development of a novel data-linkage project, in addition we will detail access and linkage capabilities in relation to this new dataset to examine health in prisoners (and former prisoners) in NI."}
{"text": "Guanglun Zhou J Laparoendosc Adv Surg Tech A. 2022 Apr 18; Online ahead of print.The high abdominal undescended testis is a challenging situation in pediatric urology. The surgery to put the testicle in the scrotal region without harming its vascularization is very important for the treatment of these cases. Fowler-Stephens surgery performed in two times is the best strategy to preservation of vascular supply to the testis. In this important paper the authors shows the benefits of performing open versus laparoscopic gubernaculum-sparing second-stage Fowler-Stephens orchiopexy (FSO). The gubernaculum is the most important structure in the inguinoscrotal stage of testicular migration , 2. The"}
{"text": "The EU-funded X-eHealth project aims to lay the foundations for a common framework for medical imaging, discharge letters, laboratory results and rare diseases to advance an interoperable Common European Health Data Space for citizens and healthcare providers in accordance with privacy and cybersecurity regulations. To ensure sustainability of the project, it is crucial to assess whether X-eHealth is achieving its planned objectives and delivers tangible results. A key challenge in evaluating project outcomes lies in the partial lack of visibility of direct impacts due to a time lag of effects or attribution problems . In X-eHealth, we address this problem by defining a framework of Key Performance Indicators (KPI) that allows the monitoring of project outcomes. In addition, qualitative interviews with a focus on the following questions are conducted towards the end of the project to complement the evaluation:\u2022\u2002Does X-eHealth advance the integration process of eHealth services in Europe?\u2022\u2002Will X-eHealth lead to increased use of the new European Electronic Health Record Exchange Format (EEHRxF) specifications?Although final results are not yet available, we expect X-eHealth to have a positive impact at all stakeholder levels by accelerating the implementation of EEHRxF through the harmonisation of health data, thus providing patients, health professionals and institutions with increased quality, safety and efficiency. There is little evidence to analyse the impact of eHealth policy interventions. For this reason, the present evaluation makes a significant contribution to impact research in this area. X-eHealth highlights the importance of international cooperation in creating a common framework for the future development of digital health in the EU. The continuous evaluation, moreover, facilitates a more efficient management of resources through KPI observance and the implementation of project results.\u2022\u2002X-eHealth aims to accelerate the implementation of the European eHealth Record exchange Format (EEHRxF) through the standardisation and harmonisation of health data.\u2022\u2002By evaluating and monitoring the project processes, it is possible to ensure the progress of the project and to measure the potential impacts of the outcomes on stakeholders and other target groups."}
{"text": "The feeling of becoming an adult plays the role of central new mental formation reflecting the specificities of emotional experience and whole new mental state during adolescent development that is often misaligned with present day society attitude to adolescents. The study was conducted to explore the relationship linking cognitive peculiarities of senior adolescents and the sense of emerging adulthoodThis research was conceptualized to explore the way cognitive development peculiarities affect the progress in solving tasks of the transition to adulthood from the point of view of objective growing-up and subjective assessment of feeling of becoming an adult.The study was based on Betensky\u2019s Adolescent Window Triptych, Akimova\u2019s Intelligence Test for Seniors, Landgarten\u2019s Personality Collage, Sacks-Levy\u2019s IST, Adolescent Social Self-Portrait Essay (D.B. Elkonin) and included 68 participants aged 15-17 years.Self-criticism degree in cognition of elder adolescents has an effect on the progress in solving specific tasks of the transition to adulthood  and cognitive autonomy , understanding importance of personal professional development  and high value of having a family . Also correlation regression analysis provides support for high correlation between self-esteem of personal autonomy, intellect , emotional autonomy and social/moral maturity variables.It was confirmed that cognitive peculiarities of elder adolescents  have an effect on the progress in solving specific tasks of the transition to adulthood.No significant relationships."}
{"text": "A widespread dissemination of effective evidence-based physical activity (PA) interventions is needed whether a greater proportion of the population, who could potentially benefit from it, wants to be reached . \u2018Sigue la Huella' (Follow the Footprint), is one of the few effective evidence-informed PA school-based interventions conducted on adolescents in Europe, with the support of the family and the community . The main aim of this study is to describe and analyze the process of dissemination of this intervention program.The \u2018Sigue la Huella' was implemented at one secondary school situated in Jaca/Huesca (Spain). The Replicating Effective Programs (REP) framework was used, because provides a roadmap for disseminating effective interventions . The intervention was delivered through workshops, ongoing technical assistance to the teachers, and the distribution of an instructional guide among the teachers and the school staff. A quasi-experimental design was adopted to examine the effect of \u2018Sigue la Huella' after its dissemination process. PA was assessed using accelerometers at baseline and after the intervention of 14 weeks. In addition, we evaluated the dissemination process using the PRACTIS guide .From an initial evaluation of the dissemination process, several key learnings emerged:To identify strategies for effective stakeholders engagement;To overcome some barriers such as the excess workload of the teachers in charge of disseminating the intervention program;For better measures to determine the success of dissemination approaches .This study provides a comprehensive overview of the dissemination process of an effective school-based program identifying contextual barriers and facilitators that influence program implementation in new contexts and the direction of specific strategies to address those barriers."}
{"text": "Psychosocial rehabilitation is a challenge in a society with demands unsuitable for those with severe mental illness (SMI). The Mental Health Department of Matosinhos Local Health Unity (MHD-MLHU) has developed a solidarity project aiming to evaluate and elaborate individualized rehabilitative responses with people with SMI, including people from the community motivated for solidarity initiatives.To describe a psychosocial rehabilitation project focused on community integration of people with SMI, considering needs and resources of the population, and to present the individualized rehabilitation plans carried out for people with SMI.In January 2019, we began the home evaluation of people with SMI monitored in the MHD-MLHU. To develop solidary based play-occupational groups, we interviewed people from the community and from the common mental pathology outpatient clinic willing to participate.We present the description and evaluation of the psychosocial responses developed by the project. These responses include recreational-occupational groups, tailored to interests of each person with SMI, and using the community support group built for the purpose. These responses promote face-to-face activities, and enhance the destigmatization of SMI. The constraints resulting from the COVID-19 pandemic led to the creation of digital responses aimed at people with SMI and the community in general.This experience has revealed the great potential of rehabilitating the community context of people with SMI, rather than just contemplating pre-existing structured responses. The pandemic created specific challenges but made the initiative even more relevant for SMI people and for promoting the mental health of the general population."}
{"text": "The processing and analysis of medical rehabilitation information data in tertiary hospitals is a hot research topic. Combining medical data analysis with machine learning algorithms to improve data mining efficiency is a problem that needs to be solved at present. This paper proposes an autonomous perception model of sports medicine rehabilitation equipment based on a deep learning algorithm for sports medical rehabilitation data.  This paper cites a deep learning multi-dimensional perception model for medical rehabilitation equipment autonomous perception. The model utilizes the automatic overhaul of medical rehabilitation equipment based on deep belief networks. This paper extracts features through a multi-layer neural network and obtains fault location results of medical rehabilitation equipment through softmax.  In similarity prediction, the accuracy rate of the first three kinds of feedback containing the target answer is 77%. The accuracy rate of the target answers included in the top five kinds of feedback was 92%.  In this study, it is feasible to apply deep learning to the quality control information system of sports rehabilitation medical equipment. This improves the management efficiency of medical rehabilitation equipment to a certain extent. The medical equipment purchased and used by many tertiary hospitals is generally under the responsibility of the equipment department. The daily maintenance and management of this medical equipment mainly include the perception of its status in the medical equipment software system and the integration of data, self-judgment of equipment failure, and evaluation of equipment failure. The active early warning of faults also includes the equipment's identification of its faults and the automatic generation of relevant information. From the beginning of use to the scrapping of medical equipment, the medical equipment software system's perception of itself and the early warning of possible failures are significant . The sofThe specific architecture of the system is shown in The monitoring module collects the voltage, current, temperature and humidity, logs, and other internal operating status data of various medical equipment in real time by integrating different sensors and processors . It tranThe monitoring module transmits the collected operating status data of the medical equipment to the data analysis module through the built-in IoT card. At this time, we can set the transmission timing to ensure the timeliness of data collection and transmission.We use big data, an expert knowledge base, and other technologies to perform data mining and analysis on these parameters according to the received real-time status data of the equipment. This article judges whether the diagnostic equipment is regular by comparing the normal parameters of the equipment . We assem is used as an actor based on the complex and variable parameters of the medical equipment state data carrier and the multi-source heterogeneity. This paper uses a value network to fit the  function of playing the critic's role. The evaluation function of the pros and cons of the self-awareness strategy m of the multi-dimensional operation and maintenance state of medical equipment under the situation of dynamic topology change is as follows:We use the Puhws-how open-source dataset for large-scale equipment state awareness to construct an unstructured multi-source heterogeneous fault data sample pool for medical equipment . In thisQ network structures. Because the multiple Q network structure adopts a random strategy, to obtain the current action, it is necessary to sample the probability distribution of the optimal strategy [Q network. In this paper, the perception strategy is determined directly through the function according to the behaviour. m in the formula is generally understood as an optimal behaviour strategy at=\u03bc(st|1 \u2212 \u03b8\u03bc), and the optimal function for the distributed perception of multi-source heterogeneous data can be characterized as follows:Based on , this pastrategy . The entQ network structure can be expressed as formula  function to play the role of critic. This paper will integrate the early warning objective function of the deep deterministic policy gradient algorithm with the empirical buffer factor:We use policy network Q function is expressed as the reward expectation for choosing an action under a deterministic policy \u03bc. In this paper, the empirical buffer factor is introduced in the coupling link between the policy network and the Q network. At this time, the iterative convergence speed of the algorithm is improved by orders of magnitude. We randomly sample mini-batch data from a pool of empirical buffer factors. Since different sub-policies will be executed in different rounds, we can get a memory replay pool for each training round. Finally, we solve the fusion objective function's gradient for each training round's sub-policy parameters [The rameters . At this\u03b8Q in the multiple Q networks has better self-evolution performance. In this paper, the expected return value is obtained by selecting an action in the s state by using the \u03bc strategy with the help of Q\u03bc). At this time, the feature framework of autonomously constructing fault information can better realize autonomous and active early warning of fault information of large-scale multi-source heterogeneous operation and maintenance data [The parameter nce data .This paper uses the data text of the operation and maintenance status of medical equipment recorded in the hospital equipment department from the second quarter of 2019 to the second quarter of 2020 as the initial training data. In this paper, based on the PyTorch open-source framework, the model is simulated and verified in the GymTorcs environment. In this paper, the algorithm is simulated and verified from the simulation diagram of the autonomous perception performance of the model's operation and maintenance state under the multi-source heterogeneous operation and maintenance data and the simulation diagram of the model's operational early warning performance under the control of the deep reinforcement learning algorithm. At the same time, this paper conducts graphical schematic simulation in Keras2.2.2 and Gym0.10.8 environments [This paper constructs an autonomous perception and active early warning mechanism of medical equipment operation and maintenance status with engineering application significance, as shown in This paper uses the TensorFlow open-source training platform to verify model performance simulation in the PyCharm integrated development environment. At the same time, this paper analyzes the engineering application of the model with the equipment department of the People's Hospital as the model effectiveness verification carrier. The system can better realize real-time perception and early warning of large-scale multi-source heterogeneous fault data."}
{"text": "This paper examines the impact of the COVID-19 pandemic on gross fixed capital formation across the euro area. The empirical analysis suggests that the intensity of the lockdown measures to contain the spread of the virus and the country-specific structure of the economy along with other traditional drivers, in particular falling output, can explain a large part of the contraction. The bold policy response at the national and EU level mitigated the impact of COVID-19 and supported the recovery. The faster-than-expected rebound in economic activity suggests that the negative economic impact of the pandemic will be more contained than initially feared. However, uncertainty over future health developments remains high, especially given the risks of new more transmissible variants."}
{"text": "A specimen observed with a transmission electron microscope (TEM) was processed by focused ion beam (FIB) from a surface-micromachined polycrystalline silicon MEMS structure. Electron irradiation and in situ observation were performed on a selected grain boundary in the specimen. The grain boundary was observed and located by using lattice-oriented selective TEM photography. An evolution progress of amorphization of small silicon grain within the grain boundary and recrystallization of amorphous silicon were observed. A silicon grain turned into several smaller bar grains within the grain boundary. The mechanism of grain-boundary evolution inducing a change of conductivity of polycrystalline silicon has been revealed. The conductivity of polycrystalline silicon influenced by electron irradiation could be attributed to the change of grain boundary. Microelectromechanical systems (MEMS) technologies are well suited for the needs of space applications due to their small size, low weight and low power consumption. One trend of space missions is to make technology smaller, faster and cheaper . DiffereThe mechanism of radiation effects on MEMS has been extended to polycrystalline materials using a grain-boundary evolution theory. This theory will help to estimate the long-term life of MEMS devices in radiation environments. One of the critical factors in the accelerated degradation experiments involving MEMS is that the failure mechanism should be the same. The observation of grain-boundary evolution in stress tests will help to determine the dose rate in accelerated degradation experiments and improve the acceleration factor. The theory will help to improve the fabrication processes of polycrystalline silicon in MEMS that are applied in radiation environments. The in situ observation of grain-boundary evolution in TEM provides a method to study the mechanism of radiation effects on different polycrystalline materials in MEMS. In addition, the further study of grain-boundary evolution will help construct the foundation of a numerical model of the radiation effects on polycrystalline silicon.The specimen was fabricated in a standard MEMS fabrication process. The fabrication process began with an n-type (100) silicon wafer. The surface of the wafer was first heavily doped with phosphorus in a standard diffusion furnace using a phosphosilicate glass (PSG) sacrificial layer as the dopant source, as shown in The scanning electron microscope (SEM) photograph of cross-section of the specimen is shown in The specimen observed with TEM in situ was processed by FIB from previously fabricated surface-micromachined polycrystalline silicon MEMS structure.An 8 \u03bcm (L) \u00d7 0.1 \u03bcm (W) \u00d7 0.5 \u03bcm (T) layer of platinum was deposited by electron beam deposition on the surface of polycrystalline silicon to protect the specimen beneath. The polycrystalline silicon beam was handled by a nano-handler and sectioned by FIB, and the sectioned beam was further reduced to 0.1 \u03bcm by FIB while it was protected by the platinum layer above.A low-resolution figure of the FIB processed specimen observed by TEM is shown in It is difficult to distinguish grains and grain boundaries of polycrystalline silicon since grains and grain boundaries are irregular in dimension. To observe and locate every grain and its boundaries, lattice-oriented selective TEM photography was performed, as shown in With the help of lattice-oriented selective TEM photography, grain boundaries are easily found and located for further high-resolution TEM photography. Moreover, specific grain boundary may be observed and relocated, as shown in The observation point was located in a certain grain boundary, and high-resolution photography was performed. Lattice of polycrystalline silicon could be clearly observed in a narrow field of view, as shown in With the help of photography of grain boundary, the point where the followed electron irradiation and in situ observation is performed was located. The photograph before electron irradiation is shown in The scale of crystalline silicon and amorphous silicon in the grain boundary ranges from several atoms to hundreds of atoms. The shape of crystalline silicon in grain boundary is usually stripe. Some of the small crystalline silicon grains in the grain boundary close to each other have the same lattice orientation. And some of the small grains have different lattice orientations.A grain boundary was selected for electron irradiation and in situ observation, as shown in Two-hundred snapshots of TEM figures were photographed in the electron irradiation experiment, and the snapshots were photographed every 2 s. Photographs at different doses were obtained from 0 to 398 krad, and the dose increment of electron irradiation was 2 krad. The grain boundary of polycrystalline silicon was observed in the snapshots, as shown in The grain-boundary evolution of polycrystalline silicon was considered as the progress of amorphization of small silicon grain within the grain boundary and recrystallization of amorphous silicon.The grain-boundary evolution is quite slow at the beginning of electron irradiation. In the first 200 s, the change of crystalline silicon and amorphous silicon in the grain boundary is small when the total dose of electron irradiation is limited to 200 krad. Between 200 s to 300 s, the crystalline silicon and amorphous silicon in the grain boundary start to change. The change of grain boundary slows down again when the time reaches 400 s.There are two typical grain-boundary evolution mechanisms shown in The second mechanism is shown in area II and area III, which are on the bottom right of the photograph. The shape of the amorphous silicon in area II and area III is short stripes before electron irradiation, as shown in The grain-boundary evolution is concluded as a small silicon grain turns into several smaller grains within the grain boundary, as shown in the bottom left area I in As shown in As shown in The segregated phosphorus atoms in the amorphous region could not be observed in the TEM photography; the interaction between phosphorus atoms and silicon atoms needs further study.According to the evolution of the grain boundary, two different mechanisms tend to decrease the volume of crystalline silicon within the grain boundary on average. Additionally, both mechanisms of grain-boundary evolution increase the defect density within the grain boundary.B, and a depletion region with a width of W in the grain is induced by the trapped charge in the grain boundary. A potential barrier with a height of EB in the grain boundary is induced by the trapped charge and the charge in the depletion region.The conductivity of the polycrystalline silicon is mainly contributed by a thermionic emission current other than the tunneling current due to high doping . The conB to Q\u2032B according to the increase in defect density induced by grain-boundary evolution. The depletion region in the grain will be increased from W to W\u2032 subsequently. And the height of the potential barrier in the grain boundary will be increased from EB to E\u2032B.As shown in The conductivity of polycrystalline silicon is significantly influenced by the potential barrier, since the effective mobility of carriers is figured out by the potential barrier, as shown in Equations (1) and (2) ,14,15,16The effective mobility of carriers will decrease according to the increase in potential barriers. The conductivity of polycrystalline silicon will decrease subsequently. The grain-boundary evolution-induced potential barrier change will decrease the mobility of polycrystalline silicon, and it will increase resistivity. This conclusion provides a theoretical mechanism for the results of research on the electron irradiation-induced resistivity change of polycrystalline silicon .The increase in defect density and redistribution of defects due to the grain-boundary evolution will also affect the trap-assisted tunneling (TAT) in polycrystalline silicon ,18. The The evolution of grain boundary will influence the effective mobility of carriers in polycrystalline silicon, which is one of key factors in the conductivity mechanism of polycrystalline silicon. Most of the energy deposition of electron irradiation is in the surface of the polycrystalline silicon membrane, due to the small penetration depth of the electrons. The vertical imbalance of energy deposition should be considered when the quantitative analysis of the conductivity of polycrystalline silicon is performed.Lattice-oriented selective TEM photography was performed to observe and locate the boundary for further in situ observation. Grain-boundary evolution under electron irradiation from 0 to 398 krad was observed in 200 snapshots of TEM figures. The grain-boundary evolution is concluded as a small silicon grain turns into several smaller grains, or amorphous silicon expands due to the amorphization of the small silicon grain. Both grain-boundary evolutions tend to decrease the total volume of crystalline silicon within the grain boundary and increase the defect density within the grain boundary. The trapped charge in the grain boundary will increase according to the increase in defect density, and the depletion region in the grain will increase subsequently. The height of the potential barrier will also increase. The conductivity of polycrystalline silicon will decrease due to the decrease in the effective mobility of carriers induced by the higher potential barrier. The grain-boundary evolution theory will help to explain the mechanism of radiation effects on polycrystalline silicon in MEMS. Furthermore, the temperature environment can be introduced in the TEM observation to study the radiation effects under multi-field coupling and improve understanding of the grain-boundary evolution theory."}
{"text": "The antibiotic resistance crisis is a worldwide healthcare concern. World Health Organization (WHO) has projected that infections generated by multi-drug resistant (MDR) bacteria will most likely increase in the near future. This situation has encouraged scientists to develop and/or improve complementary strategies to fight this threat. In this context, bacterial viruses (bacteriophages or phages) have been proposed as a therapeutic alternative due to their specificity and different mechanism of action compared to antibiotics.Phages are the most abundant microbial entity in the environment (reaching ~10 e31), and the constant interplay with their bacterial hosts shapes both phage and bacterial evolution in the so-called arms race.Castledine et\u00a0al.) and the dynamics of phage-bacteria coevolution in culture media was reported . In addition, the use of CRISPR-Cas genetic scars in the host genome as a tool to understand phage-host interplay in the human microbiome  and the characterization of novel phages able to infect and kill clinically relevant MDR pathogens was also highlighted . Altogether, these new findings increase our current understanding of phage-bacteria interactions and contribute to reinforcing the idea of a rational use of phage therapy and the identification of novel relevant aspects to consider when using phages as an antibacterial strategy for the treatment of MDR human and foodborne pathogens.This Research Topic aimed to provide an update on the impact of phage-host interactions in bacterial evolution and the cautions to consider for administering phage-based therapies. In this context, new research showing relevant aspects of phage biology during the interaction with their hosts, such as the effect of genotypic diversity and its impact on bacterial coevolution (All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "Western culture is experiencing a movement for death reform which includes aspects such as death acceptance and supporting individual choice concerning how one wishes to experience end-of-life (EOL). The underlying goal of this reform is to foster natural curiosity about death and dying in order to soothe death fears and anxiety. Over the past few decades in the U.S. there has been an increase in public support for the EOL option of medical-aid-in-dying (MAID), or legally prescribed pharmaceuticals intended to cause death. There have been mixed findings regarding the effects of age on attitudes and perspectives towards death and dying. The aim of this study was to determine the relationship between age, death fears and anxiety, values and perspectives, demographic characteristics, and approval of MAID at EOL in a U.S. nationally representative sample (N = 1994), using a partially latent structural equation model (SEM). Results show that age has a curvilinear effect on death fears and anxiety, and that as death fears and anxiety increase support for MAID decrease. This suggests that the ability to provide person-and-family-centered care at EOL must address the biopsychosocial aspect of death fears and anxiety across the life course. These findings demonstrate the need for more research documenting changes in attitude and perspectives towards EOL for different populations . The potential benefits of this approach provide a basis for expanding education and awareness of both death and dying in general, and EOL needs and wants for older adult populations."}
{"text": "The corrected page range is e111-e114.The Publisher wishes to inform that the page range of the above-mentioned article has been updated. DOI of the article is"}
{"text": "A 76-year-old man was hospitalized due to recurrent episodes of dizziness and a significant left-right blood pressure difference . Time-of-flight magnetic resonance angiography (TOF-MRA) revealed a gradual decrease in the signal intensity of the left proximal intracranial vertebral artery (VA)  arrow. A(1). Because of the use of radio frequency pulses, the MRA exhibited greater signal loss proximal to the VA. Our findings support the evaluation of the signal intensities of intracranial VA on the MRA to achieve an early diagnosis of SSS.Blood flow in the affected VA of SSS is reversed and slow NoneTT wrote the first draft and managed all of the submission processes.We have obtained informed consent for this case report."}
{"text": "It is widely recognized that racial and ethnic minorities experience lower quality of care and worse health outcomes across a wide range of health services and long-term care settings. However, less is known about racial and ethnic differences in home and community-based services (HCBS). This study used the HCBS version of the Consumer Assessment of Health Providers Survey (CAHPS) to examine participant experience of care in a large, statewide Medicaid program. The CAHPS-HCBS is a validated measure of quality of HCBS that supplements measures of health outcomes and provides policy makers with critical data on system performance. As part of a larger evaluation of Pennsylvania\u2019s transition to Managed care for users of HCBS, representative samples of older adults were interviewed before and after the program was implemented. This study takes advantage of the phased implementation of managed care to estimate the causal effect of the program on differences in participant experience by racial and ethnic group. In general, non-Hispanic whites rated their overall satisfaction with HCBS lower than non-Hispanic Black and Hispanic people. The implementation of Managed care was associated with improvements in non-Hispanic Black and Hispanic ratings of personal care and service coordination, but not that of non-Hispanic whites. One implication of these findings is that managed care organizations can have positive impact on participant experience. The CAHPS-HCBS instrument is publicly available and can be used by state agencies to monitor racial and ethnic disparities in participant experience."}
{"text": "Understanding the impact of cancer on the hopes and fears of older adult (age 60+), long-term (5 years +) survivors is important for assessing their quality of life after cancer. Prior quantitative research has shown the important role that cancer plays in the health and psycho-social well-being of survivors in the years and even decades after diagnosis and treatment. This presentation extends that research by examining both quantitative data and survivors\u2019 narratives revealing important issues survivors face such as altered sense of self/identity, feelings of social isolation, key sources of social support as well as cancer and other health-related concerns. These are examined in the context of broader existential issues related to their hopes and fears for the future and differences by race, gender and cancer type are also presented. The data analyzed are from an NCI funded, 10-year longitudinal study based on in-person interviews with 321 survivors of breast, colorectal and prostate cancer to document how cancer-related factors have affected their aspirations for the future. The findings are discussed in the context of how the issues that survivors identified as affecting their hopes and fears may be integrated into the dialogue clinical staff can have with older survivors and their families as part of after-cancer care."}
{"text": "In several disciplines such as in biomedicine and social sciences the analysis of individual-level data or the co-analysis of data from different studies requires the pooling and the sharing of those data. However, sharing and combining sensitive individual-level data is often prohibited by ethico-legal constraints and other barriers such as the control maintenance and the huge sample sizes. The graphical illustration of microdata is also often forbidden as can potentially be unsecured on the identification of sensitive information. For example the plot of a standard scatterplot is disclosive as can explicitly specify the exact values of two measurements for each single individual.www.datashield.ac.uk) is a novel approach that allows the analysis of sensitive individual-level data and the co-analysis of such data from several studies simultaneously without physically pooling the data.DataSHIELD  and demonstrate a number of new functions including ds.scatterPlot and ds.boxPlot developed based on the application of different computational approaches like the k-Nearest Neighbours algorithm and ensuring privacy protected analysis.DataSHIELD graphical functionality has certain methodological features for the representation of the relationships between different variables preserving their statistical properties and assuring the data privacy protection. These graphical approaches can be used or enhanced for application in various areas where confidentiality and information sensitivity is considered, for example in longitudinal data and survival analysis, in epidemiological studies, in geospatial analysis and several others."}
{"text": "Health Psychology is a scientific branch that studies interpersonal relationships in the field of emotions and behavior in clinical settings. Violence against women is a gender-based action that alarmingly affects the population, with sexual violence (SV) being one of its main phenomena. The complexity of the care offered to SV patients by clinical professionals impacts themselves, affecting their personal lives and the quality of their work.To explore symbolic emotional meanings attributed by health professionals to care and follow-up of women victims of SV in state service of reference of the Unified Health System.Clinical-Qualitative design was used to guide semi-directed interviews with open-ended questions in-depth. Clinical-Qualitative Content Analysis was employed to treat data. Five participants make up the multi-professional team at the Hospital of the Woman of the State University of Campinas. Theoretical framework chosen to interpret categories was Balintian Medical Psychology.Three categories were selected for this presentation: The human anguishes as the main challenge and handling of working with sexual violence; \u201cTo see things progressing\u201d: to the patient and together with the team, a facilitator of the work; and \u201cI try to leave it on the three\u2019s leaves\u201d: the difficult attempt to separate work from personal life.Taking care of SV is a very emotionally demanding task. Working with the team and see expected outcomes help clinical professionals deal with negative feelings, avoiding, for example, compensatory traumas. New research about social-cultural impacts of working with SV is important to develop institutional approaches of coping for health teams.No significant relationships."}
{"text": "The COVID-19 pandemic has been a natural global epidemiological experiment unique to our century and a massive shock to older adults and to systems that care for them. There was a lack of a global unified plan to mitigate and control the spread of COVID-19. Several middle-or-high income nations struggled to control the viral spread resulting in increased mortality due to a combination of lack of public health measures and existing disparities which were magnified during the pandemic. The purpose of this review by a team of international experts is to (1) to examine reasons for the varied COVID-19 responses within U.S. and among other middle-or-high-income countries and the emergence of variants and vaccine inequities, and (2) to examine the country specific burden of cultural/structural/political determinants on access to care and mortality among older adults in various settings."}
{"text": "Depression is one of common comorbid states that accompany cardiovascular diseases. Risk of co-morbidity can rise when patients have to undergo heart surgery, which is an additional stress-factor.To specify psychological correlations between depressive manifestations in cardiac surgery patients based on the analysis of their time perspective profile.Using the Zimbardo Time Perspective Inventory, we examined 60 cardiac surgery inpatients . We calculated the statistical estimation of the received data based on the comparison with the norm and the correlation analysis.The research revealed that cardiac surgery patients\u2019 indices significantly exceeded the norm on three out of five scales \u2013 Negative-Past , Positive-Past , and Future . We also identified essential correlations between the level of depression and the indices of Negative-Past  and Positive-Past . We distinguished a positive correlation of the negative attitude to the past with cognitive-affective  and somatic  manifestations of depression, and a negative correlation with the level of education .The personal time perspective profile in cardiac surgery patients is unbalanced due to a high level of their negative attitude to the past with an optimal level in other time perspectives. The degree of the Negative-Past attitude correlates in the patients with a low level of education and a high risk of depression in all its manifestations. The given correlations should be taken into account when conducting preventive psychological interventions.No significant relationships."}
{"text": "The crosstalk between nervous systems and other body systems is complex and is not limited to the communication for neural pathways only. The key role of the nervous system in the control of many involuntary reflexes and reactions to other body systems is generally accepted. Due to the emergence of radiologically targeted neuroimaging technology and neurotropic virus-based transneuronal tracers in recent years, the access to neural connectivity in the other body systems has greatly been improved  signaling via glia-mediated control of BDNF maturation, and, therefore, support adaptive neuroplasticity.Between rich functionality and the rather invariant structural architecture of brain neuronal circuits remains one of the major mysteries in neuroscience. Recent progress in understanding the mechanisms of brain-other body systems crosstalk pinpoints the role of the adaptive neuroplasticity. The high incidence of patients with neural circuit-related diseases such as mental disorders, highlights the importance of fundamental research, among others with interventions stimulating adaptive neuroplasticity. Trans synaptic viral tract-tracing in the toolbox of neural labeling methods has been a significant development in the skeletal muscle-brain crosstalk (Huang et al., The above manuscripts discuss a number of \u201chot topics\u201d in the crosstalk between nervous systems and other body systems , includiAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
{"text": "The compelling advancements in systemic targeted therapies for cancer drastically changed the role of histopathological analyses in recent decades. Indeed, the identification and clinical application of new diagnostic and predictive markers for malignant neoplasms have become mandatory in order to offer the best standardization for patients\u2019 prognosis and the best therapeutic options. The aim of this Special Issue was to focus on the identification, feasibility, and reproducibility of recent tissue markers in gastro-intestinal tumors.These advancements in common knowledge can be achieved in two ways: by enhancing diagnostic methodologies and by discovering brand new markers for diagnosis and predictivity. As for methodology, the review from Renzulli et al. visibly reflects this need for new diagnostic and therapeutic tools from a radiologist\u2019s point of view : the autThe work of Okuno et al. explores the diagnostic process in liver and bile duct malignancies from a completely different point of view : the autThis Special Issue also focused on new and upcoming diagnostic and therapeutic biomarkers: In this regard, the review by Pekarek et al. introduced a very comprehensive state-of-the-art analysis on various up-and-coming biomarkers that are useful in the diagnosis and therapy of pancreatic carcinoma . The autThe work by Salmikangas et al. brought us a new immunohistochemical (IHC) marker in the diagnosis of gastrointestinal stromal tumours (GIST): tensin-2 . This prPezzuto et al. aimed to validate a ddPCR assay for the 124G>A mutation of a TERT promoter in hepatocellular carcinoma (HCC) in a local cohort of resected patients . They coFinally, Fernandez-Palanca et al. performed a review and meta-analysis of the literature regarding the presence of Neuropilin-1 (NRP1) overexpression in IHC as a pejorative marker in colorectal cancers (CRCs) and in primary liver cancers ,12: TheyThe papers included in this Special Issue depict a wide range of neoplastic processes that comprehended the gastrointestinal tract, liver, and pancreas and different methodologies ranging from imaging techniques to cytology and molecular biology. The portrait that emerged from these works is a promising effort towards a personalized approach for patients with gastrointestinal malignancies, encompassing all aspects of the diagnostic and predictive processes."}
{"text": "The COVID-19 pandemic caused significant disruptions in services and necessitated innovation to continue care provision to the vulnerable population of older adults with psychiatric needs.The objective of this study was to examine the experiences of staff and patients using a hands-free electronic smart-hub (eSMART hub) intervention to keep patients connected with psychiatry of old age following COVID-19 restrictions.A risk stratification register was created of all patients known to the Psychiatry of Old Age service in the North-West of Ireland to identify those at highest risk of relapse. These patients were offered a smart-hub with remote communication and personal assistant technology to be installed into their homes. Smart-hubs were also installed in the team base to facilitate direct device to device communication. Semi-structured qualitative interviews were conducted with 10 staff members and 15 patients at 6-12 months following the installation of the smart-hubs.The smart-hubs were utilized by the POA team to offer remote interventions over video including clinician reviews, regular contact with key workers and day-hospital based therapeutic interventions such as anxiety management groups and OT led physical exercises. Patients also used the personal assistant aspect of the hub to attend to personal hobbies such as accessing music and radio. Positive feedback related to companionship during isolation and connectivity to services. Negative feedback was mainly related to technology, particularly internet access and narrow scope of communication abilities.Electronic smart-hub devices may offer an acceptable avenue for remote intervention and communication for isolated high-risk older persons.The smart hub devices used in this study were donated by Amazon. However, the company was not involved in any other aspect of the study and the researchers have no significant financial interest, consultancy or other relationship with products, manufactur"}
{"text": "The covid-19 pandemic is having a significant impact on the mental health of the entire population.To determine the dynamics of emotional disorders in medical students in the context of the covid-19 pandemic.Methods of research. An online survey of medical university students was conducted during the covid-19 pandemic. The Beck scale was used.Results and its discussion. According to a dynamic study of emotional disorders in medical students, which was held during 12 months of covid-19 pandemic, emotional disturbance in the form of depressive manifestations associated with the covid-19 pandemic did not reduced. In addition, the results of the study indicated a change in the structure of depressive manifestations in the surveyed in favor of milder depressive manifestations  and a decrease in the prevalence of moderate and severe manifestations of depression .The long-covid pandemic has a negative effect on the mental health of medical students and lead to emotional disturbances in the form of depressive manifestations of varying severity. The compensatory possibilities of mental activity proceed unilaterally with a change in the structure of emotional disorders; adaptation to a stress factor is not formed. Disclosure of interest.\u2013 The authors have not supplied a conflict of interest statement.No significant relationships."}
{"text": "One thing is certain though: back pain in children and adolescents greatly impacts the everyday lives of these young individuals and their medical care . Like ad\u201cWhy is there a need for special consideration of back pain in childhood and adolescence?\u201dIn the current absence of evidence, it is important to ensure that this population of young individuals are not exposed to under- (or over-) diagnosis or to over-treatment. This balance is truly difficult, as many questions regarding the origin and treatment of back pain remain unanswered. To guide clinical practice, Frosch et al.  have pro\u201cWhat is the difference between back pain in younger children and in adolescents?\u201dWe see an increasing prevalence of \u201cnon-specific\u201d back pain in adolescence ,5. Even Developing a reliable differential diagnosis of specific and non-specific back pain, including validating red flags;Clarifying the indications and procedure of imaging and multidisciplinary diagnostics;Optimizing non-drug treatments for non-specific back pain;Improving the prevention of back pain;Avoiding chronicity of back pain;Improving the self-management of non-specific back pain in children and adolescents.Despite numerous scientific efforts to emphasize the problem of back pain in children and adolescents and to improve diagnostics and therapy, many research questions remain unanswered . Future In this Special Issue, we address these challenges of back pain in children and adolescents and give an overview of the current state of knowledge and future needs."}
{"text": "The COVID-19 epidemic and mitigation actions had major impacts on health and healthcare use by the French population. Since 2004, the French public health agency daily collects individual data of visits in the emergency departments (ED) OSCOUR\u00ae network . We aimed to analyse the evolution of non-Covid ED visits from 2020 to March 2022, in order to identify potential indirect impact of the epidemic.The main medical diagnosis (MD) coded in ICD-10 from each ED visit from 2017 to March 2022 was classified into 17 ICD-10 chapters and in 95 disjoint subgroups of pathologies. The observed numbers of ED visits by age group and by chapters/subgroups were compared to expected numbers, estimated using an overdispersed Poisson regression model based on 2017-2019 data.The observed numbers of ED visits for all chapters and for a large part of subgroups were significantly lower than the expected numbers during the three lockdowns in all age groups and progressively returned to the expected level in 2021. A change in the pattern of a limited list of subgroups was observed: ED visits for purpura, chronic blood diseases and neurologic disorders in children decreased during the first lockdown and remained under the expected level until March 2022. Inversely the number of ED visits for mental health and wheezing in children, for pulmonary embolism in adults and for neoplams in the elderly increased and remained over the expected values until 2022.Syndromic ED system was a pillar of the French reactive surveillance of direct and indirect impacts of COVID-19 epidemic. The changes observed for different subgroups of pathologies may reflect a negative impact of the epidemic, a positive effect of protective measures on the spread of other infectious diseases, a modification in the organization or in the use of health care in specific domains. Further studies using hospitalization data could explore these hypotheses.\u2022\u2002Existing syndromic surveillance system implemented before the emergence of SARS-COV2 enabled to monitor non-Covid-19 visits to emergency departments and assess changes in patterns of pathologies.\u2022\u2002An increase in the number of emergency department visits during the COVID-19 epidemic was observed for mental health in children, for pulmonary embolism in adults and for neoplams in the elderly."}
{"text": "This study will be helpful for scientific researchers interested in the chemistry of bifunctional versatile compounds as it provides a collection of all the methods for the preparation of 3-substituted-4-amino-5-mercaptotriazoles with aliphatic, aromatic, and heterocyclic moieties during the period from 2000 to mid-2020. 4-Amino-5-mercaptotriazole and its 3-substituted derivatives have proven to be of biological interest and provide access to a new class of biologically active heterocyclic compounds for biomedical applications. Numerous scientific researchers in the fields of chemistry and pharmaceutical science are interested in the study and utilization of these compounds as building blocks in the synthesis of important bioactive compounds.The authors declare that there is no conflict of interests regarding the publication of this paper."}
{"text": "The research field of disability and mental health is politically and socially relevant, because the psychological well-being of people with intellectual disabilities has often been trivialized in therapy and legislation. Since the pursuit of mental health is coming into focus due to removal of stigma and emerging awareness, people with disabilities must have equal opportunities to choose their place of residence and get suitable psychosocial support.Our aim is to investigate the influence of assisted outpatient treatment (AOT) on the quality of life and resilience of people with intellectual disabilities who are living self-determined.A participatory mixed-methods design is chosen as it enables the greatest possible standardization and allows a high flexibility. The project will be divided into three parts: A systematic literature search to gain knowledge about the field and to estimate the sample size, a pre-post-comparison of the WHOQOL-BREF to evaluate AOT in terms of self-perceived quality of life and a focus-group of handicapped people to reflect the study results with attention on resilience.To foster the doctoral thesis, several questions can be discussed: 1) How is the relation of disability and mental health to be described? 2) What might be the pros and cons of self-determined living? 3) Which steps need to be taken to implement AOT more often?The topic is relevant in the public health sector and the results could help to sensitize professionals and the general society regarding to participation in everyday life. The recommendations developed may serve to implement comparable forms of housing.No significant relationships."}
{"text": "Acoustics is one of the most studied fields in the 21st century, encompassing underwater acoustics, architectural acoustics, engineering acoustics, physical acoustics, environmental acoustics, psychological acoustics, signal processing in acoustics, and so on. With the application of entropy and information theory in acoustics, many acoustic problems have been solved or improved. Additionally, the current trend seems to indicate that the role of entropy and information theory in the field of acoustics will also steadily increase and lead to many exciting new discoveries. This Special Issue of \u201cEntropy and Information Theory in Acoustics II\u201d aims to collect the latest research results and latest developments in the application of entropy and information theory in the field of acoustics. This collection contains eight papers representing the latest applications of entropy and information theory in the field of acoustics.In order to extract useful features from nonstationary and nonlinear ship-radiated noise signal (SNS), Xie et al. propose an SNS feature extraction method based on optimized variational mode decomposition, displacement entropy, and normalized Spearman correlation coefficient . The expLi et al. introduce slope entropy (SIEn) into feature extraction in ship-radiated noise signals for the first time, and proposed a single-feature extraction method based on slope entropy and a double feature extraction method based on SIEn combined with permutation entropy . By extrWasiq et al. propose an intelligent computing paradigm built on a nonlinear autoregressive exogenous (NARX) feedback neural network model with the strength of deep learning, presented for the accurate state estimation of an underwater passive target. To improve tracking accuracy, effective feature estimation, and minimizing the position error of dynamic passive objects, the strength of NARX-based supervised learning is exploited. The root mean square error between the estimated and real position of the passive target in rectangular coordinates is computed for evaluating the worth of the proposed NARX feedback neural network scheme .In order to improve the communication rate of existing bionic concealed-hydroacoustic communication (BC-UAC) and improve the concealment and effectiveness of the constructed bionic communication signal, Xie et al. proposed a bionic covert UAC method based on the time\u2013frequency contour of the bottlenose dolphin whistle, which can overcome the security problems of traditional low-signal\u2013noise-ratio covert communication and exclude detected communication signals such as marine biological noise . The perBased on the theory of fluid\u2013solid coupling, combined with the aeroacoustics computational fluid dynamics method and the frequency domain acoustic wave equation, and using the track\u2013wheel interaction noise software noise simulation prediction model, the rolling aerodynamic noise model of wheel\u2013rail of a high-speed railway is established, and the vibration and noise characteristics of the wheel-rail area of a high-speed railway are analyzed, and the joint simulation and prediction of vibration, rolling noise, and aerodynamic noise of a wheel\u2013rail system are realized. The field test data of the Beijing\u2013Shenyang line is considered to verify the reliability of the model . By analWang et al. propose two spectral methods, the Chebyshev\u2013tau and Chebyshev\u2013collocation spectral methods, to solve the normal mode of atmospheric acoustics, and corresponding programs are developed. An artificial absorber layer is added above the atmosphere of interest to reduce the impact of the truncated half-space on the area of interest. Numerical experiments are examined for both downwind and upwind conditions to verify the effectiveness of the methods. The running time data indicated that both spectral methods proposed in this article are faster than the Legendre\u2013Galerkin spectral method proposed previously .Wasiq et al. proposed an application of deep-learning-based neural computing for efficient the real-time state estimation of the Markov chain underwater-maneuvering object . State eMa et al. apply the Chebyshev\u2013Galerkin and Chebyshev\u2013collection spectral methods to directly solve the two-dimensional Helmholtz model equation; implement the parallel code of the collection method to effectively improve the calculation effectiveness; and use the analytical solution to verify the feasibility of the two methods for directly solving the two-dimensional ocean acoustic propagation problem .Entropy editorial board for facilitating this opportunity to present all of these works. The editors extend their sincerest gratitude toward all of the authors for their excellent contributions to this Special Issue. Special thanks go to all of the reviewers for their time and feedback provided to the authors. Additionally, we sincerely thank the publishers, editors, and all of the members of the"}
{"text": "More specifically,we expect that it will have a naocif effect on the pregnant women\u2019s mental health and their well being, since they are more likely to be hospitalized The aim of this work was to evaluate the evolution of depression symptoms in the time of pandemic and their associated factors.In the current work, we conducted a comparative in field cross-sectional study. We compared depressive scores and prevalences before and after the COVID-19 outbreak in Tunisia in pregnant women.The sampling period was outside the lockdown period to avoid quarantine bias. The sampling period was from September to October 2020.showed a significantly higher prevalence of depressive symptoms in expecting mothers during the pandemic. Multivariate analysis showed that the pandemic multiplied by 3 the risk of severe depression symptoms. The impact of the COVID-19 period on depression was independent of sociodemographic and obstetric changes related to the pandemic.These results highlighted the emergency of preparing strategies to avoid post-partum psychiatric disorders and to enable a healthy development of born. Screening the post-partum depression and assessing the mother-children early interactions should be considered in the up-coming births.No significant relationships."}
{"text": "In 2020, the Namibian Ministry of Health and Social Services (MoHSS) and the Robert Koch Institute (RKI) started a twinning project with the long-term goal of establishing a Namibia Institute of Public Health (NIPH). A fundamental pillar of an NIPH is a fully operational Public Health laboratory system. Due to the COVID-19 pandemic, the need for strengthening the existing Namibian Laboratory system became eminent. Following the Intra-Action Review (IAR) of the COVID-19 response in Namibia in 2020, three regional diagnostic laboratories, at points of entry, were assessed. The major issues identified were long delays between sampling of both suspected cases and COVID-19 patients and receiving test results due to extended sample transport times to the central laboratory in Windhoek and the overload of the central capacities due to overwhelming numbers of samples during peak times. This led to the establishment of three SARS-CoV-2 PCR diagnostic laboratories through procurement and installation of equipment, provision of consumables/reagents, and on-site training of laboratory technicians with continued virtual technical support. Consequently, an important reduction of the diagnosis turnaround time was achieved. Of great value was the technical support given by the staff at the central laboratory during the trainings allowing for immediate validation of the newly established laboratories and to strengthen the communication between regional laboratories and the central laboratory. The Namibian molecular diagnostic capacities have increased in important regions in Namibia and will provide data to support the health policies of the future NIPH. New diagnostic protocols will be developed to foster the sustainability of the established laboratories and could support the implementation of genomic surveillance capacities. Finally, stronger relationships were built through these joint activities, which will support and the next steps of the establishment of the NIPH.\u2022\u2002Supporting and Strengthening the Namibian Public Health Laboratory system.\u2022\u2002Long-term goal of establishing a Namibia Institute of Public Health (NIPH)."}
{"text": "Liu et al.) The key metabolic processes for orally delivered drugs were reviewed for the assessment of current experimental systems to evaluate drug metabolism and potential interactions. A supportive manuscript on drug metabolism in this Research Topic was written by Dong et al., which investigated the effects of X-ray radiation on the pharmacokinetics of apatinib in rats and how radiation alters absorption, tissue distribution, and excretion. They found that X-rays led to significantly decreased plasma concentrations of apatinib, a tyrosine kinase inhibitor (TKI) that is used for advanced gastric cancer. The higher drug metabolic rates with X-rays are likely regulated by the expression of the cytochrome P450 or glucuronidation enzymes  isozymes were reviewed as a state-of-the-art roadmap for the metabolic fate of oral drugs  and alanine aminotransferase (ALT) levels. While they did not specifically study the gut microbiome, the antibiotic might impact the liver-gut axis as indicated by ALT levels  that are used as ultrasound contrast agents in clinical diagnosis. The MBs could possibly be used in ultrasound-mediated therapy due to their drug-loading capabilities. The MBs offer the advantage of tissue-specific delivery, potentially leading to increased target-site exposure to relevant drugs.The last study included in the Research Topic was by In conclusion, the research presented in this Research Topic highlights the quality and diversity of early-stage researchers across the field of drug metabolism and transport and how drug transporters and metabolizing enzymes are affected and regulate the pharmacokinetics of experimental compounds and FDA-approved drugs. The topics covered were in areas such as metabolism and transport of drugs, endogenously formed compounds, and environmental chemicals."}
{"text": "Mental disorders are globally among the leading causes of disability in the working-age population. Psychotherapies have proven to be effective in the improvement of mental health. The current evidence on the benefits of psychotherapies is mainly based on randomized control trials and patient-reported outcomes, whereas the potential impact of long-term psychological therapy on work disability and income is not so well known. This emphasizes the need for longitudinal studies on the effects of psychological therapies in a \u2018real-world study setting\u2019, and on the distribution of the availability and the use of psychological therapies in different populations. In Finland, rehabilitative psychotherapy is the major single form of publicly provided psychological therapy. It is targeted at those aged 16 to 67 who are at risk of disability or not being able to study because of mental health problems. It is granted an annual period (maximum three years), a maximum of 80 sessions per year and 200 sessions per 3 years. From 2011 on this psychotherapy has been statutorily granted to all at risk of work disability due mental health disorders. The number of annual users has increased from 15 757 (2010) to 56 682 (2020). This workshop presents the results from a research project investigating the use and real-world effects of long-term psychotherapy in the Finnish working-age population in the 2010s. It shows 1) whether the use of psychotherapy is associated with subsequent work disability and labour market outcomes , 2) how the use of long-term psychotherapy differed between socio-demographic groups in the 2010s in Finland, and 3) the extent to which state-subsidized psychotherapy is linked to the distinctive profiles of mental health problems in the population. The five presentations offer new results from the Rise of Mental Vulnerability in Work Life Study drawn from the national registers. The presentations are mostly based on three randomly selected population cohorts which each included 33% of the 18-64-year-old permanent Finnish residents at the baseline. These data were sampled  by and derived from the Population Register maintained by Statistics Finland and included information on various socio-demographic characteristics . These were linked to the national health registers. Information on reimbursed psychotherapy and mental health indicators  were obtained from the Social Insurance Institution of Finland and complemented by the disability pension data from the Finnish Centre for Pensions. The data provide a unique opportunity to observe how the use of state-subsidized long-term psychotherapy was distributed across population groups in the 2010s, and to the extent to which disability trajectories and economic outcomes have developed in different groups during and after psychotherapeutic treatment.\u2022\u2002Psychotherapy is likely to decrease the risk of work disability and improve labour market outcomes.\u2022\u2002The provision of long-term psychotherapy is related to social inequality in the working population."}
{"text": "The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.This research was supported by the ANR research grant (no. ANR-17-CE39-0014).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "This Research Topic collects different contributions that highlight various aspects related to the deployment of MR devices for neuromorphic and AI applications. These contributions provide new insights toward utilizing emerging devices and approaches to mimic biological behavior of the brain.Poduval et al.), proposes a brain-inspired system that displays HDC memorization ability over a graph of relationships. The authors introduce GraphHD, hyper-dimensional memorization that displays graph-based information in high-dimensional space. This approach provides superior cognitive functions over the encoded memory graph, which allows the representation of complex graph-based data structure into high-dimensional space.The first article of this Topic  spiking model, and introduces memristive-based LIF (MLIF). The authors prove the superiority of MLIF over LIF via comparing the firing patterns of both models. It's shown that MLIF can efficiently mimic the firing behavior of biological neurons. Experimental results show that a single memristive cell can emulate the synapse and demonstrate the function of integration and filtering of both the dendrite and soma. Thus, this work could provide a basic building block for reproducing the behaviors of biological neurons and building neural networks.The contribution proposed by Fang, Duan et al.. The reported approach easily mimics the spiking and bursting patterns of distinct brain neurons. The MIZH neural network demonstrates both synchronous and asynchronous collective actions. The firing patterns of excitatory, inhibitory, and other neurons are also studied in this work using the MIZH model. Due to the inherent characteristics of memristor devices, MIZH will have a great impact on the design and implementation of artificial neural network models.As an alternative approach, a memristive-based Izhikevich (MIZH) spiking neuron model is proposed in Fang, Tan et al. propose replacing the resistor with a memristor in the Resistor-Capacitor (RC) neuron circuit, and name the new circuit as Memristor-Capacitor (MC) circuit. It's shown that the charging and discharging time has been reduced using the MC circuit. Thus, due to the key advantages of memristor devices through the non-linear and non-volatile switching, this work proves the potential of utilizing memristor-based circuit to reproduce the behaviors of the biological neurons.The authors in Garg et al. proposed a novel approach for brain-inspired unsupervised local learning. This study focuses on voltage-dependent-synaptic plasticity (VDSP). The authors show that the new methodology helps in reducing the number of updates compared to the standard spike timing dependent plasticity (STDP). Also, results prove that VDSP can be successfully deployed in pattern recognition applications.On a different study, the work reported in We hope this Research Topic will be a great asset for the reader to enrich the knowledge and understanding of utilizing the unique and promising properties of emerging memristor devices for neuromorphic and AI applications.The author confirms being the sole contributor of this work and has approved it for publication."}
{"text": "The use of smoking and smokeless tobacco causes pigmentation on the oral mucosal as mucosal pigmentation, which is one of the clinical features of tobacco-induced melanosis. Tobacco-induced pigmentation is seen on the tongue of the presented case . He had"}
{"text": "We introduce the Astronomy New Talent collection, a collection of invited papers by tomorrow's leaders in astronomy and astrophysics. This collection showcases the strength of some of the research funded by the Royal Society. Comprising both research articles and review papers, this collection is a continuation of the series of commissioned New Talent collections which started with the Chemistry New Talent collection , which hThe authors published within this collection are recent awardees of a Royal Society University Research Fellowship (URF) , Newton We hope that readers of the journal will explore this collection and enjoy reading these pieces as much as we did. Royal Society URF Grant Kennedy, at the University of Warwick, investigates the origin and frequency of warm dust in the so-called \u2018habitable-zones\u2019 around stars . KatheriWe look forward to growing and expanding this collection from more contributors who are funded by the Royal Society. This collection highlights some of the exciting work from tomorrow's leaders in the field who are delving into the most pertinent questions within astronomy.https://royalsocietypublishing.org/topic/special-collections/astronomy-new-talent [These papers are all curated at w-talent ."}
{"text": "The financial pressures associated with a gerontological education are significant given the rising costs associated with education. This fact is particularly relevant for economically vulnerable university students. One source of stress is the cost of textbooks and other required course materials. Indeed textbook prices have increased at a rate faster than other educational expenses. Additionally, the perspectives of diverse and underrepresented scholars are often not as readily available in some textbooks. In this presentation, our process of adapting an undergraduate Aging and Mental Health course to reduce cost and also showcase diverse perspectives is described in detail. The goals of this project were to: 1) adapt a preexisting course to include low- and no-cost content through the integration of open educational resources (OER); 2) provide the most up-to-date evidence based information for content and skills development in the area of aging and mental health; and 3) highlight the perspectives of diverse or traditionally underrepresented scholars in this field of study. We will also share the process of developing an interactive Pressbooks webbook from a strengths-based perspective wholistic perspective."}
{"text": "The long-term services and supports (LTSS) sector is a microcosm of systemic racism that exits in our society. Nationally, half of frontline professional caregivers are nonwhite, while mid- and executive-level managers and board members are predominately white. Research has identified this lack of diversity in management and leadership as a major contributor to turnover and recruitment challenges among frontline staff. We will summarize the findings from three applied research activities: 1) DEI survey of chief executive officers (CEOs) of multi-setting LTSS organizations; 2) interviews with chief diversity officers and CEOs on current workplace DEI efforts and the challenges; and 3) interviews with leaders of color who have had experience with the LTSS sector. Not-for-profit multisite organizations and life plan communities lack diversity among the senior leadership team and board members (12% are people of color). A DEI initiative is more likely to be successful if it has buy-in from the CEO and board members, aligns with the organization\u2019s strategic plan and mission, is integrated into the organizational culture, and is assessed regularly to measure its impact and identify needed adjustments. Leaders of color in aging services acknowledge the barriers \u2013 lack of diversity among leaders and residents and the microaggressions that people of color experience - that make it challenging for people of color to work in the field. They recommend increasing diversity among senior leaders, investing in enhancing DEI, and spreading awareness of the LTSS field and its career opportunities to communities of color."}
{"text": "Scientific Reports 10.1038/s41598-022-18120-z, published online 02 September 2022Correction to: The original version of this Article contained an error in the Acknowledgments section.\u201cWe gratefully acknowledge the support and the funding sources that are provided by the University of Tabuk (Saudi Arabia). We are thankful to Professor Sergei Petrovskii  for careful reading of the manuscript.\u201dnow reads:\u201cWe gratefully acknowledge the support and the funding sources that are provided by the University of Tabuk (Saudi Arabia) and the Vice-Presidency for Graduate Studies and Scientific Research for the project number (0148-1442-S). We are thankful to Professor Sergei Petrovskii  for careful reading of the manuscript. \u201dThe original Article has been corrected."}
{"text": "The diagnosis of pediatric cancer is a traumatic event that is considered to be one of the most adverse situations the child and his family can experience. The psychological impact of this diagnosis on the parents has triggered a great scientific attention in these recent years.Estimate the prevalence of depression and post-traumatic stress among parents of children with cancer.Our study was cross-sectional over a period of 1 month in the medical carcinology department at the Salah Azaeiz Institute. We used the Beck Depression Scale II and the Post Traumatic Stress Disorder Cheklist-Civilian assessements.Thirty parents participated in our study. Most of whom were mothers (73%). The educational level was primary in 63% of cases and socio-economic level was average in 60% of parents. 40% of parents were assessed within six months after diagnosis. Prevalence of depressive disorder and post-traumatic stress disorder were 73% and 57% respectively. The low educational level was correlated to the presence of these two disorders. Similarly, the low educational level was correlated to the presence of depressive disorders (p=0.008). The number of children in the family was also associated to the presence of post-traumatic stress disorder (p=0.029).The prevalence of depressive and post-traumatic stress disorders was high among parents of children diagnosed with cancer. The low socio-economic and educational level and the large number of children in the family are risk factors for psychological distress. Psychosocial support should be offered to parents of children with cancer to optimize the management of this disease.No significant relationships."}
{"text": "The COVID-19 pandemic and concomitant lockdown restrictions in South Africa pose critical challenges for adolescents living with HIV (ALHIV) and on ART, impacting their ability to remain engaged in care and adherent to antiretroviral therapy (ART). Not only has this pandemic directly impacted the health care that ALHIV receive, but it has also consequently had devastating effects on society and has negatively affected the mental health and well-being of ALHIV. The challenges associated with the impact of the COVID-19 pandemic on disadvantaged groups such as ALHIV on ART need to be further explored as it may offer hope to ALHIV and restore confidence in the health system. The COVID-19 pandemic brought about severe economic and social inequalities that continue to negatively impact the lives and experiences of already disadvantaged groups such as adolescents living with HIV (ALHIV) . This coSub-saharan Africa houses the largest population of ALHIV as 89% of the 1.6 million ALHIV globally reside here . It has Social and health service delivery restrictions caused by national responses to curb the spread of COVID-19 disrupted and hindered access to facility-based services such as medication pick-ups, adherence counselling and support groups . The losThe impact of the COVID-19 pandemic on the mental health of children can be noted in social isolation, the loss of loved ones, the disruption of school programmes as well as food insecurity all directly and in increased levels of stress in households . The resAdolescents are in the critical stages of biological, psychological, behavioural, cognitive and social development, and it is found that adolescents greatly benefit from and place great value on social interaction and in-person peer contact . However"}
{"text": "His neurological examination results were normal, except for a visual field defect in the lower quadrant of the right eye. A slightly hyperintense appearance was observed in the cortical gyri of the occipital and frontal lobes on diffusion-weighted magnetic resonance imaging . Long-te"}
{"text": "The COVID-19 crisis requires an integrated effort from governments, institutions, organizations, and communities to attack this crisis. The COVID-19 pandemic has imparted several economic and financial shocks to society. We believe that the nature of work everywhere will be transformed in the aftermath of this global pandemic; for example, online working from home is increasingly adopted by companies wishing to reduce fixed costs and minimize organizational risk. Also, there should be significant changes in lifestyle and access to basic infrastructures, such as energy and transportation systems. Therefore, governments should promote green energy and transportation in the post-COVID-19 world. This issue can also change the pollution levels in the 2020s. Finally, the COVID-19 pandemic provided a significant inequality between developing and advanced economies. Decreasing inequality  should also be essential, especially in the United States and the United Kingdom's free-market economies.Given this background, this Research Topic aims to investigate the effects of the COVID-19 pandemic on leading economic and financial indicators in developing and developed economies. Each paper also aimed to discuss the potential implications for the post-COVID-19 era.This Research Topic covers 46 papers on COVID-19 and the post-COVID-19 era.Sun, Cai et al.). It is also shown that the COVID-19 pandemic has had a critical incentive effect on knowledge collaboration . It is indicated that Artificial intelligence technology can alleviate the plights of firms in the post-pandemic era . Investors' uncertainty sentiment is negatively related to the Chinese stock return from 2 March 2020 to 2 March 2021 . Another paper discusses how governments should evaluate their pandemic policies to determine their effectiveness . The paper also measured China's market power in medical product exports, including the COVID-19 era, from 1992 to 2020 . It is observed that the negative impact of the COVID-19 pandemic on Corporate Social Responsibility efficiency from 2012 to 2020 in China . A significant convergence of the vaccination rates in seven clubs across 30 Organization for Economic Co-operation and Development countries . It is shown the significant role of China's monetary policy implementation on the industrial structure during the COVID-19 pandemic . It is stated that the significant impact of the COVID-19 pandemic on consumer behavior in China's stock market . Another paper discussed the role of lockdowns on economic losses during the COVID-19 pandemic . It is shown that the digital economy significantly positively affects economic growth in the Chinese regions, and this may be a valuable finding for digital transformation during the COVID-19 pandemic . It is observed that pandemics-related uncertainty decreased fertility rates in the panel dataset of 126 countries from 1996 to 2019 . It is found that the COVID-19 pandemic enhanced the congestion effect of tourism industry agglomeration on total factor productivity in China (Wang and Ma). It is stated that the COVID-19 pandemic has promoted job opportunities in the healthcare sector . It is discussed that China's carbon Emissions Trading System would be necessary for carbon reductions after the post-pandemic era .The first paper finds that pandemic uncertainty decreases human capital in the panel dataset of 122 countries from 1996 to 2019 . It is shown that digital finance promoted economic development in the Chinese regions from 2013 to 2020 . It is observed that the market mechanism motivates enterprises' green technology innovation during pandemics (Gong and Dai). It is found that the COVID-19-related uncertainty increased the corporate tax rates in the panel dataset of 113 countries from 2020 to 2021 . It is indicated that listed private firms in China became more valuable with the \u201cblack swan\u201d events, such as the COVID-19 pandemic . It is observed that public health emergencies hurt insurance companies' stock returns .Furthermore, it is found that bilateral investment agreements improved the efficiency of the contract execution panel data of 73 developing countries from 2005 to 2019 (Jin). It demonstrated the negative impact of the COVID-19 pandemic on Chinese cross-border retail enterprises. It is found that the COVID-19 pandemic significantly negatively affects the stock market returns of cultural industries . It is indicated that the COVID-19 pandemic has negatively affected economic performance in panel data of 14 prefecture-level cities in Hunan from 2015 to 2020 . It is also discussed the policies related to the COVID-19 pandemic crisis management of the Spanish healthcare sector . It is found that global pandemics sentiment positively affects the returns of the global art market (Wang). It is stated that green finance is the key to the Chinese economy from the recovery from the COVID-19 pandemic . It is indicated that the industrial sector would be more critical during the post-COVID-19 pandemic era to enhance global economic activity . It is observed that the COVID-19 pandemic decreased financial flexibility and firm performance in the listed hotel firms on Taiwan Stock Exchange .On the other hand, the escalating impact of the COVID-19 pandemic on China's stock price volatility was found in the daily data from July 2020 to October 2021 . It is shown that policy uncertainty in China increases the fluctuation of exports in the country from January 2002 to April 2021 (Hu andLiu). Another paper discussed the role of supply chain distortions in the COVID-19 pandemic by focusing on the case of China . It is found that the digital economy increased China's cultural tourism integration during the COVID-19 pandemic . It also stated the negative impact of pandemics on Chinese firms' corporate innovation behavior . It is indicated that stringency measures are negatively related to the COVID-19 pandemic outcomes in the United States from 11 March 2020 to 13 August 2021 . It is also observed that the digital economy increased economic development in the regions of China, and the data included the COVID-19 pandemic era . Another paper used the data in China from January 2015 to April 2021 and found the significant role of the COVID-19 pandemic on the effectiveness of the monetary policy . Another paper discussed the impact of the COVID-19 pandemic on working conditions using the case of survey data for dentists . It provided the negative impact of the COVID-19 pandemic on life insurers in the United States . It is found that the effects of the COVID-19 pandemic are permanent in Indonesia and the Philippines but temporary in Malaysia . It is observed that the COVID-19 pandemic significantly affected revenues and openings of small leisure and hospitality firms in the United States . It is also stated that the COVID-19 pandemic harmed the international trade volume between Australia and China . It is suggested that isolation and quarantine policies as the most cost-effective intervention during the COVID-19 pandemic . It is also shown that the COVID-19 pandemic negatively affected Malaysia's economic indicators .Meanwhile, It was found that foreign direct investments and international trade increased income inequality in China, and the data included the COVID-19 pandemic era (In conclusion, this Research Topic shows the significant effects of the COVID-19 pandemic on various economic and financial indicators in different countries, regions and markets. It also discusses the potential implications for the post-COVID-19 era.GG and CL: writing the editorial. All authors contributed to the article and approved the submitted version."}
{"text": "This is the second of two guidance articles produced by the British Infection Association (BIA), the Healthcare Infection Society (HIS), the Infection Prevention Society (IPS) and the Royal College of Pathologists (RCPath). Both articles refer to the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using evidence that emerged during the first wave of the pandemic, the articles summarise aspects of the transmission dynamics of SARS-CoV-2 and provide guidance on how to reduce the risk of transmission. This article focuses on the risks of presymptomatic, asymptomatic and post-symptomatic SARS-CoV-2 transmission, allowing healthcare workers and the public to understand how transmission occurs and to take action to protect themselves and others. The guidance recognises further waves of the pandemic, the possibility of reinfection, the emergence of new variants of the virus and ongoing immunisation programmes.confirmedpresymptomatic transmission  is probable.asymptomatic transmission (meaning that an index case never develops symptoms or signs of infection) is Having considered the evidence, the COVID-19 Rapid Guidance Working Party concluded that:The Working Party was unable to assess the likelihood of post-symptomatic transmission  because of an absence of evidence.The Working Party formulated recommendations for practice taking account of the evidence reviewed. The recommendations were developed for acute healthcare settings , but they might be useful in other health and care settings such as dental practices and care homes. The Working Party also identified areas for future research.people without noticeable symptoms may transmit the SARS-CoV-2 virus to other peopletransmission of SARS-CoV-2 from people without symptoms may occur in all settings in which people are in close proximityhowever, it is likely that the risk of transmission of SARS-CoV-2 is greater from people who have symptoms compared with those who do not.Be aware that:Even in the absence of symptoms, adhere to legislation and guidance regarding measures to reduce the risk of transmission of SARS-CoV-2 .nature of further waves or outbreaks of COVID-19emergence and circulation of SARS-CoV-2 variants of concernpotential for people who have had COVID-19 previously to be reinfectedeffectiveness of available vaccines, including the longevity of immunity they confer.Be aware that the future transmissibility of SARS-CoV-2 from people carrying the virus without symptoms might depend on the:Be aware that it is not yet known to what extent or for how long people recovering from acute infection can transmit the SARS-CoV-2 virus to other people.Covid-19 is a worldwide problem, and we are learning not just how to treat and vaccinate (immunise) people, but also how and when the infection is spread from person to person. Unlike some infections, you cannot necessarily see who is likely to infect another person; this is because sometimes the infection is transmitted before (pre) someone develops symptoms. It is also the case that some people have the infection and can transmit it but never develop symptoms themselves; this we call asymptomatic transmission.This guidance document is one of a pair which have reviewed the scientific evidence on how Covid-19 is spread. This part of the guide provides recommendations on how to help stop the spread of infection before someone becomes obviously ill (presymptomatic) and for those who never become ill themselves (asymptomatic). We did not find evidence for post symptomatic transmission (someone transmitting Covid-19 after they have recovered).The recommendations based on the evidence we have reviewed give confidence that the things we are all doing such as social distancing, hand washing, wearing face coverings and keeping rooms well ventilated by opening windows are the things that we should be doing to prevent people getting infected with Covid-19. We hope that this guide will help everyone try and prevent spreading Covid-19.Coronavirus disease 2019 (COVID-19) was first detected in Wuhan, Hubei province, China; it spread around the world as a pandemic and by November 2021 had affected more than 260 million people [As an emerging and pandemic disease, COVID-19 attracted worldwide attention and interest in understanding the dynamics of SARS-CoV-2 transmission and treatment options for COVID-19 patients. This Working Party Report is the second of two guidance articles developed using evidence published during the first wave of the pandemic to summarise aspects of the transmission dynamics of SARS-CoV-2 and advise on measures to reduce the risk of transmission in health and care settings. The article examines the risks of presymptomatic, asymptomatic and post-symptomatic SARS-CoV-2 transmission. Understanding the risk of transmission according to the index case\u2019s symptom status at the time of exposure of  their close contacts is important to allow healthcare workers and the public to take action to protect themselves and others. The guidance acknowledges the possibility of reinfection, the emergence of new variants of the virus (particularly variants of concern), and ongoing immunisation programmes.Key technical terms used in this guidance article are explained in the accompanying glossary  Guidelines Committee for reviewing this document.The authors received no specific funding for this work. Financial support for time required to identify and synthesise the evidence and to write the manuscript was provided by the authors\u2019 respective employing institutions.No authors reported any conflicts of interest , HIS, the Infection Prevention Society (IPS) and the Royal College of Pathologists (RCPath) commissioned the authors to develop the Working Party Report. The authors are members of the participating organisations and together comprise the COVID-19 Rapid Guidance Working Party convened to develop the guidance. MAM and AB are employed by HIS as guideline developers. Further information is provided in Additional file The views expressed in this publication are those of the authors and have been endorsed by BIA, HIS, IPS and RCPath following rapid consultation.This report is the second in a pair of guidance documents covering key aspects in the prevention of SARS-CoV-2 transmission in health and care settings. The guidance also reviews the evidence for SARS-CoV-2 transmission dynamics in broader settings. The diagnosis and management of COVID-19 in general is outside the remit of this guidance.The Working Party recommendations have been developed systematically through multidisciplinary discussions based on currently available evidence from published, preprint and grey literature sources. They should be used in the development of local protocols for relevant health and care settings such as hospitals, nursing/care homes, primary care and dental practices.The first wave of the COVID-19 pandemic occurred amid uncertainty as to how it could be prevented and controlled. Concern still exists about further waves and new outbreaks occurring. Evidence that emerged during the first wave provides an opportunity to develop evidence-based guidance for preventing and controlling future waves/outbreaks, acknowledging the possibility of reinfection, the context of newly emerging variants of SARS-CoV-2, and ongoing immunisation programmes.The main purpose of the recommendations is to inform clinicians, managers and policy makers about SARS-CoV-2 transmission dynamics and to provide evidence-based guidance to prevent and control the spread of SARS-CoV-2 in health and care settings. The report highlights current gaps in knowledge, which will help to direct future areas of research.The scope of the guidance is to provide advice for the optimal provision of effective and safe health and care services during the period in which COVID-19 remains a health threat. The guidance was developed for acute healthcare settings, but it might be useful in other health and care settings such as dental practices and care homes.Topics for this guidance were derived from initial discussions of the Working Party and specific review questions were developed in accordance with the population\u2013exposure\u2013comparator\u2013outcome (PECO) framework for investigating the likelihood of developing a certain condition after an exposure event. To prepare the recommendations, the Working Party collectively reviewed relevant evidence from published, preprint and grey literature sources. The processes and methods used were in accordance with the National Institute for Health and Care Excellence (NICE) manual for developing guidelines  . The proThe Working Party included infectious diseases, microbiology and virology clinicians, academic infection prevention and control experts, systematic reviewers, and a lay representative.Any healthcare practitioner, manager or policy maker may use this guidance and adapt it for their use. It is anticipated that most users will be clinical staff and infection prevention and control teams. Some aspects of this guidance might also be beneficial to patients, their families/carers, and the public.To provide advice rapidly, the guidance is being produced as two separate articles, each addressing a different review question. Each article will comprise an introduction, a summary of the evidence, and recommendations graded according to the available evidence.The guidance will be considered for update within 1\u00a0year of publication to determine whether new evidence exists that would require a change in the recommendations.The aim of the guidance is to evaluate evidence for presymptomatic, asymptomatic and post-symptomatic transmission of SARS-CoV-2 with the intention of preventing transmission in hospitals and other health and care settings.As noted above, the processes and methods used to produce this Working Party Report were aligned with those described in the first Working Party Report . Topics Two electronic databases (MEDLINE and Embase) were searched for articles published between 1\u00a0January and 29 May 2020. Search terms were constructed using medical subject headings (MeSH) and free-text terms  or asymptomatic transmission (in which the index case never developed symptoms or signs of infection) was undertaken to aid presentation and interpretation of the evidence.Many of the cluster/outbreak investigations permitted only a categorical  assessment of the credibility of transmission by presymptomatic or asymptomatic people . Other cluster/outbreak investigations allowed calculation of an attack rate  and an associated confidence interval (CI). Stratification of the evidence from cluster/outbreak studies according to the time at which contacts were exposed to SARS-CoV-2 relative to the index case acquiring the virus  was also undertaken.Where cluster/outbreak studies reported the use of personal protective equipment (PPE) this was noted to aid interpretation of the evidence.The possibility of identifying comparative epidemiological studies relevant to the review question had not been anticipated because the pandemic was associated with a novel disease and was still in its early stages when the evidence review was initiated. However, several such studies were identified and included as noted above. For these epidemiological studies  that reported  a measure of transmission risk according to the index case\u2019s symptom status at the time of exposure of their close contacts, the convention of expressing risks based on exposure to people with fewer symptoms compared to risks based on exposure to people with more symptoms was applied where possible.Mathematical modelling studies were included in the review only where they distinguished between transmission risks according to the index case\u2019s symptom status during exposure of their close contacts.Included epidemiological studies were appraised for quality using checklists recommended in the NICE guidelines manual . Criticahttps://www.gradeworkinggroup.org/ for details). The resulting GRADE tables are presented in Additional file .Feedback on the draft guidance was received from the HIS Guidelines Committee and through rapid consultation with relevant stakeholders. The draft report was placed on the HIS website for 10 working days along with the HIS standard response form, including a conflict-of-interest disclosure form. The availability of the draft guidance was communicated via email and social media. Stakeholders were invited to comment on format, content, local applicability, patient acceptability and recommendations. The Working Party reviewed stakeholder comments, and collectively agreed revisions in response to the comments  , 26, 41 The reported cluster/outbreak investigations focused on potential transmission of SARS-CoV-2 in both community and nosocomial settings  is reflected in the evidence tables for the cluster/outbreak studies  , 35, andThree of the mathematical modelling studies included in the review used adaptations of the susceptible\u2013exposed\u2013infected\u2013recovered (SEIR) compartmental modelling framework to model transmission dynamics in hypothetical populations , 29, 45.For each type of study for which it was possible to produce an overall GRADE rating of the quality of the evidence the rating applied was very low  and imprecision associated with no CIs or other measures of precision being reported . Among those cluster/outbreak investigations that evaluated the risk of asymptomatic transmission, several had evidence downgraded for indirectness because the definition of an asymptomatic infection included having mild symptoms (such as a pre-existing cough that might or might not have been associated with or exacerbated by SARS-CoV-2 infection), or signs of infection on a computerised tomography (CT) scan of the chest. See Additional file Another aspect of the evidence from the cluster/outbreak investigations was the use of PPE as recorded in the evidence tables for these studies  relative measures of transmissibility according to the index case\u2019s symptom status during exposure of their close contacts, a frequently occurring reason for downgrading the quality of the evidence was risk of bias associated with potential confounding factors  not being accounted for in the design or analysis of the study. Another common reason for downgrading the quality of evidence from such studies was that CIs for estimated effects crossed default thresholds for defining imprecision according to the GRADE approach. See Additional file The quality of the evidence from the mathematical modelling studies included in the review was downgraded for indirectness in several cases because relative measures of transmissibility according to the index case\u2019s symptom status during exposure of their close contacts were not wholly aligned with the symptom statuses of interest to the Working Party . In one such study, asymptomatic infections and mildly symptomatic infections were grouped together . AnotherThere was strong evidence from 36 cluster/outbreak investigations  , 57, 58 There was moderate evidence from seven cluster/outbreak investigations , 42, 55 There was weak evidence from two further cluster/outbreak investigations , 37 regaThere was moderate evidence from four epidemiological studies reported across six articles , 52, 56 There was inconsistent evidence from four mathematical modelling studies , 29, 45 There was weak evidence from one mathematical modelling study  regardinNo evidence was identified regarding the possibility of SARS-CoV-2 being transmitted by post-symptomatic people.The Working Party\u2019s interest focused on whether transmission occurs as a result of presymptomatic, asymptomatic or post-symptomatic SARS-CoV-2 infection. For the most part, this was evaluated through consideration of absolute risks of transmission. At the start of the evidence review process, it was not anticipated that relative risks of transmission based on the symptom status of an index case would have been examined (because the pandemic was in its early stages and research was just starting to be published). However, it became evident when sifting the results of the systematic literature searches that some studies had investigated relative risks of transmission and this evidence was eligible for inclusion according to the review protocol.The evidence from the cluster/outbreak investigations and epidemiological studies providing estimates of relative risks of transmission based on an index case\u2019s symptom status during exposure of their close contacts was assessed for quality using the GRADE framework. All of the evidence from these studies was classified as being of very low quality. Recurring reasons for downgrading the evidence included: risk of bias  not being accounted for in the case of epidemiological studies providing relative risks of transmission based on the index case\u2019s symptom status during exposure of close contacts); imprecision due to CIs for effect estimates crossing predefined thresholds or being unavailable; and indirectness . The overall assessment of the evidence as being of very low quality did not, however, prevent the Working Party reaching conclusions about characteristics of SARS-CoV-2 transmission and making recommendations for practice (see below).The evidence from the mathematical modelling studies included in the review could not be fully assessed using the GRADE framework, but some GRADE domains were applicable, for example, inconsistency and indirectness. A recurring reason for downgrading the evidence from these studies was indirectness due to relative measures of transmissibility according to an index case\u2019s symptom status during exposure of close contacts not being fully aligned with symptom statuses of interest to the Working Party .confirmedpresymptomatic transmission  is probable.asymptomatic transmission (meaning that an index case never develops symptoms or signs of infection) is Having considered the evidence, the Working Party concluded that:There was uncertainty regarding the evidence related to asymptomatic transmission, with the Working Party noting that a lack of awareness of symptoms or suppressed symptoms  could not be distinguished from a complete absence of symptoms in the reported investigations. The Working Party recognised the potential for subclinical or pauci-symptomatic infection while emphasising that truly asymptomatic infection or carriage of SARS-CoV-2 occurs and transmission is to be expected .The Working Party recognised that the list of symptoms suggesting COVID-19 had expanded during the pandemic, reflecting growing knowledge of the condition. The evidence review and synthesis involved extracting any information about symptoms reported by the study investigators, although it was acknowledged that people\u2019s perceptions of symptoms differ and this could influence the types of symptoms reported. The Working Party emphasised the importance of clarity in defining and reporting symptoms in future research related to COVID-19.The settings in which presymptomatic or asymptomatic transmission was demonstrated mirrored those reported in the first of the pair of guidance articles in which routes of transmission, regardless of the symptom status of the index case, were explored . In partThe Working Party agreed that from the perspective of preventing transmission by people without symptoms, it is immaterial whether they later develop symptoms. The recommendations were therefore phrased in terms of people without symptoms rather than using the terms presymptomatic and asymptomatic. The Working Party anticipated that this phrasing would also make the recommendations more meaningful to the public.The benefits of preventing transmission of SARS-CoV-2 by people without symptoms include the prevention of ill health due to COVID-19 among their close contacts and the prevention of onward transmission to ever greater numbers of people. Possible harms associated with actions intended to prevent transmission of SARS-CoV-2  arise through restriction of personal freedoms and a need to modify behaviours with potential adverse consequences in terms of, for example, mental health and wellbeing. These benefits and harms apply to healthcare workers, patients and their families/carers, and the public. On balance, the Working Party recognised that since anyone might carry the virus without knowing it, or be infected without having noticeable symptoms, the recommendations should reinforce the importance of adhering to existing legislation and guidance intended to reduce the risk of transmission of SARS-CoV-2 in the general population.The Working Party noted that the evidence regarding relative risks of transmission according to symptom status suggested that presymptomatic infections are less transmissible than are symptomatic infections, and that asymptomatic infections are less transmissible than are presymptomatic infections. The Working Party was aware that the viral load associated with asymptomatic and pauci-symptomatic infections is typically lower than that associated with symptomatic infection , lendingAlthough the evidence from the mathematical modelling studies was regarded as indirect, the Working Party noted the reported differences in asymptomatic transmission rates in indoor environments under different ventilation scenarios. This prompted the Working Party to emphasise the importance of ventilation in enclosed spaces in the recommendations.The Working Party was acutely aware that the development of the guidance was occurring during an evolving pandemic. When formulating the recommendations, the Working Party recognised the possibility of reinfection in people who previously had COVID-19 , the emeThe likelihood of post-symptomatic transmission  could not be assessed because of an absence of evidence. The Working Party agreed that post-symptomatic transmission should be prioritised as an area for further research.The Working Party did not undertake a detailed economic analysis because the recommendations focused on raising awareness of the possibility of presymptomatic and asymptomatic transmission of SARS-CoV-2 and reinforcing existing legislation and guidance aimed at preventing transmission. However, the Working Party considered costs and resource use from the perspective of health and care systems and identified that costs associated with transmission that is not prevented include the costs of managing COVID-19 in infected patients and the costs of needing additional resources such as PPE. Considerations related to the value of time as a resource included the time taken to don and doff PPE and time away from work for healthcare workers who are unwell or required to self-isolate. Taken together, these considerations emphasise increased pressure on healthcare systems when COVID-19 is prevalent. The Working Party recognised potential inconvenience and possible adverse consequences  of implementing measures such as social distancing and using PPE. The Working Party also recognised that the cost effectiveness of preventing transmission would be greater in aspects of healthcare focusing on people more vulnerable to COVID-19.when a person who has acquired SARS-CoV-2 becomes infectious andhow long infectivity lasts in the absence of symptoms.As outlined above, the Working Party highlighted several areas for future research. These included consideration of:While the evidence available to the Working Party demonstrated presymptomatic transmission within 7\u00a0days of an index case acquiring the virus, later transmission could not be ruled out. Moreover, the available evidence did not permit a detailed analysis of infectivity during the first 7\u00a0days since acquiring the virus, which was of interest to the Working Party and could form part of future research. The Working Party also highlighted potential seasonality in transmission rates, and indoor versus outdoor transmission, as areas to explore in future research.The Working Party discussed the relevance and possible consequences of lung damage revealed by CT scans in people who did not report symptoms. The Working Party questioned whether such features might have longer-term consequences for a person who although infected has no noticeable symptoms and recommended this as an area for future research.The Working Party made several observations regarding the quality of the evidence identified in the review. While the importance of rapid evaluation during a pandemic caused by a novel disease such as COVID-19 was appreciated, the value in ensuring robust and efficient research activity was also recognised. The Working Party agreed that this value could be promoted by avoiding duplication and repetition in data collection, analysis, and reporting, and acknowledged the time needed to ensure high quality research outputs. The Working Party highlighted the desirability of concerted global action to coordinate research activity and formalised data gathering and sharing in the event of future pandemics caused by novel diseases. The Working Party acknowledged that some of the areas recommended for future research might already have been addressed in primary studies or systematic reviews published after the searches for the evidence review had been completed. Although the Working Party had considered updating the review to take account of more recently published evidence, the rate at which additional evidence was being published prohibited such an approach. For example, rerunning the MEDLINE and Embase searches in April 2021 indicated that approximately 20,000 further articles would need to be considered; it was, therefore, not feasible to undertake a timely and systematic update of the review using the original search terms. The Working Party emphasised that the research recommendations were intended to build on the evidence review and allow the guidance to be refined or extended, preferably with reference to evidence of higher quality and allowing more focused or nuanced consideration of SARS-CoV-2 transmission dynamics. By November 2021, rerunning the MEDLINE and Embase searches resulted in an additional 30,000 articles, which when filtered to select records containing the phrase \u2018systematic review\u2019 in the title, abstract or keywords identified nearly 600 articles. Among these systematic reviews, a handful investigated relative transmissibility of presymptomatic, asymptomatic and symptomatic infections \u201369; howeThe Working Party noted that evidence included in the review suggested that using PPE (such as face masks or coverings) reduced the risk of transmission of SARS-CoV-2 by people with presymptomatic or asymptomatic infection. The current evidence review was not designed to explore this systematically, whereas the first of the pair of guidance articles  includespeople without noticeable symptoms may transmit the SARS-CoV-2 virus to other peopletransmission of SARS-CoV-2 from people without symptoms may occur in all settings in which people are in close proximityhowever, it is likely that the risk of transmission of SARS-CoV-2 is greater from people who have symptoms compared with those who do not.Even in the absence of symptoms, adhere to legislation and guidance regarding measures to reduce the risk of transmission of SARS-CoV-2 .Be aware that the future transmissibility of SARS-CoV-2 from people carrying the virus without symptoms might depend on the:nature of further waves or outbreaks of COVID-19emergence and circulation of SARS-CoV-2 variants of concernpotential for people who have had COVID-19 previously to be reinfectedeffectiveness of available vaccines, including the longevity of immunity they confer.Be aware that:Be aware that it is not yet known to what extent or for how long people recovering from acute infection can transmit the SARS-CoV-2 virus to other people.Based on the evidence review, which included research published to the end of May 2020, the Working Party considered presymptomatic transmission of SARS-CoV-2 to be confirmed, and asymptomatic transmission to be probable. The evidence for these forms of transmission was sufficient for the Working Party to formulate several strong recommendations with the intention of raising awareness in health and care settings of the potential for transmission in the absence of symptoms. The recommendations were intended to reinforce existing legislation and guidance specifying measures for reducing the risk of transmission from people who have no noticeable symptoms. The Working Party formulated recommendations for future research to address areas of uncertainty, such as the relative transmissibility of presymptomatic, asymptomatic and symptomatic infections, the period of infectivity in people without symptoms, and the possibility of transmission in the post-symptomatic period. The Working Party emphasised the importance of good quality design, analysis and reporting of research studies even in pandemic situations. The Working Party also highlighted the desirability of concerted action to coordinate research activity and share outputs effectively.The rationale for the following research recommendations is presented in \"What is the relative transmissibility of SARS-CoV-2 from people with presymptomatic, asymptomatic and symptomatic infection, and how does transmission correlate with quantification of viral shedding?How long after acquiring SARS-CoV-2 do people without symptoms become infectious and how long does infectivity last?To what extent or for how long can people who have acquired SARS-CoV-2 and are post-symptomatic transmit the virus to other people?What are the long-term consequences of lung damage associated with SARS-CoV-2 infection in people who do not report symptoms?What impact do reinfection, variants of concern, and immunisation programmes have on transmission of SARS-CoV-2?Additional file 1. Working Party Report appendices."}
{"text": "The Author Replies:We appreciate the interest from Hakroush and Tampe in our manuscript describing compassionate use of avacopan in 8 difficult-to-treat patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV).The disease course of the patient described by the authors is in line with the disease course of 6 refractory AAV patients we previously described.,In the era of big data analyses, it is important to appreciate that case-reports and case-series remain pivotal as hypothesis-generating clinical observations. In contrast to the pivotal randomized ADVOCATE trial that produced evidence for a steroid-free treatment strategy for active AAV patients,In summary, the unique and beneficial clinical observation described in the case by Hakroush and Tampe should prompt clinicians to collaborate in collecting and describing the real-world experience of treating in a low-prevalent AAV patients with a novel complement-targeting drug avacopan."}
{"text": "Worldwide agriculture faces enormous challenges. Global warming, a growing world population with a constantly growing need for high-quality food, increasing demand for animal welfare, and reducing the ecological footprint represent the greatest challenges for the present and the near future.Florez et al. generated the first KISS1-edited large animal using CRISPR/Cas9-ribonucleoproteins and single-stranded donor oligonucleotides. Though follow-on research will be necessary to evaluate the efficacy of this approach, this proof-of-principle study gives a good example of how genetic engineering could be employed to address urgent problems in livestock production. The knockout of Myostatin (MSTN), a negative regulator of muscle growth, is accompanied by a significant increase in skeletal muscle mass and has been discussed to increase the meat yield from livestock species (Pei et al. provide the first evidence that MSTN-KO pigs show no significant difference in the size and average weight or length of visceral organs in adult pigs. These findings are important for the further application of this technology.Deciphering the function of the CRISPR-Cas9 system and adapting it for genome editing of the mammalian genome has revolutionized the genetic engineering of farm animals and offers novel opportunities to address these challenges . Besides species . SeveralDavies et al. that generated a unique type I Interferon Receptor knockout sheep model for viral immunology and reproductive signaling. The mini-review by Greising et al. reviews the recent developments and options for the treatment of volumetric muscle loss in gene-edited pigs, while Ruan et al. provide a comprehensive opinion on the recent developments in altering the pig genome.The importance of genetically engineered livestock is further displayed in the article by Wu et al. employed transcriptional sequencing and proteomics to investigate the differences between the uteruses of laying hens with high- and low-breaking eggshells. They identified the KRT14 gene which may promote calcium metabolism and the deposition of calcium carbonate in eggshells.The establishment and culture of PGCs enabled the targeted genetic modification of the chicken genome to address productive traits such as eggshell strength and thickness which are critical factors in reducing egg breaking and preventing economic losses . To idenSince its advent, CRISPR-Cas9 has proven its disruptive potential for animal breeding. A multiverse of different CRISPR variants has been developed in the last 10 years increasing the efficiency of precisely altering the genome of livestock species and reducing the number of unwanted mutations . Except"}
{"text": "The Therapeutic Engagement Questionnaire (TEQ) has been developed and validated in partnership with service users (SUs), registered mental health nurses (RMHNs) and nurse academics in the UK in accordance with psychometric theory. The TEQ is highly relevant and useful to clinical practice. The TEQ measures therapeutic engagement (TE) in two contexts - 1-1 interactions between SUs and RMHNs, as well as the overall environment and atmosphere of the units - from the perspective of both SUs and RMHNs. The TEQ has been translated into Finnish by two expert panels and was pre-tested and validated in ten adult acute psychiatric in-patient units in two hospitals in Finland.To measure TE in Finnish adult acute in-patient psychiatric settings from the perspectives of both SUs and RMHNs.The Finnish version of the TEQ (Hoidollinen yhteisty\u00f6) will be completed by RMHNs and SUs in 15 adult acute psychiatric in-patient units. Nine of the units are within the University Hospital and six in a municipal psychiatric hospital. The data will be collected within a 3-month period (October - December 2020). The coordinating nurse of each unit will organise the operational side of the study including obtaining consent from SUs. The nurses will participate in the survey via Webropol which includes nurses\u2019 consent. Sociodemographic information will be collected from the SUs and nurses.The results of the measurement study will be reported at the 29th European Congress of Psychiatry.The conclusions of the measurement study will be reported at the 29th European Congress of Psychiatry.This study is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London)."}
{"text": "In this session we will present results from the English Longitudinal Study of Ageing (ELSA) Covid-19 substudy. Data were collected during the pandemic at two separate occasions to capture the experiences of older people and to compare them to pre-covid periods. The session will include results among people with cognitive impairment, people who contracted infections and explore the consequences on their mental health, well-being and health in general"}
{"text": "Teaching Point: When performing ultrasound examination of a cephalhematoma, the occurrence of a mirror-image artifact can mimic the presence of an epidural hematoma. A 3-day-old neonate was referred to the radiology department for ultrasonographic evaluation of a parieto-occipital cephalhematoma. The neonate was born through spontaneous vaginal delivery and no forceps nor suction cup was used. There were no clinical problems other than the presence of the cephalhematoma, and neurologic findings were normal.Figure 1) showed the presence of an anechoic biconvex structure (dotted line A) resembling an epidural hematoma in the parietal region underlying the cephalhematoma (dotted line B). This was a curious finding because the delivery hadn\u2019t been traumatic and there were no neurological symptoms present.Coronal grayscale ultrasound image  at the same level as the ultrasound image in Figure 1 shows the cephalhematoma without underlying intracranial abnormalities.Because angulation of the probe could not clearly eliminate the possible presence of an epidural hematoma, in consultation with the treating paediatrician it was opted to further evaluate the infant through non-contrast-enhanced computed tomography (NECT) of the brain. Coronal NECT image  [Mirror-image artifacts occur when the primary beam encounters an obliquely oriented highly reflective surface and is reflected by this surface but encounters another structure in its path before being reflected to the transducer. The transducer interprets the delayed echo as being reflected from a structure deeper down and this creates the mirror-image artifact on the other side of the reflective surface (igure 3) .In this case the ultrasound beam is reflected by the skull bone and a mirror-image artifact of the cephalhematoma is created on the opposite side, mimicking an epidural hematoma.Other common examples of mirror-image artifacts include reflection of ascites across the diaphragm mimicking pleural effusion and reflection of the gestational sac mimicking heterotopic pregnancy.The mirror-image artifact may closely resemble the original structure, but it may also appear weaker, distort the image of the original structure, or appear on images that do not simultaneously show the original structure. It is important to recognize such mirror-image artifacts and not mistake them for pathology so that unnecessary additional examinations and anxiety in patients can be avoided.The occurrence of a mirror-image artifact can be evaluated by changing the angle of the primary beam or in case of a cephalhematoma applying graded compression, which shows simultaneous compression of the true image and the false mirror image. Doppler ultrasound may also be used, showing the presence of normal cerebral blood flow within the false mirror image ."}
{"text": "The world has given serious thought to epidemics, disasters and crises. One of the most important mental disorders that can be caused by epidemics, disasters and crises is the Post-Traumatic Stress Disorder (PTSD). The Coronavirus (COVID-19) pandemic is one of the most serious global health crises.We deal with the appearance of symptoms of PTSD among Bahraini society as a consequence to COVID-19 pandemic. We aim to investigate two main aspects: PTSD and the correlation between the pandemic COVID-19 and the appearance of PTSD symptoms in the Bahraini society.This research was conducted based on the Davidson Trauma Scale (DTS), developed by Jonathan Davidson in 1995, according to the DSM-IV criteria.The findings of our research concluded that the percentage of PTSD among a group of Bahraini society members following the outbreak of COVID-19 was 11.1%.conducting awareness campaigns as part of the media plan to combat COVID-19. Designing and applying treatment programs for PTSD for those in need. Allocating mental institutions from the public and private sectors to be used as rehabilitation centers for PTSD patients.No significant relationships."}
{"text": "Versus Arthritis (UK) and ReumaNederland (The Netherlands) have made a particular contribution at the project proposal stage and invited founding PC members. Ingrid Lether participated in the MRI test and re-test study , together with two co-authors of this paper. Merck KGaA kindly allowed the authors to utilize drawings from its 350th anniversary research day ; the artist was Andreas Gaertner from die-zeichner.de. The authors would also like to acknowledge two former PC members from Germany and Spain, respectively; when still active members of the PC, their contribution and experience was highly valued. The authors would like to thank specifically the IMI reviewers and expert panels who encouraged the involvement of patients from the inception of this project.The correct Acknowledgements section should read:Leonie Hussaarts (Lygature) was the PC coordinator from the start of the APPROACH project; in this role she initiated and managed a number of trivial PC activities . Ingrid Lether participated in the MRI test and re-test study , together with two co-authors of this paper. Merck KGaA kindly allowed the authors to utilize drawings from its 350th anniversary research day ; the artist was Andreas Gaertner from die-zeichner.de. The authors would also like to acknowledge two former PC members from Germany and Spain, respectively; when still active members of the PC, their contribution and experience was highly valued. The authors would like to thank specifically the IMI reviewers and expert panels who encouraged the involvement of patients from the inception of this project.The authors would like to thank all partners of the APPROACH consortium for their continued collaboration and support of the PC. Versus Arthritis (UK) and ReumaNederland (The Netherlands) have made a particular contribution at the project proposal stage and invited founding PC members. All the changes requested are implemented in this correction and the original article  has been"}
{"text": "Population level changes in physical activity (PA) may benefit from policy intervention. In response to the UN Sustainable Development Goals, Wales introduced legislation  Act 2015) to holistically improve health and well-being, including the translation of national policy into practice. This audit provides a case study approach that could be replicated by researchers in other countries to appraise the role of PA actions in national and sub-national policies.An audit of policies published by national and sub-national public bodies between 2015 and 2020 was conducted. The list of identified policies was reviewed by an external panel to act as a ?critical friend? to verify its inclusiveness. Content of the policies were extracted and synthesised to determine: (i) how many policies included a PA action; (ii) what the drivers of those policies were; (iii) the content of the PA actions; and (iv) how the PA actions aligned with the Well-being of Future Generations  Act 2015.A final list of 73 policies was obtained. Only 16 national-level documents had a PA action, which had been published by 4/13 public bodies (who are bound by the Act). Of the 19 sub-national well-being policies, 15 included PA actions. Most policies were considered reactive and varied in terms of the clarity and specificity of the actions, the assignment roles/responsibilities, and the setting of targets; all overarching principles which can be used to strengthen national and sub-national policy in the future. The most common theme of action across the national-level documents was the broad action of PA promotion, which was identified in nine of the 16 documents. The actions within the national-level documents were reflected in the sub-national well-being plans.This research used a novel approach to assess alignment of policies related to PA and the Sustainable Development Goals (SDGs) in Wales. It provides an overview of the current status of policy related to PA in Wales, which can be used in manifestos and frameworks to shape the subsequent actions of public bodies.This case study provides a valuable example of how to utilise PA to address broader health and wellbeing agendas, and specifically the SDGs. It also demonstrates an approach to achieving stronger connections between national and sub-national policy to support the translation of policies into practice."}
{"text": "Anorexia nervosa (AN) is one of the most common chronic disorders in adolescence with still high mortality rates. Knowledge on gut-brain interaction might help to develop new treatments, as severe starvation-induced changes of the microbiome in AN-patients have been demonstrated, which do not alleviate with weight gain. In our own pilot study alpha-diversity was increased in patients with AN after short-term weight recovery, while beta diversity showed clear group differences with healthy controls before and after weight gain. A reduction of taxa belonging to Enterobacteriaceae at admission and discharge and an increase in taxa belonging to Lachnospiraceae at discharge were typically found in patients with AN. The work plan of our European project comprises an observational study and two phase II RCTs with the application of omega-3-PUFA and a multistrain psychobiotic to both, humans and rodents. With the help of a well-established animal model for AN , the effect of stool transplants from patients to rodents will be analysed. Longitudinal MRI will be conducted in rodents together with cellular and molecular brain analyses. In addition, immune response and circulating antibodies associated with the presence of certain bacterial strains and interaction with hunger and satiety hormones will be explored. We hope that by this translational research we may systematically investigate the role of an altered microbiome for the course of AN and to identify new therapeutic tools.This project is funded by ERA-NET of the European Union."}
{"text": "An error was present in the published article in the final sentence of the Abstract. The correct sentence should read as follows:Additionally, the methodological capability of PFG NMR for measuring self-diffusion coefficients of long-chain hydrocarbons (up to C19) confined to narrow mesopores of catalytically active materials is demonstrated for the first time.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "The presentation is dedicated to employees who care for others in addition to their work. The starting point is the representative cohort study on mental health at work (S-MGA), which covered both care at home and care outside the home in the second wave of the survey. In this regard, cross sectional associations with exhaustion and work-life balance as indicators of mental health were examined taking into account full-time and part-time employment.The sampling frame consisted of all German employees being subject to social security contributions and born between 1951 and 1980. The baseline sample consisted of 4511 survey participants of whom 1279 males and 1358 females were asked for informal care at the follow-up interview. Employment conditions as well as work-life balance were obtained by personal interview; exhaustion was obtained in a paper and pencil questionnaire. Statistical analysis was conducted descriptively and in linear and logistic regressions stratified by gender and controlled for age.Informal care at home was reported by n = 74 individuals (2.8%) and care outside of their home by n = 236 (8.9%). The association between both types of care with exhaustion was below the level for significance. There was an increase of work-life-imbalance for females caring at home but not for those who were caring outside. For males there were no effects of both types of care. Including the part-time/full-time distinction indicator within the regression models showed that women who cared at home had lower exhaustion scores and lower work-life imbalance when they were employed part-time.The results show that caring at home for females leads to work-life imbalance and that part-time employment mitigates the negative effects on work-life imbalance and exhaustion. However, there are strong limitations by the sample size and the number of observations at the second wave of assessment.The results show that caring at home among females seems to lead to work-life imbalance.Part-time employment seems to mitigate the negative effects on work-life imbalance and exhaustion."}
{"text": "Societies can be confronted with disasters and major incidents that form a serious threat to population well-being, safety and health. The Covid-19 pandemic challenged governments at different levels in many countries across the world for over two years to address a variety of public health risks. This also applies to the Netherlands, a densely populated high income country in Europe with approximately 17 million citizens. Experience with previous crises - such as the Bijlmermeer Airplane Disaster in Amsterdam (1992), the Q fever outbreak (2007-2011), the MH17 airplane disaster in Ukraine (2014) and gas-mining induced earthquake problems in the north of the Netherlands (ongoing) - shaped the current Dutch public health response structure and knowledge base, designed to assist local and national authorities to anticipate disaster-related population health risks. During the Covid-19 pandemic this structure was used as a starting point to develop and implement a five-year monitoring program: the integrated GOR-Covid-19 health monitor; GOR stands for \u201cGezondheidsonderzoek bij rampen\u201d . The main objective of the GOR-Covid-19 monitor is to collect and promote the uptake of reliable and timely monitoring information for the benefit of regional and national public health decision-making in the Netherlands, focusing on the public health impact of the Covid-19 crisis (virus infections and mitigation measures) among children and adolescents, adults and public mental health care, a potentially vulnerable group including homeless and former drug addicts. The monitor is carried out under coordination of the \u201cNetwork GOR\u201d, comprised of the National Institute for Public Health and the Environment, GGD GHOR Netherlands , Nivel, and ARQ National Psychotrauma Centre. The current workshop consists of five presentations by members of Network GOR. The first contribution gives an overview of the research objectives and the outline of the study protocol of the monitoring program. The other contributions focus on particular study components, that are shaped and aligned during the timeline of the monitor. One presenter will share the findings from the first series of systematic literature reviews. Two contributions are based on a combination of surveys in representative samples and an analysis of primary care registry data: one with an emphasis on quarterly results (short-cycle monitoring), the other on (bi-)annual reports, which zoom in on long-term developments and differences between subgroups based on vulnerability factors and geography (long-cycle monitoring). The fifth contribution details the participatory stakeholder-engagement process designed and implemented to promote that monitor findings are used for local and national public health sense-making and decision-making.\u2022\u2002The workshop describes the background and design of a national longitudinal monitoring program to track the public health impact of the Covid-19 pandemic in the Netherlands.\u2022\u2002An overview is given of the first findings on the health impact of the pandemic for different populations and related vulnerability factors as well as the stakeholder engagement process."}
{"text": "The more preterm they are, the greater the riskPoor neonatal care increases the risk, even in less premature babiesHigh quality neonatal care. If there is not enough equipment to safely deliver and monitor oxygen, this must be strongly advocated forScreening: All babies at risk must be screened before 30 days after birthTreatment: Laser treatment should be given urgently, with confluent spotsFollow-up: All children born preterm are at risk of visual impairment and must be followed up by an ophthalmologist and/or optometristInvolve parents in the day-to-day care of the baby and encourage kangaroo careKeep parents informed of the need for screening and the results of screening, and the need for urgent treatment, if requiredEnsure parents understand the need for follow-up visits"}
{"text": "The COVID-19 pandemic had a significant impact on economic development, lifestyles and health systems in all countries. Due to the lack of medical interventions, many countries adopted restrictive measures to slow the spread of the virus and reduce the burden on the healthcare system. Quarantine measures have had an impact on the transmission of SARS-CoV-2. However, the unintended consequences of such drastic measures were inevitable. In developing countries, there have been adverse effects of disruptions in health services, including the provision of timely medical services in detecting cases of tuberculosis in the population. The aim of this study was to study the influence of COVID-19 pandemic on the tuberculosis incidence in the Republic of Kazakhstan.We analyzed national data on the reported tuberculosis cases and screening results of tuberculosis in Kazakhstan for 2019-2020. The primary data were collected from regular reporting of cases through surveillance.The number of registered patients identified during screening activities in 2020 were 2,854 cases compared to 4,288 cases in 2019 before COVID-19 era. The proportion of cases with antibiotic-resistant  forms of tuberculosis increased up to 6.7% in 2020 in comparison with 2019.There is a need to conduct an analysis of the reasons for the increase in cases of multidrug-resistant and extensively drug-resistant tuberculosis. The working process should be adapted to epidemics and emergencies to ensure the availability of medical services, as well as to improve the system of preventive examinations and screening for the early detection of TB cases.The abstract was submitted under the \u2018CATINCA - Capacities and infrastructures for health policy development\u2019 project which is coordinated/led by Robert Koch Institute and supported by the WHO Regional Office for Europe.The detection of tuberculosis during preventive examinations and screenings significantly decreased in 2020 compared to 2019.In recent years, there has been a significant increase in the number of cases with poly-, multi- and superantibiotic-resistant forms of tuberculosis."}
{"text": "Breast cancer (BC) is one of the leading causes of cancer death worldwide. The problem of mental health and quality of life of patients is currently particularly relevant. Most patients with breast cancer in the process of adapting to the disease experience certain mental disorders: depressive, anxiety-phobic and psychosomatic disorders.To study the severity of anxiety-depressive disorders in the clinical picture in patients with breast cancer and evaluate the effectiveness of specialized pharmacotherapy using antidepressants in combination with antitumor therapy.The study included 30 patients with a first established diagnosis of breast cancer and 52 patients with a follow-up history of 3-17 years. The main method of work was the clinical, psychopathological, and statistical research methods .To assess the severity in the clinical picture of anxiety-depressive tendencies and the effectiveness of treatment, special scales were used: hospital scale of anxiety and depression (HADS); general clinical impression scale (CGI) for assessing disease severity (CGI-S \u201cseverity\u201d) and improvement (CGI-I \u201cimprovement\u201d). High antidepressant therapy efficacy indicators were obtained in combination with benzodiazepine drugs and hypnotics in a group of patients with anxiety-depressive nosogenia , in the group with chronic hypochondriac dysthymia and cyclotymic endoform depression.The data obtained in the study confirm the effectiveness of psychopharmacotherapy with antidepressants in breast cancer patients with identified disorders of the anxiety-depressive spectrum.No significant relationships."}
{"text": "Errors were present in the published article in terms of corresponding authors and e-mail addresses; Chen Yu is the sole corresponding author, extra e-mail addresses have been deleted, and the correct version is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
{"text": "A forecasting model for prevalence and mortality based on a trend partitioning approach which models trends in age-adjusted prevalence and incidence-based mortality in terms of changes in interpretable epidemiologic quantities such as disease incidence and survival, is developed and applied to generate forecasts of Alzheimer\u2019s disease (AD) and related dementia (ADRD) prevalence and mortality up to 2035 using health data drawn from a 5% sample of the total Medicare population. Forecasts are generated for entire AD population and for unique subgroups characterized by age groups and the presence of high-impact health conditions  prior to AD diagnosis. Then methodology using B-splines in key time points allows is used to analyze scenarios of possible interventions focused on the prevention and treatment of AD/ADRD. Prevalence of AD/ADRD is predicted to be stable between 2017 and 2035 primarily due to a decline in prevalence of pre-AD/ADRD-diagnosis stroke. Mortality, on the other hand, is predicted to increase. In all cases the resulting patterns come from a trade-off of two disadvantageous processes: increased incidence and disimproving survival. The projections are constructed with the assumption that future trends represent a superposition of historic trends in different time periods taken with weights. Sensitivity to assumptions on choice of specific weights are studied, and the approach to choose an optimal combination of weights and therefore, to minimize uncertainties of future forecasts of AD/ADRD prevalence and mortality is suggested and discussed."}
{"text": "Parental reflective function is the ability of a parent to attribute mental states to their child and to themselves. The Parental Reflective Functioning Questionnaire is widely used for the measurement of this construct, the adolescent version of which can be used by parents of children aged 12-18.The aim of our research was to adapt the adolescent version of The Parental Reflective Functioning Questionnaire to the Hungarian language.In our study 240 mothers completed the adolescent version of The Parental Reflective Functioning Questionnaire (PRFQ-A), and the Reflective Function Questionnaire (RFQ).Confirmatory factor analysis did not confirm the original three-factor structure. The principal component analysis resulted in a two-factor structure. Factors corresponded to the original questionnaire\u2019s certainty in mental states (Alpha = .81) and interest and curiosity subscales (Alpha = .70). When analyzing the relationship between parental reflective function and reflective function, the subscales of the parental reflective function questionnaire were examined with two types of median coding in addition to polar coding. During the first median coding, the frequency of scores in the middle of the scales reflected optimal mentalization, while the frequency of extreme values on the scales corresponded to less favorable reflective functioning. With the second median coding, hypermentalization and hypomentalization subscales were also created. The second median transcoding proved to be the most suitable for capturing the relationship between RFQ and PRFQ-A.The questionnaire proved to be a reliable measure on the Hungarian sample and we recommend using the additional subscales.No significant relationships."}
{"text": "The relevance of studying of self-regulation styles of young people who face various difficulties at a stage of vocational training has increased in the situation of a pandemic.The purpose of our work is to describe the functional states of students at different stages of education, characterized by different degrees of satisfaction with educational and professional activities and different levels of self-regulation, to substantiate programs of psychological support for students during the formation of their professional identity.The sample consisted of 153 students enrolled in 1 and 3 courses in Moscow higher educational institutions. They were asked to fill out a package of methods aimed at diagnosing self-regulation styles , the severity of states of reduced performance .Indicators of reduced working capacity among third-year students are statistically significantly higher (p\u22640.05) and are in a critical range of severity than among freshmen. Despite a similar level of satisfaction, third-year students demonstrate a whole palette of states of reduced performance, characterized by the experience of monotony of activity with high tension associated with the requirements of the educational situation. The absence of significant differences in the diagnostic indicators of self-regulation obtained in these two groups does not give grounds to assert that the general self-regulation of senior students is higher than that of first-year students.The data obtained confirm the \u201cpainfulness\u201d of the crisis of the \u201cmiddle\u201d of education and necessarily raise the question of developing a targeted program for mastering the means of conscious self-regulation by students.No significant relationships."}
{"text": "Sleep is essential for life, but its measurement has a brief history in evolutionary terms. The most widely accepted way of measuring sleep is via sleep stages derived from analysis of the electroencephalogram (EEG) which was first introduced by Loomis et al.  in 1937.To standardize recording and scoring techniques and increase the equivalence of results between laboratories, the manual of Rechtschaffen and Kales (R&K) was introduced in 1968 . In the To address some of these criticisms and improve the interscorer agreement, the American Academy of Sleep Medicine (AASM) manual was released in 2007 . The AASPartially due to the historical development of sleep analysis and because there is no true gold standard for sleep analysis, epoch-based manual sleep scoring is the current standard. Manual scoring can be performed by an individual scorer or a panel of scorers with the assumption that a panel of scorers is more consistent than a single scorer. Many studies have looked at the overall agreement between scorers. A very recent meta-analysis of 11 eligible studies  selectedConsiderable progress has been made with machine-based sleep stage scoring and current evidence suggests that the performance of machine-based scoring is comparable to human scoring. A review of the state-of-the-art machine-based scorers in 2019 revealed that the overall agreement of machine-based sleeping staging against individual scorers was a kappa value in the range 0.73\u20130.86 [The development of machine-based scoring sleep systems requires a training stage whereby sleep stages from human scorers along with PSG signals are provided to machine learning algorithms and the system uses these manually labeled sleep stages to learn associations between the signals and the sleep stages. Given that human and machine scoring achieve comparable agreement the obvious question arises as to whether machines can provide better performance than they currently do. In this issue of Sleep, van Gorp et al.  provide One path forward may be through the wider use of panel-based scoring but, given the high workload for panel-based scoring, our field must test the assumption that panel-based scoring is actually more consistent than individual scoring. Another approach is to consider observing sleep as a continuous, non-discrete dynamic phenomenon. These definitions of \u201ccontinuous sleep\u201d have been recently proposed using both machine learning, with the description of hypnodensity  as well"}
{"text": "Burden of disease (BoD) studies are an established method of quantifying health loss across - and within - a population. They aim to combine the impact of living with, and dying from, various health conditions to allow for comparability of conditions in an equitable manner. A key component of this is the calculation of the loss of years of life arising from premature death (Years of Life Lost (YLL)). Most high-income nations have robust death registration systems which ensure that deaths are routinely recorded, the causes are medically certified and the age at death is accurate. However, even in these situations the recording of ill-defined death (IDD) causes remains widespread and to some extent unavoidable, in that it is not always appropriate to undertake extensive investigation to establish an exact cause of death or the cause of death recorded does not map directly to disease groupings used routinely in BoD studies. The Scottish Burden of Disease (SBoD) uses cause of death data from the National Records of Scotland. These patient-level records include one underlying cause of death and up to 10 supplementary causes of death, all coded using ICD classifications. Around 12% of these deaths do not map directly to a BoD cause group and could therefore be considered ill-defined. The SBoD study have developed a 9-step hierarchical methodology for the redistribution of ill-defined deaths, utilising uses a mix of fixed and proportional redistribution and focusses on exploiting the data recorded on the death certificate at both an individual and population level. In this presentation we will describe the methodology used to redistribute ill-defined deaths in the Scottish study - the development, the application and the strengths and weaknesses of our approach. We will also discuss the example of COVID-19 and how competition between the underlying cause of death is likely to impact how we need to approach IDDs in the future."}
{"text": "Barker\u2019s fetal origins hypothesis and the critical period theory suggest that early life events have long-term health effects. However, evidence of the famine exposure in early life and its effects on health in later life is scarce and inconsistent. To explore the effects of early-life exposure to the Chinese famine of 1959-1961 on later-life multimorbidity, we performed Poisson growth curve models using CHARLS Life History 2014 and CHARLS 2011-2018 . Our analyses revealed two findings. First, there was an overall detrimental effect of the early-life famine exposure on multimorbidity, although there was no effect of severity of famine exposure. Second, there was no overall interaction between famine exposure and life stages, although a more parsimonious model suggested that the detrimental effect of famine exposure was more pronounced in earlier life stages than in later life stages. Findings suggest that early life is a critical period in the life course and provides developmental origins of health and disease in later life."}
{"text": "Classical light sources emit a randomly-timed stream of individual photons, the spatial distribution of which can be detected with a camera to form an image. Quantum light sources, based on parametric down conversion, emit photons as correlated photon-pairs. The spatial correlations between the photons enables imaging systems where the preferential selection of photon-pairs allows for enhancements in the noise performance over what is possible using classical light sources. However, until now the technical challenge of measuring, and correlating both photons has led to system complexity. Here we show that a camera capable of resolving the number of individual photons in each pixel of the detector array can be used to record an image formed from these photon-pair events and hence achieve a greater contrast than possible using a classical light source. We achieve an enhancement in the ratio of two-photon events compared to one-photon events using spatially correlated SPDC light compared to uncorrelated illumination by a LED. These results indicate the potential advantages of using photon counting cameras in quantum imaging schemes and these advantages will further increase as the technology is developed. Operating in photon sparse regimes such systems have potential applications in low-light microscopy and covert imaging. The ability to observe these correlations at the single photon level is afforded by low noise detector technologies that are sensitive to single photons. These quantum enhancements can be extracted from correlations between pairs of single photon detection events, however, photon-pairs that arrive within the same pixel and/or time bin may not be easily distinguished from a single photon event due to limitations of detector technology. The inability to make this distinction prevents the full extent of the correlations between photon-pairs from being utilised in some imaging contexts. The capacity to distinguish between a two-photon event and a one-photon event would enable an increased amount of information to be extracted from experimental data thereby improving the efficiency of quantum imaging systems. Such improvements will allow quantum imaging techniques such as quantum enhanced microscopy to be implemented in real-world applications.Quantum imaging utilises correlations between entangled photon-pairs to achieve enhancements beyond classically achievable limits8. Such measurements can be made due to the capability of single photon sensitive detectors to distinguish a single photon from the absence of a photon by the setting of an appropriate threshold and/or by time-gating the detector. However, due to the stochastic nature of the gain process within Electron Multiplying CCD detectors (EMCCD) and Intensified CCD detectors (ICCD) it is not possible to accurately resolve the actual numbers of photons in each pixel in a frame and as a result it is not possible to simply\u00a0identify the two-photon events10. This is a disadvantage because in the case of the detector being positioned in the image plane of the downconversion source the most strongly correlated photon-pairs will arrive within the same pixel and time bin.A common source of entangled photon-pairs that are used in many quantum enhanced imaging experiments is spontaneous parametric down-conversion (SPDC) within a non-linear crystal. In SPDC, a photon-pair is created by the\u00a0spontaneous parametric downconversion of a single pump photon and due to conservation laws the downconverted\u00a0photon-pairs are strongly correlated in their position and anti-correlated in their transverse momentum. With a spatially resolving detector array it is possible to image and measure the correlations between photon-pairs realising a large number of entangled states12, ghost imaging16, imaging through scattering media17, interaction-free ghost imaging18, and sub-shot-noise imaging21. Further to these applications, quantum illumination schemes that are resilient to the effects of noise and losses have been demonstrated27.To date the inability to distinguish two-photon events from one-photon events has not prevented the development of quantum enhanced imaging systems using entangled photon-pair sources and single-photon-sensitive array detector technologies. Enhancements have been realised in terms of image resolutionIn this work we utilise a photon number resolving array detector that is based on CMOS technology which allows us to report a simpler method for the detection of correlated photon-pairs. The capability to distinguish two-photon events from one-photon events presents an advantage over the preceding technologies in imaging using SPDC photon-pairs because the photon-pairs can be detected in the same pixel in the same frame. Selecting these events allows the construction of an image consisting of two-photon events. We demonstrate an advantage in the ratio of two-photon events to one-photon events for images obtained under SPDC illumination when compared to images obtained under illumination from a LED source. This advantage is shown to be present across a range of illumination levels. In the context of quantum imaging the ability to identify two-photon events will allow the full extent of the correlations between photon-pairs to be utilised by image-plane applications in which the photon-pair events occur in the same pixel at the detector. Whilst we acknowledge the limited performance of our experiment, the method that we present method will improve efficiency with which data is collected and increase the rate at which images are populated with events, thereby increasing the opportunity for quantum imaging technologies to transition into real-world applications.The experimental setup used is shown in Fig. L is the length of the crystal, 28. For the system presented here, with a camera with a pixel size of We choose the de-magnification and crystal length of our system such that the number of pairs detected in the same pixel is maximised. The correlation strength The ability to distinguish the number of photon events occurring in a pixel is crucial to our experiment. The signal output of the camera is digitised into ADU , from which a histogram of events can be built up in order to set thresholds corresponding\u00a0to the number of photon events. For a histogram constructed over events on all pixels in the region of interest a series of global thresholds can be determined. An example of a global histogram constructed using all pixels in the region of interest over 100,000 frames can be seen in Fig. The offset of each pixel is determined as its average value under dark conditions. The gain of the sensor is determined by measuring the mean and variance in pixel output for series of images acquired under different intensities of poisson distributed light. For the camera used in this experiment the relation between ADU and electrons for the complete sensor was determined to be 1 ADU equals The probability of the output of a specific pixel depends on the input photon statistics as well as on the readout noise of that specific pixel. While the readout noise is typically a continuous gaussian distribution (which is digitised in a later step), the photon distribution is discrete in nature and depends on the source. The total output probability function will be a convolution of the photon statistics with the readout noise of the specific pixel. This method needs as input parameters the readout noise of the pixels and the photon distribution. The readout noise is derived from dark frames, while the photon distribution is estimated empirically from 10 pixels with a below average noise value (around Such a scenario is indicated in Fig. With the ability to distinguish the number of events in each pixel per frame images consisting of only one-photon events or two-photon events were obtained. One-photon and two-photon event images of a binary star target obtained over 10,000 frames may be seen in Fig. 29.To compare the performance of the imaging system at selecting correlated photon-pairs two-photon event images for the downconversion source are compared with a LED source. These comparison images for increasing illumination levels can be seen in Fig. The improved two-photon to one-photon event ratio provides an increased contrast in images where the object was illuminated by the SPDC source compared to the LED. This can be seen from the corresponding cross section image intensity plots in Fig. The key performance parameter in our experiment is the ratio between the number of pixels containing a one-photon event, whether it be signal or noise, and the number of pixels containing two-photon events for the LED and SPDC photon-pair source respectively. Considering first the limit of zero detector noise, and assuming a low illumination level with the number of events per pixel per frame Replacing the LED with the SPDC photon-pair source at the same illumination intensity, and assuming that the position correlation between the pair of photons is small compared to the pixel size, then the increase in the two event to one event ratio depends upon the efficiency of detecting both photons in a pair, the heralding efficiency, The camera noise of the detector is gaussian in nature and does not hold the above relation in that the number of events corresponding to two-photon events It follows that the largest difference in the two-photon and one-photon event ratios between the LED source and SPDC photon-pair source will be obtained when operating at a low number of total events per pixel per frame, We have reported a new method for the detection of spatially correlated photon-pairs from a SPDC source with a photon number resolving camera. With this imaging system images an improved ratio of two-photon events to one-photon events are obtained with a quantum SPDC photon-pair source when compared with a LED source across a range of illumination levels. Resulting images consisting only of two-photon events show a maximum improvement in the two-photon event to one-photon event ratio for the SPDC source compared to the LED source when operating at a low illumination level so as to minimise the contribution of accidental event-pairs. The presence of an enhancement in the 2/1 ratio for the quantum photon-pair source demonstrates the validity of the concept and is encouraging for the application of photon counting cameras in future quantum imaging applications.Quantum enhanced imaging experiments that require the detection of both photons in a photon-pair to realise an enhancement could benefit from the ability to distinguish one-photon events from two-photon events using the technology and methods described here. In an experimental configuration that places the detector in the image plane of the downconversion crystal the most tightly correlated photon-pairs arrive in the same pixel and this information is not easily recovered in the case of using a conventional CCD or CMOS detector technology for which it is difficult to distinguish between one-photon events and two-photon events. The ability to distinguish the number of photon events allows an increased amount of information to be recovered on a per frame basis thereby allowing increased efficiency and reduced acquisition times.Further improvements in the performance are set by the efficiency of photon-pair detection and camera readout noise, we expect improvements to these factors to yield more dramatic enhancements in the contrast of images. Higher detection efficiency could be achieved for example by creating down-converted photon-pairs at a shorter wavelength where the quantum efficiency of the sensor is higher. Furthermore, advancements in CMOS camera technology should result in lower sensor readout noises. With more dramatic contrast enhancements it is expected that images could be acquired on fewer frames where it is only possible to reveal the object with a quantum pair source. Such an experiment approaching real time imaging could point to applications in low light level microscopy or covert target detection systems.The pump beam source used here was a JDSU xCyte CY-355-150 Nd:YAG laser with quasicontinuous output at"}
{"text": "All authors of the Cell Death and Disease article appeared as authors of the Molecular Therapy - Nucleic Acids article. Image analysis performed by the editorial office confirmed findings of image duplication in Figure\u00a04B of the Molecular Therapy - Nucleic Acids article. This reuse (and in part misrepresentation) of data without appropriate attribution represents a severe abuse of the scientific publishing system.This article has been retracted at the request of the editor-in-chief. Similarities were found between images in this article and an article in"}
{"text": "Alcohol screening and brief interventions (ASBIs) for risky drinkers are known to reduce alcohol consumption and alcohol-related harm. The present study was the first to investigate the effectiveness of an ASBI for high-risk drinkers of low socioeconomic status (SES) in the Korean community social service setting.This study aims to evaluate the effectiveness of an ASBI for clients in community social service settings in South Korea.A total of 153 clients in social service agencies participated in this study. Clients in the experimental group received alcohol use screening and two sessions of brief motivational interventions (MI). Clients in the comparison group received alcohol problems screening test only. Primary outcome variable was the amount of weekly alcohol consumption, which was measured once before the intervention and three times after the intervention.When analyses were conducted separately for participants from the self-sufficiency centers and those from the community welfare centers, there was a significant time and group interaction effects. The amount of weekly alcohol consumption of the experimental group was gradually reduced over time. However, the amount of the comparison group was reduced at the four-week follow-up but was increased both at the eight-week and 12-week follow-ups.This study demonstrates the need to provide training and education in the ASBI to social service workers working with the underprivileged, as such training would increase the identification of alcohol-related risks of the people most vulnerable to alcohol-related problems.No significant relationships."}
{"text": "Social dysfunction is a significant feature of schizophrenia leading to deminution of quality of life (QoL).To explore the correlation between social functioning and quality of life in patients diagnosed with schizophrenia.The study sample comprised 32 patients diagnosed with schizophrenia  recruited from the Clinic for mental disorders \u201cDr Laza Lazarevic\u201d in Belgrade, with a mean age of 41.28 years , assessed by the Social Functioning Scale (SFS) and the World Health Organization Quality of Life questionnaire (WHOQOL-BREF).There were two significant quasi-canonical positive correlations between social functioning and QoL  The first structure is formed through the set of SFS subscales- Recreation, Independence-performance and Independence-competence and set of QoL subscales- Mental health, Physical health, Environment and General assessment of QoL. The second structure is formed through the set of SFS subscales- Interpersonal functioning and Social engagement/withdrawal and the set of QoL subscales- General assessment of QoL and Environment. Furthermore, the first canonical component indicates a greater overlap of the opposition set by social functioning (23%) which leads to the assumption that the direction of influence goes from social functioning to QoL. Due to the equality of redundancy in the second canonical component, the direction of influence can only be inferred on the basis of the first canonical component.Social functioning and quality of life are related in patients diagnosed with schizophrenia, and this relationship is based on specific subfactors within those areas.No significant relationships."}
{"text": "Recently, the realization of the spiral mass transfer of matter has attracted the attention of many researchers. Nano- and microstructures fabricated with such mass transfer can be used for the generation of light with non-zero orbital angular momentum (OAM) or the sensing of chiral molecules. In the case of metals and semiconductors, the chirality of formed spiral-shaped microstructures depends on the topological charge (TC) of the illuminating optical vortex (OV) beam. The situation is quite different with polarization-sensitive materials such as azopolymers, azobenzene-containing polymers. Azopolymers show polarization-sensitive mass transfer both at the meso and macro levels and have huge potential in diffractive optics and photonics. Previously, only one-spiral patterns formed in thin azopolymer films using circularly polarized OV beams and double-spiral patterns formed using linearly polarized OV beams have been demonstrated. In these cases, the TC of the used OV beams did not affect the number of formed spirals. In this study, we propose to use two-beam  interference lithography for realization spiral mass transfer with the desired number of formed spirals. The TC of the OV beam allows for controlling the number of formed spirals. We show the microstructures fabricated by the laser processing of thin azopolymer films can be used for the generation of OAM light at the microscale with the desired TC. The experimentally obtained results are in good agreement with the numerically obtained results and demonstrate the potential of the use of such techniques for the laser material processing of polarization-sensitive materials. The fabricated multi-spiral microstructures were used for the generation of OV beams with the desired TCs corresponding to the number of formed spirals. The proposed method provides the possibility of the use of structured interference patterns generated with a single spatial light modulator for the fabrication of microelements generating OAM light at the microscale for laser manipulation, integral optics, and biophotonic applications. Thus, our results represent a pathway towards the easy-to-implement inexpensive fabrication of spiral-shaped microstructures for advanced photonic applications. We believe that the fabricated structures can also be used for sensing chiral molecules and controlling helical dichroism. The control of light\u2013matter interactions in these cases may present new opportunities with regard to chiroptical spectroscopy, light-driven molecular machines, optical switching, and the in situ ultrafast probing of chiral systems and magnetic materials [An approach for the fabrication of multi-spiral microstructures in azopolymer thin films with direct laser patterning was realized. The approach was based on the use of structured laser beams in the form of spiral-shaped interference fringes generated through the interference of an OV beam with a Gaussian beam with a spherical wavefront. In contrast with demonstrated earlier spiral-shaped mass transfer with OV beams, this technique allows for the fabrication of spiral-shaped microstructures with a desired number of spirals. In addition, there is no significant difference in the profiles of the fabricated multi-spiral microstructures when we use linearly or circularly polarized radiation. The profiles of the fabricated microstructures measured with a scanning probe microscope were very well approximated with the inversion of the intensity of the longitudinal component of an illuminating laser beam, as was noted in our previous studies ,25. Hereaterials ."}
{"text": "Early Intervention Programmes in Psychosis Mental illness is associated with high burden of disease and it has severe individual and societal consequences. In first episode psychosis, specialised Early Intervention Services with team-based intensive case management and family involvement are superior to standard treatment in reducing psychotic and negative symptoms and comorbid substance abuse and improving social functioning and user satisfaction. The results of the OPUS-trials will be presented together with meta-analyses based on similar trials. The sustainability of positive effects will be highlighted with results from three different trials. Results of long-term follow-up studies indicate that the prognosis of first episode psychosis is very diverse with the extremes represented by one group being well functioning and able to quit medication without relapse; and another group having a long-term chronic course of illness with a need for support to maintain daily activities. The latter is, in spite of many efforts, still poorly served. A substantial proportion of patients with psychosis have treatment resistant auditory hallucinations. The UK-based AVATAR-trial was the first to demonstrate effect of simulation training on devaluating voices. The Danish CHALLENGE-trial aim to replicate the findings from the AVATAR trial in a virtual reality setting.No significant relationships."}
{"text": "The Covid-19 pandemic has had a significant impact on the mental health of adolescents. Several descriptive studies and systematic reviews have shown an increase in suicide rates in this age group.- To present a literary review on the impact of the Covid-19 pandemic on the mental health and suicidal behavior of adolescents around the world. - To present data on admission rates due to suicidal behavior during the first year of the Covid-19 pandemic in a Spanish child-adolescent psychiatric hospitalization unit.- We will present a literature review and a retrospective cross-sectional study on admission rates for suicidal behavior in a child-adolescent psychiatric hospitalization unit. - Admission rates for suicidal behavior during the year prior to the pandemic will be compared with rates relative to the first year of the pandemic.- We have found a significant increase in admission rates for suicidal behavior during the year of the pandemic. Similar results have been found in different studies and meta-analyzes. - The socio-demographic characteristics of the patients are quite similar in the two periods of time analyzed, but the reference to intra-family problems has been more frequent in the year of the pandemic.Our data is in line with other studies suggesting that the Covid-19 pandemic has had a strong impact on teenage suicidal behavior.No significant relationships."}
{"text": "Due to the non-linear nature of relativistic laser induced plasma processes, the development of laser-plasma accelerators requires precise numerical modeling. Especially high intensity laser-solid interactions are sensitive to the temporal laser rising edge and the predictive capability of simulations suffers from incomplete information on the plasma state at the onset of the relativistic interaction. Experimental diagnostics utilizing ultra-fast optical backlighters can help to ease this challenge by providing temporally resolved inside into the plasma density evolution. We present the successful implementation of an off-harmonic optical probe laser setup to investigate the interaction of a high-intensity laser at  It requires predictive power of simulation tools in quantitative agreement with experimental results and it is still challenging to achieve for laser-solid interactions3. One important reason is the large range of interaction physics at different time scales and laser intensities impacting the solid prior to the arrival of the laser peak7 and connected to that the difficulty of capturing the dynamics by a single simulation tool. Although the relativistic laser-plasma interaction can be mapped by particle-in-cell simulations8, the computable time window is limited and the captured physics must be dominated by the laser field. For lower intensities in the laser rising edge, approaches of radiation-hydrodynamic codes are often used to capture the longer time scales and approximate the more localized energy deposition10.Full control of high-intensity laser-matter interaction is key to enable applications like fast ignition for inertial confinement fusion17. However, for ultra-relativistic laser intensities approaching 20, strong plasma self-emission, scattered light and surface harmonics often mask the central region of the plasma on the detector. This complicates the application of advanced probing techniques like polarimetry or few-cycle optical probing23. A promising path to overcome this issue is the shift of the probing wavelength away from the fundamental and the harmonic wavelengths of the high-intensity pump laser25, hereafter referred to as \u201coff-harmonic optical probing\u201d.An alternative approach is the use of time-resolved experimental diagnostics that infer properties of the target shortly before the arrival of the laser peak. Microscopy techniques utilizing ultra-fast optical backlighters are a common tool to characterize the plasma density distribution in high intensity laser-solid interactions32 serves as a test bed and facilitates recording of optical probing data and comparison with particle-in-cell simulations. Based on spectral measurements of the plasma self-emission at different pump laser contrast conditions, the applicability of the probing technique and the importance of spectral backlighter fluence are discussed. Conducting a time delay scan, the concept enables observations of target ionization within the rising edge of the laser and target expansion before and after the peak of the pulse, so far not accessible at this intensity level. Providing realistic starting conditions for the interaction of the relativistic main pulse, a three dimensional particle-in-cell (PIC) simulation is conducted and compared to the experiment. The experimentally observed expansion dynamics are confirmed and discussed.Here, we demonstrate this technique using a 19 at the Helmholtz-Zentrum Dresden\u2013Rossendorf and the experimental setup is sketched in Fig.\u00a033. In this study, a continuously flowing jet of cryogenic hydrogen35 with 36 . In general, the temporal synchronization is based on three pillars. The first is the high-frequency synchronization at the level of the laser oscillator frequency or higher. It determines the temporal shot-to-shot stability of the pump-probe delay in the experiment and is desired to be close to the laser pulse duration. The core is a highly stable external clock laser. The optical signal of this laser is distributed over individual fiber links to the lock-electronics of pump and probe laser oscillator, each located in a different experimental cave. Accumulating the electronic and optical jitters in the whole chain up to experiment yields an RMS pump-probe delay stability of 25. Together with the pulse duration of the probe laser, the temporal resolution of a time delay scan is calculated to be For long-term availability of optical probing capabilities of a laser-plasma laboratory it is beneficial to implement an independent laser system instead of picking a probe from the pump laser beam after compression. The alignment of target and probe is completely independent from the pump laser settings and by utilizing different laser media for pump and probe laser the possibility for off-harmonic probing is intrinsically given. An important aspect is the temporal synchronization of both laser systems and two options are commonly used. Either pump and probe laser share the same laser oscillatorFor the present installation, the temporal synchronization stability of the pump-probe setup is sufficiently precise to scan the high-intensity laser-matter interaction within hundreds of fs around the pump laser pulse.Equally important to the appropriate choice of the backlighter wavelength is the discrimination of the probe signal from the plasma self-emission. Both sufficient spectral filtering and spectral fluence of the probe are needed. Dielectric coatings on vacuum windows and spectral bandpass filters can have low damage thresholds and need to be protected against high fluences, especially from the ultraviolet light of the mentclass2pt{minim39. Depending on the pre-pulse timing, the pre-pulses utilized here generate a scalelength of multiple pump laser wavelengths. Therefore, the observation of a reduced signal of the tail of the second harmonic with increased pre-pulse delay is expected. The homogeneous spectral emission that is observed for both pre-pulse settings can be attributed to an interplay between several mechanisms. First, the generation of a plasma density surface-scalelength increases the coupling efficiency of laser energy into electrons and produces a higher number of photons in a broad energy range41. Second, as the target is pre-expanded it features a larger surface area to emit thermal radiation. Third, the increased amount of undercritical plasma acts as a highly non-linear medium to the incident pump laser and spectral broadening and self-phase modulation occur44.The efficiency of the first filter stage against the fundamental and the harmonics of the pump laser is measured with the spectrometer in the spectral band between mentclass2pt{minimThe technical implication of the measured plasma self-emission to off-harmonic optical probing becomes clear by comparing the signal heights of the self-emission to the probe spectrum (probe only) in Fig.\u00a0entclass1pt{minima23. For few-cycle probe pulses it has been shown that spectral filtering behind the probed interaction does not diminish the time resolution of the probing data22. A careful choice of spectral filters and a precise characterization of the plasma self-emission will enable future developments into this direction.In general, viewing the non-spatial parameters of the probe beam, e.g. pulse duration and energy, it is important to consider that the Fourier-limited laser pulse duration is inherently linked to spectral bandwidth by the time-bandwidth product. Shorter probe pulses require a broader bandwidth and the pulse energy is always distributed over the whole spectrum. It follows that, at constant pulse energy, shorter pulses have a lower spectral energy per unit wavelength than longer pulses. However, for a probing image without saturation of the detector it is required that the probe beam is spectrally brighter than the plasma self-emission but at the same time the probe needs to stay non-invasive, i.e. non-ionizing. Depending on the pump laser contrast, a concentration of the probe pulse energy into a narrow bandwidth can be beneficial. For example, reducing the time resolution by using a picosecond probe in conjunction with narrow bandpass filters on the camera could outshine the self-emission in the The appropriate choice of backlighter wavelength, sufficient spectral filtering in the imaging beamline and a good contrast between spectral probe laser fluence and spectral plasma self-emission enables the optical investigation of the plasma dynamics at 45 into a partially ionized plasma, where the density of electrons in the conduction band is close to or higher than the critical plasma density of the probe wavelength  of high-intensity laser pulses on thin plastic targets up to a pump laser peak intensity of 49) and second by the dissipation of hot electrons from the center of the interaction when the pump laser intensity becomes relativistic. The hot electrons stream into the surrounding target volume and cause additional colder return currents. Thus, the hot electrons ionize the solidified hydrogen either directly by collisions or indirectly by field-ionization51.The time-dependent increase of the opaque target volume between For pump-probe delays later than Three characteristic transient target states are identified, each in a different time domain. Close-ups of representative shadowgrams are depicted in Fig.\u00a053 version 0.4.3 is conducted (see Methods section). In the PIC simulation the target is initialized as a fully ionized plasma cylinder with a density of solid hydrogen and a diameter of The ultra-fast plasma expansion following the pump laser peak occurs on a time-scale close to the probe laser pulse duration and motional blurring of the individual shadowgrams is expected. To compare the experimental obervation to the theoretically expected plasma expansion dynamics and to get more inside into the role of relativistically induced transparency to full target transparency at 54. Therefore, a top view slice of the electron density Due to the mass ratio of protons and electrons, light transparency of plasmas is governed by electron interaction. For relativistic laser plasmas, the high velocity of electrons can be considered as a mass increase quantified by the relativistic gamma factor 54To compare the PIC simulation to the experiment, the shadowgram formation for a given particle density distribution obtained from the PIC simulation needs to be modeled. For this, a dispersion relation of the plasma is required and the refractive index The simulated front and rear side shadow radii from the particle densities at For investigating the origin of the spikes, a more detailed view into the simulation results would be required. The same applies for the plasma dynamics for times between mentclass2pt{minimAnother experimental observation is the full transparency of the target at The temporal evolution of We demonstrated the application of an off-harmonic optical probing setup at a high intensity laser interaction with a cylindrical cryogenic hydrogen jet target. We have shown the temporal synchronization concept and confirmed the necessity of a beam arrival monitor if a timing precision comparable to or below the probe laser pulse duration is required. We explored the laser-contrast-dependent spectral emission characteristics of the plasma self-emission and discussed the results and its implications on optical probing of similar interactions concerning the choice of backlighter wavelength, spectral bandwidth, spectral fluence and spectral filters. The efforts and concept allowed to make hitherto impossible observations of the target evolution via optical shadowgraphy at a pump laser intensity of In conclusion, we have shown that off-harmonic optical shadowgraphy probing provides realistic initial target parameters as input for three dimensional PIC simulations at the discussed laser intensities and the technique is able to provide quantitative feedback to simulations of the relativistic laser-plasma interaction.36. The imaging system of the target uses a custom-made finite conjugate apochromatic objective with a numerical aperture (NA) of 0.28 and a working distance of The probe laser pulses with A schematic of the temporal synchronization setup is given in the supplementary Fig. 25. The supplementary Fig. 25. From this data we retrieve an RMS pump-probe delay stability of To benchmark the temporal delay stability between pump and probe laser we first conduct noise measurements of each individual laser oscillator with a stable external clock (FSWP by Rohde-Schwarz) and secondly of the combined and amplified laser systems on the beam arrival monitor (BAM)To minimize optical image distortion, to protect all following optical elements and to minimize the fluence on the filter for all wavelength that are contained in the plasma self-emission, the first spectral filter stage is placed directly behind the objective \u00ae V100 and the run time is 4.5h.The PIC cycle uses the Yee field solver, Esirkepov current deposition and Boris particle push. The simulation uses 18 particles per cell. The pump laser pulse in the PIC simulation is initialized with p-polarization, Supplementary Information."}
{"text": "Teaching Point: Air trapping is a useful sign for early detection of worsening lobar collapse in the follow-up of obstructive atelectasis. A 40-year-old female patient with paraplegia due to a motor vehicle accident 22 years earlier was admitted to the critical care unit after a surgery for colonic volvulus. She had a persistent left lower lobe collapse over the course of several weeks as seen in the first bed-side chest radiograph . This raCollapse (or atelectasis) is defined as the absence of gas exchange and loss of volume of a pulmonary lobe or a whole lung. Atelectasis can be of obstructive or non-obstructive etiologies. In adults, obstructive atelectasis can be caused by a tumor or a mucus plug. In case of central bronchial obstruction, collapse with loss of volume may be preceded by air trapping or hyperinflation due to a valve-like mechanism of the bronchial obstruction. The same mechanism of air trapping occurs in the setting of bronchiolitis obliterans in which the obstruction occurs at the level of small airways by a fibroproliferative process . Of noti"}
{"text": "Studies have shown that engaging family caregivers of people with dementia in creative activities can provide therapeutic benefits by relieving stress and promoting well-being. However, there is a dearth of studies focusing on the involvement of racial minority family caregivers of people with dementia in research involving art and creative activities. The purpose of this study is to present the results of a case study interview with an artist-educator-community collaborator who acted as a key facilitator for the ACTION ARTS study. The purpose of the ACTION ARTS study was to utilize mobile technology applications for facilitating creative activities to enhance health and well-being of African-American family caregivers and their loved ones in the middle-to-late stages of dementia. The study included activities such as memory stimulation, art viewing, art making, and other forms of creative expressions. The research question for the current case study was: What are the best practices for engaging African-American family caregivers of older adults in the middle-to-late stages of dementia in research involving art and creative activities? Thematic analysis of the qualitative data from the case study interview yielded the following recommendations/results (1) Design the program of art and/or creative activities in an easy way to facilitate interaction among participants; (2) Make the program as accessible and relevant as possible so everyone is able to relate to it; (3) Emphasize areas of commonality that could help in giving both the facilitators and participants food for thought."}
{"text": "Telemedicine has been at the heart of healthcare system\u2019s strategic response to the COVID-19 pandemic. Within psychiatry, there has been a surge of research and guidelines into the use of video-teleconferencing to replace face to face consultations across clinical settings. Clinical ward rounds are central to inpatient psychiatric care yet little guidance is available on how best to integrate telemedicine into the multidisciplinary work of inpatient psychiatry.We report on the introduction of video teleconferencing for psychiatric ward rounds on our acute inner-London psychiatric unit during the outbreak of COVID-19.In undertaking the rapid transition to tele-ward rounds, we had to reconcile the multiple functions of psychiatric ward rounds with the technological resources available to us.Tele-ward rounds helped simplify care delivery, facilitate multidisciplinary collaboration and improve accessibility for patients and relatives in a time of crisis. The transition to tele-ward rounds also brought about technical, operational and communication issues that may impact on the patient experience and quality of care including governance challenges, contextual dissonance and technological limitations.The routine use of newer technology in psychiatry ward rounds is unlikely to succeed on the basis of improvisation, particularly given the stream of technical innovations in telemedicine, and the multifarious quality of social interactions in our clinical setting. Staff training and the development of an adapted etiquette and code of communication are both essential. Patient participation in future developments will also help ensure tele-ward rounds continue to meet the standards of high quality inpatient psychiatric care beyond the COVID-19 pandemic.No significant relationships."}
{"text": "Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader alerting the Editorial Board to an apparent duplicate region within the si-NC and the miR-143-3p mimic + pcDNA-MSI2 panels of Figure 7H. Additional concerns exist over the western blots within the paper. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries or the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.This article is being retracted from"}
{"text": "Fostering health literacy is considered an important objective within school-based strategies of health promotion. To effectively strengthen health literacy in the school setting the approach of organizational health literacy can be transferred to and implemented in schools. This approach combines behaviour-focused measures  and environment-orientated measures (changing school's framework conditions). The HeLit-Schools project aims at developing a school-based concept of organizational health literacy and tools to support schools in becoming health-literate schools.Existing concepts of organizational health literacy of other setting are analysed and adapted to the school setting. The concept development includes the expertise of actors from the school field, health literacy research and health sector. They contribute by commenting, reviewing and validating the conceptualization at different stages in the development process. A quantitative assessment of schools\u2019 organizational health literacy is planned to further validate the concept. Furthermore, a screening of existing materials and programs for schools to use to foster health literacy is being conducted.The developed HeLit-Schools concept describes eight standards of a health-literate school. Every standard focuses on a specific area within the school's organization that can be addressed and changed in order to strengthen everyone's health literacy at school more effectively. To additionally support schools in fostering health literacy in school as well as in the classroom, a structured collection of existing (teaching) materials and programs was assembled.Enhancing schools\u2019 organizational health literacy and thus promoting school development by optimizing schools\u2019 structures, processes and conditions in a health-literate matter can lead to an effective and sustainable strengthening of health literacy of every individual at school."}
{"text": "Quality of life is one of the most important and holistic measures of perceived overall well-being across the lifespan. For older adults living with cognitive impairment, quality of life has been conceptualized as consisting of an array of intertwined domains, such as relationship quality, physical health and ability, and opportunities for roles and activities. A subset of measures have been developed to gauge quality of life in older adults living with cognitive impairment, yet no \u201cgold standard\u201d in measurement has emerged. Quality of Life \u2013 Alzheimer\u2019s Disease (QOL-AD) is one of the most commonly used and long-standing measures, yet it was developed in 2002 and has yet to be updated to reflect the evolution of our understanding of quality of life in adults living with cognitive impairment. Drawing from the literature on adults living with intellectual and developmental disabilities (IDD), the researchers identified several domains and items to update and expand the applicability of the QOL-AD measure. The proposed revised measure, Quality of Life \u2013 Alzheimer\u2019s Disease/Intellectual and Developmental Disabilities (QOL-AD/IDD), is intended for adults living with cognitive impairment regardless of age or cause of impairment . The QOL-AD/IDD retains the format of the original measure, most notably the useful prompts that accompany each item and the supplemental proxy measure for caregivers. In this presentation, the researchers will discuss the development of the QOL-AD/IDD and ongoing  and planned steps to evaluate the reliability and validity of this promising measure."}
{"text": "The decline in physical and mental well-being is common with age. The negative impact of poor quality of sleep and depressive symptomatology contributes to the decline in well-being among middle to older adults. African Americans are more likely to report a decrease in well-being as they age. They are also disproportionately affected by poorer sleep quality and may be at greater risk for depressive symptomatology. Dispositional mindfulness is linked to improved well-being. Research has shown dispositional mindfulness is related to adaptive health behaviors, improved sleep quality, and reduced negative affect. Mindfulness allows engagement of early regulation of intense emotional responses because of nonjudgmental acceptance of thoughts and emotions. Therefore, this study aims to examine the impact of mindfulness on physical/mental well-being and depressive symptomatology through sleep. 131 African American participants were recruited for the study, with an average age of 58 years. The results showed a significant effect of mindfulness on well-being and depressive symptoms. Additionally, the impact of mindfulness on mental and physical well-being was mediated by sleep quality  and sleep disturbance . The results also showed an indirect effect of mindfulness on depressive symptoms through sleep quality . This study demonstrates the positive impact of mindfulness on well-being and depressive symptomatology. Sleep quality also plays an important role in the relationship between dispositional mindfulness and physical/mental well-being and depressive symptomatology in middle to older African Americans."}
{"text": "Quality of life (QOL) instruments can provide unique information on various aspects of children\u2019s everyday functioning beyond clinical symptoms and clinical measures. The study of the QOL in the siblings of individuals with an Autism Spectrum Disorder (ASD-siblings) is a new direction in the field of ASD-research.This study aimed to investigate the QOL in ASD-siblings in comparison with an age and sex matched group of siblings of neurotypical children.The sample included 233 neurotypical children (8-13 years old) of whom 118 comprised the observational group (ASD-siblings) and 115 comprised the comparison group. The Kidscreen-27 and a demographics questionnaire were administered to all participants.The two groups differed significantly in all subscales and in the overall score of the Kidscreen-27, with the children in the observation group having a significantly worse quality of life . Additionally, the largest difference in the averages of the subscales occurs in the subscale General Mood and Emotions, where the observation group had significantly lower scores  than the comparison group .QOL in children has been recognized as an important outcome indicator in detecting subgroups of children at risk within the general population, while ASD-siblings\u2019 QOL is an important concept in the implementation of appropriate services for these children. This study revealed poorer QOL in ASD-siblings and highlighted the importance of assessing QOL in those siblings as well as the use of the Kidscreen-27 as a screening tool in order to detect children at risk of maladjustment.No significant relationships."}
{"text": "The paper describes the displacement function approach first proposed by AJMSpencer for the formulation and solution of problems in second-order elasticitytheory. The displacement function approach for the second-order problem resultsin a single inhomogeneous partial differential equation of the form Rubber-like elastic materials are characterized by their ability to sustain largestrains without fracture and damage. The seminal works of RS Rivlin and co-workerspresented a comprehensive and systematic approach to the description of hyperelasticmaterials, commencing with the formulation of constitutive relations by appeal tothe theory of invariants, the solution of benchmark problems involving homogeneousstrains, inflation and eversion of annular regions, torsion and bending of prismaticbodies, and performing experiments to validate the mathematical approach. Referencesto these accomplishments are also contained in the collected works of RS Rivlinedited by Barenblatt and Joseph  and well221When dealing with hyperelastic materials, it is essential to consider themathematical formulations and the relevant strain energy functions that canaccommodate large strains in a consistent fashion. In addition, the realm ofapplication of the hyperelasticity theory is also important. For example, the formof a strain energy function needed to model very large strains in biological tissues\u201343, and 44theelastica). An appraisal of the work of Signorini is also provided byCapriz and Podio-Guidugli [pseudo body force term. The procedure was used to examine thesecond-order torsion of a bar with a square cross-section. Hill [The equations governing large strain behavior of rubber-like materials are highlynon-linear and unless recourse is made to computational approaches \u201359, the 60Guidugli . ReviewsGuidugli ,Green aGuidugli ,SpencerGuidugli , and extGuidugli  presenteGuidugli ,73 were Guidugli  also disGuidugli  continueGuidugli  generaliGuidugli  presenteGuidugli  also useGuidugli  subsequeGuidugli  who reduGuidugli .The proGuidugli  to incluGuidugli  using a Guidugli  investigGuidugli  and the Guidugli  continueGuidugli  examinedon. Hill  re-examion. Hill  and provThe application of a displacement function approach for the analysis of thesecond-order problem for incompressible elastic materials was first identified bySpencer in 1968 see . A formaOther approaches have been used for the formulation and solution of problems insecond-order elasticity theory. For example, Shield  used an 9898In this study, we illustrate the application of Spencer\u2019s displacement functionapproach for the formulation and solution of the second-order problem related toKelvin\u2019s fundamental problem, which deals with the application of a concentratedforce at the interior of an incompressible elastic medium of infinite extent. Thestrain energy function for the elastic medium is assumed to be of the Mooney\u2013Rivlinform. In the case of an incompressible elastic medium, the similarity betweenKelvin\u2019s problem for the concentrated force acting at the interior of an infinitespace region and Boussinesq\u2019s problem for a normal force acting at the surface of anelastic half-space is well known 99,113,114.axially symmetric problems in terms of thedisplacement function approach. We denote particles in the reference configurationby We follow the developments documented in Green and Adkins , Green aWe consider incompressible elastic materials for which,The matrix of physical components of the left Cauchy\u2013Green strain tensor, referred tothe and, using The basis for the method of successive approximations is that the displacement fieldcan be expanded in a power series in terms of a small parameter, where the suffixes For an isotropic incompressible elastic solid, the general form of the constitutiveequation for the symmetric contravariant stress tensor T  can be rwhere The first-order constitutive equation can be reduced to the forms:where The constitutive equations for the second-order stress components can be writtenas:and the components For axial symmetry, the equations of equilibrium for the symmetric contravariantstress Using the expansions in powers of the first-order equations of equilibrium take the forms:and the second-order equations of equilibrium take the forms:where:The second-order equations of equilibrium can be expressed in the forms:first-order problem in incompressibleelasticity, Spencer introduced the approach involving Stokes\u2019 stream function, whichsatisfies the incompressibility condition for any choice of the function. Thisapproach for the first-order problem bears a similarity with the problem of slowviscous flow for Newtonian fluids in terms of Stokes\u2019 stream function .This aon  and the first-orderequations of equilibrium, we arrive at the following partial differential equationsgoverning the first-order displacement function where The extension of the displacement approach to the formulation of the second-orderproblem requires a representation that can exactly satisfy the second-orderincompressibility condition given by As was indicated by Selvadurai and Spencer , there awhere:andBy successively eliminating which govern the axisymmetric second-order problem for an incompressible elasticmaterial. For the solution of specific boundary value problems, both traction and/ordisplacement boundary conditions need to be specified on the deformedboundaries.The development of solutions to the first-order problem is straightforward andeither traction or displacement boundary conditions could be specified onsurfaces referred to the undeformed configuration. In the case of thesecond-order problem, the displacement and traction boundary conditions have tobe specified in relation to surfaces that are prescribed on the deformed body.The components of the traction vector on a surface in the deformed body,resolved in the where:and the traction boundary conditions are normally specified in relation to asurface in the deformed body defined by:From Using these relationships, the expressions (27) can be expressed as:The state of stress in an elastic solid of infinite extent subjected to aconcentrated force of magnitude d Kelvin   satisfy the first- and second-orderincompressibility conditions in andZ-direction is zero, andthere is no second-order contribution to We note that the second-order solution is symmetric about It may be noted that the order of any singularities that may exist in the first-ordersolution \u2013132 is u141Considering the homogeneous Considering the substitution We seek solutions of which can be used to reduce We note that the operators in Solving the resulting ordinary differential equations (ODEs), we obtain thefollowing homogeneous solutions:where andasymmetric aboutWe observe that since where tance d , is givetension in close proximity to a doublet incompression) can be obtained by taking the partialderivative of where where Z-direction .For an incompressible elastic material, the first-order displacement and stresscomponents for the doublet problem can be written as:where:Omitting details, the partial differential equation governing the second-orderdisplacement function The second-order expressions for the displacement and stress components obtained fromthe particular solution of The second-order displacement and stress components (57) satisfy the second-orderincompressibility condition (6) and the second-order equations of equilibrium (23),where:The solution to the problem of an isotropic elastic half-space that is subjected to aconcentrated normal force at the origin of coordinates is identified as Boussinesq\u2019sproblem (Boussinesq ) Figure. The sol98161The application of the theory of second-order elasticity to Boussinesq\u2019s problem is anatural extension of the study dealing with Kelvin\u2019s problem. The first-ordersolution for Boussinesq\u2019s problem is identical in form to Kelvin\u2019s solution given byThe stress field given in r- andz-directions are given by:The components of the unit normal in the which reduces to:The traction-free boundary conditions for the second-order stress components on thedeformed surface of the half-space reduce to:Since The first boundary condition of While this approach is feasible, the divergent integrals can only be evaluatednumerically, which is a limitation. Also, consideration of a hemi-sphericalinclusion at the surface of the half-space results in the first-order solution thatis a series in the Legendre polynomials, which cannot be manipulated easily inconstructing the second-order formulation. Subsequently, the second-order solutionto Boussinesq\u2019s problem for a concentrated normal force was provided in a compactand closed form by Carroll and Rooney , using tThe theory of second-order elasticity is a mathematically consistent theory formodeling hyperelastic materials undergoing moderately large strains, as opposed toeither media exhibiting large deflections and rotations but with small strains orsmall deformations superposed on large. The expansion of the dependent variables interms of a small non-dimensional parameter forms the basis of the approach and if aparticular problem is formulated in a consistent manner, the small parameter willnaturally evolve in the formulation. The solution of problems in second-orderelasticity theory also becomes meaningful in terms of technological applicationsinvolving rubber-like elastic materials used as load bearing components ormountings. Also, when the incompressibility constraint is introduced, the strainenergy function of the Mooney\u2013Rivlin form can completely accommodate thesecond-order moderately large strain phenomena. The formulation and solution ofproblems in second-order elasticity can be facilitated through the use of complexpotentials and complex variable theory, stress functions based on the adaptation ofthe functions proposed by Love, Neuber\u2013Papkovich, and integral transform techniques.Spencer\u2019s displacement function approach is also a convenient method for thetreatment of the second-order incompressible elastic problem and reduces thegoverning partial differential equation for the function to a canonical linear form.A similar result is obtained for the second-order component of the isotropic stress.The displacement function approach is applied to develop solutions to certainaxisymmetric localized loading problems of an infinite space and a half-space. Thefirst-order problem corresponds to the classical elasticity solution and the orderof the stress singularities present in the first-order problems are generallyincreased in the second-order problem. The issue of singularities in the first-ordersolution can be alleviated by selecting suitable boundary conditions where the loadsare applied over finite regions. The ensuing formulations can involve algebraiccomplexity. In such cases the solution of the second-order problem entails a greatdeal of routine mathematical operations and computer-aided symbolic mathematicalmanipulation techniques can be used to solve the second-order problem with speed andaccuracy."}
{"text": "The COVID-19 virus continues to generate waves of infections around the world. With major areas in developing countries still lagging behind in vaccination campaigns, the risk of new variants that can cause re-infections worldwide makes the monitoring and forecasting of the evolution of the virus a high priority. Having accurate models able to forecast the incidence of the spread of the virus provides help to policymakers and health professionals in managing the scarce resources in an optimal way. In this paper, a new machine learning model is proposed to forecast the spread of the virus one-week ahead in a geographic area which combines mobility and COVID-19 incidence data. The area is divided into zones or districts according to the location of the COVID-19 measuring points. A traffic-driven mobility estimate among adjacent districts is proposed to capture the spatial spread of the virus. Traffic-driven mobility in adjacent districts will be used together with COVID-19 incidence data to feed a new deep learning LSTM-based model which will extract patterns from mobility-modulated COVID-19 incidence spatiotemporal data in order to optimize one-week ahead estimations. The model is trained and validated with open data available for the city of Madrid (Spain) for 3 different validation scenarios. A baseline model based on previous literature able to extract temporal patterns in COVID-19 incidence time series is also trained with the same dataset. The results show that the proposed model, based on the combination of traffic and COVID-19 incidence data, is able to outperform the baseline model in all the validation scenarios. The coronavirus disease 2019 (COVID-19) is a respiratory illness. Since the first cases reported in the Chinese province of Wuhan in December 2019, COVID-19 has caused millions of infections and deaths worldwide. The virus has caused an outbreak of viral pneumonia, which has been named coronavirus disease (COVID-19) . In factSeveral methods have been proposed in order to provide accurate estimations for the spread of the COVID-19 virus. Each method has its own requirements, provides a simplification of the underlying process, and tries to provide optimal estimations using the observed information. The different types of methods and models can be grouped in families such as epidemic, simulation-based, statistical, machine learning-based, and hybrid models. Epidemic models characterize the spread of the virus in terms of variables such as the number of infected people, recoveries, deaths, and infection rates. Compartmental-based epidemic models have been largely used, dividing the population into compartments or groups, and the dynamics of the spread of the virus is captured by mathematical expressions which define the movement of individuals among compartments. Examples of compartmental models are the susceptible, infected, and recovered (SIR) model and the susceptible, exposed, infected, and recovered (SEIR) model . SimulatUsing a new deep learning model that combines both traffic and COVID-19 incidence data to optimize one-week ahead COVID-19 forecasting.Using traffic data to estimate mobility among adjacent zones (districts).Enhancing the accuracy of single zone models by combining the temporal patterns in adjacent zones modulated by inter-zone estimated mobility.Validating how the proposed machine learning model is able to learn spatiotemporal patterns from sequences of incidence and traffic-based mobility estimation to forecast the evolution of the COVID-19 pandemic for each zone (district) in a region.The spread of the COVID-19 virus is influenced by both space and time features . The virThe paper is organized as follows. Shallow machine learning models have been studied and validated as effective tools to model the COVID-19 outbreak since the first months of 2020. The authors in  providedDeep learning models have also been applied to the COVID-19 incidence time series data in order to try to optimize predictions. The research in  proposedSeveral research studies have compared the performance of different machine learning models when applied to forecast the evolution of the COVID-19 incidence, recovered cases, and deaths. The study in  investigThe spread of the COVID-19 virus has both temporal influence and spatial influence. Several studies have tried to define models that incorporated spatial information to time series pattern extraction. The authors in  developeThe spatial component in the COVID-19 virus propagation should incorporate the information related to the mobility of the people. The initial lockdowns in different parts of the world were intended to reduce the mobility of the people in order to control the spread of the virus. The authors in  analysedIn this paper, we propose a traffic-driven mobility impact measure among adjacent zones (districts) in a city in order to provide spatial information to a new deep learning model which will use traffic mobility data to complement COVID-19 incidence time series in order to optimize one-week ahead estimations. The proposed model will combine adjacent zone mobility with COVID-19 incidence data in order to feed an LSTM-based RNN network that will extract combined mobility and COVID-19 incidence data from adjacent zones.This section describes the datasets used in this paper to validate the results, the method proposed to estimate the mobility between adjacent zones (districts) based on traffic data, and the proposed machine learning model that combines traffic estimated mobility and COVID-19 incidence data for each zone (district) in order to optimize one-week ahead COVID-19 predictions.Two major datasets are going to be used in order to validate the results in this paper: the traffic data provided as open data for the city of Madrid by the Madrid City Hall and the COVID-19 incidence data for each zone (district) of the city of Madrid provided as open data by the Community of Madrid regional government.Traffic data for the city of Madrid were obtained from . The datThe location of each traffic sensor was obtained from . For eacThe locations of the traffic sensors are shown in The COVID-19 epidemiologic information was obtained from . The datThe datasets in , 32 are In this paper, we are going to use the period from July 2nd 2020 to March 29th 2022 because of the maturity of the data gathering process and since it is the longest homogeneous period in the dataset.b to district a is estimated according toa and b represent 2 adjacent districts (district a and district b)s represents each sensor in district b whose closest district is ais is the traffic intensity measured at sensor sN is the number of sensors sdsb is the distance between sensor s and the centre of district bdab is the distance between the centres of the districts a and biab represents the average weighted traffic intensity for the traffic measured by the sensors in b closest to a weighted by a proximity measure of each sensor to zone aThis section presents a method to estimate an inter-district mobility related indicator based on the average of the traffic intensity for the sensors at each district closest to a particular adjacent district, weighted by the proximity of the sensor to the adjacent district. The idea behind the proposed method is that the traffic that is measured closer to the border of 2 districts is more likely to cross that border (propagating the virus between the 2 districts).. The mobility impact from the traffic in district b whose closest district is a will be used in equation  layers.The model in In order to simplify the optimization process, all the LSTM layers for processing the input signals have been configured with the same internal configuration. The 2 dense layers have also been configured with the same number of neurons. As a future work, other configurations will be tested in order to further optimize results.A grid search approach has been used to train the model in The same optimization process has been carried out for the baseline model in order to provide a fair comparison between models. The model in A 10-fold cross validation approach which randomly splits the data in the dataset into 10 different segments of data. Each data segment is used once as the validation set. Finally, the results are averaged. This validation approach makes it easier for the model to learn the internal patterns in the validation data since there are adjacent similar data samples in the training set.A leave one district out validation approach which uses the entire time series for all the districts except one for training and the left-out district is then used for validation. The process is then repeated for all the districts, and the average of the MSE and MAPE values is computed. This validation approach allows us to assess if time patterns learnt from different zones generalize to new zones.A leave one wave out validation approach which removes the data from an entire wave in the time series for training and uses the information for that wave for validation is used. This approach is used to assess if the patterns learnt from previous waves of data generalize to new waves. The information in the dataset contains data from the second to the sixth wave. The last wave was dominated by the omicron COVID-19 variant and exhibited a particular behaviour. Therefore, the information in the fifth wave has been used to implement this validation approach.Three different validation approaches have been used in order to better assess the results and their generalization:AIr is the average improvement ratev represents each validation approachThe average improvement rates for the 3 validation schemes in terms of MSE values when using traffic information model in  comparedThe geographic locations for the districts with higher improvement rates in The results for the 10-fold cross validation approach for the particular district of Madrid-Salamanca are shown in Figures The results for the leave one district out validation approach for the same district of Madrid-Salamanca are presented in Figures The results for the leave the 5th wave out validation approach are captured in Figures The results in Tables 9This paper has proposed and validated a new deep learning LSTM-based model able to learn from both human mobility and COVID-19 incidence time series. The model processes COVID-19 geolocated information by dividing a geographical area into zones or districts and performing their independent COVID-19 detection of new cases. Traffic dada are used to estimate the degree of interaction between adjacent districts in order to modulate the influence of the current COVID-19 incidence values from adjacent districts when forecasting the number of new cases in the district of interest. The spatiotemporal COVID-19 incidence information for each adjacent district is processed together with the estimated mobility data using an LSTM layer. The output for each district is summarized by a dense (fully connected) layer, and combined patterns are extracted by processing together the information from all the adjacent districts using fully connected layers.The proposed model has been trained with open data for the city of Madrid and has been validated using 3 different validation approaches: 10-fold cross validation, leave one district out, and leave one COVID-19 wave out. The mean square error (MSE) and the mean absolute percentage error (MAPE) values have been compared with a baseline model used in previous literature and optimized and trained for the same dataset. The proposed model has outperformed the baseline model by reducing the MSE in 4.37, 6.01, and 2.40 times correspondently. Results show that adjacent geographical zones have an influence in the spread of the virus and that the estimation of mobility between zones helps in improving the achieved accuracy.The current model only uses mobility estimates for adjacent zones. As a future work, a new model to estimate mobility for non-adjacent zones will be studied. The current model is based on traffic mobility data. There also exist open datasets capturing pedestrian mobility and shared bike mobility. As a future work, these datasets will be used to enhance the mobility estimation model. Finally, there are other factors that influence the propagation of the virus such as the use of masks and the percentage of people vaccinated. As a future work, the model will be expanded to use vaccination and use of mask data as inputs to complement the mobility information to better estimate the propagation of the COVID-19 virus."}
{"text": "The Cornell Scale for Depression in Dementia (CSDD) was developed to measure depressive symptoms among older adults with dementia. The psychometric qualities of the CSDD have been inconsistent regarding the factor structure, with some studies showing a four-factor model and others a five-factor model. The purpose of this study was to test the factor structure of the CSDD as a measure of depression among a sample of assisted living residents. It was hypothesized that a four-factor version of the CSDD would provide a better fit than a five-factor version of the CSDD. The present study used baseline data from the Function-Focused Care for Assisted Living Using the Evidence Integration Triangle (FFC-AL-EIT) intervention study. A total of 511 residents from 85 assisted living facilities were included in the analyses. Confirmatory factor analyses were conducted to examine the factor structure and a chi-square difference test was conducted to compare model fit. Three items were removed from both models due to small factor loadings. The chi-square difference test indicated that the five-factor model fit the data significantly better  than the four-factor model, although both the five-factor and four-factor models produced very poor model fits. These findings may be due to the fact that the CSDD relies on information from caregivers, and the measure might benefit from including observational signs of depression. Future work should examine other factors or items that belong in a depression measure among assisted living residents."}
{"text": "Frontiers in Cardiovascular Medicine: Rising Stars 2021. The goal of this Research Topic is to promote the high-quality work of researchers at the early stages of their careers. The publications in this collection were selected based on their advancement in cardiovascular medicine and the research potential of the investigators. Here we celebrate the achievements of early-career investigators who thrive in the increasing hardships of academic research, including the fierce competition to secure research grant funding, and the publish-or-perish lifestyle of research dissemination . This original report demonstrates that pro-inflammatory factors such as MMP-1 and IFN-\u03b3 positively correlate with each other within valvular tissue and contribute to the localized degradation of collagen. Understanding the underlying mechanisms responsible for leaflet integrity disruption not only advances the fundamental insights into complications of PMV, but also is important for developing treatment strategies to treat mitral valve disease.Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis, by Miller and Sewell-Loftin. Angiogenesis is essential for many cardiovascular diseases , National Natural Science Foundation of China (82020108002 to JX), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JX), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to JX), Natural Science Foundation of Shanghai (19ZR1474100 to LW), and the Dawn Program of Shanghai Education Commission (19SG34 to JX).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "Identifying a feasible model of chronic schizophrenia would be valuable for studying the possible underlying mechanism and to investigate emerging treatments. Our hypothesis starts from the observation that combining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like features; thus, it could probably be used as the first model of chronic schizophrenia that emphasizes the characteristic of having a multifactorial etiologycreation of a complex animal model capable of exhibiting the multifactorial origin and manifestation of schizophrenia.we investigated the effects of ketamine administration combined with isolation in inducing schizophrenia-like symptoms in male albino rats and the brain reactive oxygen species levels.Our results showed that the number of lines crossings in the open field test, the number of open arm entries in the elevated plus maze, and the spontaneous alternations percentage in the Y-maze were significantly lower in the ketamine + isolation group compared to both the control and ketamine + social housing group (p < 0.05). Furthermore, the ketamine + isolation intervention significantly increased the MDA levels and decreased the GPx levels both in the hippocampus and the cortex of the rats. In addition, our premise of creating a model capable of exhibiting both positive and negative symptoms of schizophrenia was also based on adding the aripiprazole treatment to a group of ratscombining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like featuresNo significant relationships."}
{"text": "Multi-user multiple-input multiple-output (MU-MIMO) technology can significantly improve the spectral and energy efficiencies of wireless networks. In the uplink MU-MIMO systems, the optimal precoder design at the base station utilizes the Lagrange multipliers method and the centralized iterative algorithm to minimize the mean squared error (MSE) of all users under the power constraint. The precoding matrices need to be fed back to the user equipment to explore the potential benefits of the joint transceiver design. We propose a CNN-based compression network named PCQNet to minimize the feedback overhead. We first illustrate the effect of the trainable compression ratios and feedback bits on the MSE between the original precoding matrices and the recovered ones. We then evaluate the block error rates as the performance measure of the centralized implementation with an optimal minimum mean-squared error (MMSE) transceiver. Numerical results show that the proposed PCQNet achieves near-optimal performance compared with other quantized feedback schemes and significantly reduces the feedback overhead with negligible performance degradation. In recent years, the multi-user multiple-input multiple-output (MU-MIMO) technology has offered great advantages over conventional point-to-point MIMO systems due to its improvement on the spectral and the energy efficiencies ,2. SpeciNowadays, the joint optimization of the transceiver has attracted increasing research activities as an effective interference management technique for the uplink MU-MIMO systems . Since tThe online implementation of the centralized solution with the optimal MMSE receiver requires the necessary information feedback for the user equipment (UE) to perform real-time updating, whereas the offline one requires the feedback of the optimal precoding matrix. With the subsequent development of beyond fifth-generation (B5G) or sixth-generation (6G) technologies, the dimensions of the precoding matrices scales with the number of antennas, which gradually become rather large ,11. The Limited feedback of precoding techniques has been intensively investigated to reduce the feedback overhead in the uplink wireless communication systems ,13,14, wRecently, as the success of deep learning reaches more fields, the neural-network-based auto-encoder has been recently applied to enhance the performance of MU-MIMO systems in ,17,18. IWe propose a CNN-based architecture named PCQNet to produce the data-bearing bitstreams for each UE to recover the precoding matrices. It can achieve near-optimal performance and further reduce the feedback overhead compared with the existing 3GPP codebook scheme in certain scenarios.We develop a general trainable compression and quantization framework for the precoding matrices in the uplink MU-MIMO systems. The proposed PCQNet architecture as well as the Lloyd-Max quantization scheme can flexibly adjust the feedback overhead by training an auto-encoder.The precoding matrices with different compression ratios (CRs) are evaluated on the performance of the centralized implementation with an optimal MMSE transceiver. As far as we know, the effect of the feedback accuracy on the performance has not been investigated before. Specifically, we explore the trade-off between the block error rates (BLER) and the CRs of the precoding matrices.Multiple works of the transceiver optimization are limited to single-user scenarios or the particular MU multiple-input single-output (MISO) systems ,24. We fThe remainder of this article is organized as follows: Notations: Symbols for matrices (vectors) are denoted by boldface upper (lower) case letters. In this section, we introduce a simple signal model of an uplink MU-MIMO system, the joint transceiver design and the channel models.K UEs as depicted in k-th UE equipped with k-th UE to the BS.Without loss of generality, we consider the uplink MU-MIMO system consisting of one BS equipped with k-th  between the recovered precoding matrices and the original ones. A smaller value of m reflects lower feedback overhead of the precoding matrices. The binary vector k-th UE.The CR and the number of quantization bits k-th UE outputs the restored complex-valued precoding matrix The decoder network at the In the offline stage, we compute the precoding matrices in advance by the aforementioned Algorithm 1 and generate the training, testing, and evaluation datasets. In the online stage, we can directly obtain the low dimensional feedback bitstreams with the well-trained neural network. The gradient of the quantization module is treated as a constant to make the network differentiable, and for this reason the encoder and the recovery network can be trained end-to-end. We jointly optimized the encoder and the decoder modules with back-propagation and gradients can pass through the quantization layer during back-propagation.We formulate the feedback of the precoding matrices into a reconstruction problem by The PCQNet is trained and evaluated on an Nvidia GeForce 3090 platform. We use the Adam  optimizei represents the index of the standard precoding matrix defined in the 3GPP protocol supporting limited scenarios  as much as possible. The Lloyd-Max quantization scheme stores the designed codebooks and partitions at the UEs and the BS, thus the BS only needs to transmit the indexes to specify the precoding matrices.In the offline stage, we first acquire the datasets generated by Algorithm 1. The empirical probability distribution function of the real and the imaginary parts of the precoding matrices is obtained for the design of the Lloyd-Max quantizer in ,28,29. TIn the online stage, the UEs can readily recover the precoding matrices utilizing the received indexes with the prestored Lloyd-Max quantization partitions and codebooks. Each element in the precoding matrices has to be quantized individually, thus the minimum number of feedback bits is We consider the optimal scheme labeled as w/o compression which directly feeds back the precoding matrices without compression.In this section, we evaluate the NMSE of the precoding matrices with different CRs and the influence of the feedback accuracy on the BLER performance. The comprehensive performance comparisons of the uplink MU-MIMO system with different number of UEs, different modulation orders, and different channel models are provided. The uplink MU-MIMO system parameters and the coefficients of the channel coding are listed in L channel realizations L data frames from the iMaster NAIE platform [L training data We firstly generate platform  for the k-th UE is randomly picked from the set of At the training and evaluation stage for the networks, the precoding matrix LloydMax scheme is depicted in The NMSE performance between the recovered and the original precoding matrices utilizing the The NMSE performance of the LloydMax scheme and the PCQNet is not correlated with SNRs. Only the generation of different test datasets is related to SNRs and the testing of NMSE performance is not necessarily related to the value of the SNRs. We provide a guideline for subsequent research of BLER performance via the visualization of NMSE performance in The codebook-based LloydMax scheme is sensitive to the number of bits, the SNRs, and the realistic channel distribution. The NMSE will significantly drop when the k-th UE. The number of the feedback bits for the 3GPP codebook scheme is We compare the PCQNet with the aforementioned baselines as depicted in The proposed PCQNet can dramatically decrease the feedback overhead and exhibit a slight BLER degradation with the further reduction of feedback bits  as well as the NAIE channel in practical scenarios provided by the iMaster NAIE platform .The LloydMax scheme has to design multiple codebooks which are optimized for specific channel conditions. The best NMSE performance can be achieved when the Compared with the w/o compression scheme which fully attains the precoding matrix, the CNN-based PCQNet can enhance the recovery quality of the precoding matrix with adaptive feedback overhead and obtain near optimal reconstruction performance. Similar performance can be seen over the NAIE channel in The PCQNet achieves the near-optimal BLER performance when the NMSE of the recovered precoding matrix is lower than \u221220 dB. The transmission tends to stop if the NMSE of the recovered precoding matrices is worse than the threshold of \u22125 dB. We also observe that, when the NMSE performance exceeds a certain threshold , the overall BLER performance is quite close to the ideal w/o compression scheme. From the results, we can see that it is a reasonable compromise to set the CR to 1/4 for the compression of precoding matrices.The provided numerical results show that our proposed PCQNet achieves a better trade-off between the feedback overhead and the BLER performance over the i.i.d. Rayleigh channel and the NAIE channel. This CNN-based compression scheme significantly enhances the BLER performance compared with the 3GPP codebook scheme and the LloydMax scheme under the same CRs.The proposed PCQNet has achieved considerable gains in BLER performance compared with the protocol codebook-based precoding scheme and the Lloyd-Max quantization scheme under the same CRs. The adaptability of trainable PCQNet architecture to different channel bandwidths is more competitive than the Lloyd-Max quantization scheme in bandwidth-limited scenarios. The PCQNet also provides better resilience to the mismatch between the trained SNRs and tested SNRs than the Lloyd-Max quantization scheme due to channel variations. Our experiments demonstrate that the application of the CNN-based PCQNet greatly improves the adaptability and the generality of the precoding matrix feedback in the uplink MU-MIMO systems. Importantly, it preserves only a slight degradation of BLER performance with high compression rate of the precoding matrix, making the compression architecture more attractive for the deployment of practical systems."}
{"text": "The main goal of this study is to evaluate the field performance of crumb-rubber-modified asphalt mixtures used as a surface layer on high-volume traffic roads. For this purpose, several road sections were constructed under different climate conditions and using control mixtures  and crumb-rubber-modified mixtures. After the construction of the different road sections, cores were taken at different periods of their service life (up to 63 months) and they were tested in the laboratory in order to assess the evolution of the density, stiffness and fatigue resistance of the layers. Based on the results obtained from tests, it can be concluded that under real severe traffic and climate conditions, asphalt mixtures manufactured with crumb-rubber-modified bitumen offer ageing and mechanical performance very similar to that offered by asphalt mixtures manufactured with traditional SBS-modified bitumen. Based on these considerations, this application can be an interesting solution to minimize environmental problems caused by end-of-life tires in landfills. End-of-life tires are one of the most widely produced types of solid waste around the world . They arIts application as a modifier in bituminous mixtures permits the recovery of this waste in huge quantities, helping to contribute to circular economy principles . In addition, many laboratory studies have demonstrated that the use of crumb rubber as a modifier of asphalt mixtures improves their resistance to fatigue cracking ,9 and toAfter decades of use, there are many experiences that have already proven the advantages of the application of crumb rubber from end-of-life tires as a bituminous mixture modifier ,22,23,24In order to determine in depth the real performance of crumb-rubber-modified asphalt mixtures, during the last few years, the road administration of the government of Andalusia (Spain) has applied them on the surface layers of some highway sections that experience high volumes of traffic and unfavorable climate conditions. To evaluate these materials, a study on the evolution of the mechanical performance of them during their service life in comparison to traditional SBS-modified material has been carried out in collaboration with the Laboratory of Construction Engineering of the University of Granada. For this purpose, cores directly extracted from the surface layer of the pavement at different dates were tested at the laboratory, determining the evolution of important parameters such as density, stiffness or fatigue cracking resistance. This paper summarizes the main results obtained in this research work so far.This paper is focused on the study of 3 sections of the high-traffic-capacity road network of Andalusia (Spain), on the A-316 highway (Jaen) and A-92 highway . The main characteristics of these highway sections are summarized in All these sections were constructed using a surface layer of 3 cm thickness and using different job mix formulas of BBTM 11B PMB 45/80-60 C . In allDuring the service life of the three highway sections studied, cores from the surface layers were extracted at different times . A totalThe superficial aspects of the highway sections studied during the last campaign are shown in Once the cylindrical cores were obtained from the road on the different dates, their apparent density (according to UNE-EN 12697-6  for specThe evolution of the stiffness of the layers as a function of the service life is shown in -The density of the surface layers studied was not affected by the service life (being constant over time and very similar to those reached after the pavement\u2019s construction), regardless of the type of asphalt binder used (SBS or crumb-rubber-modified).-The stiffness of the surface layers studied was significantly affected by the service life due to the effects of the environmental agents. The mixture BBTM 11B showed a rate of stiffness increment between 43 and 105 MPa per month, but we did not observe a clear dependence of this rate on the type of binder used or the climate conditions in the highway section studied. Thus, it can be concluded that surface asphalt mixtures manufactured with SBS or crumb-rubber-modified binders offer a similar stiffening process during their service life.-The results obtained in terms of long-term resistance (fatigue cracking) also demonstrated that the mixtures manufactured with SBS or crumb-rubber-modified binders offer similar performance. In both types of materials and in the three highway sections studied, it was observed that during the first 20\u201340 months of service life (depending on the volume of traffic supported), the surface asphalt mixtures increased in resistance to fatigue loading (due to the strain hardening phenomenon), and after this period, they became susceptible to fatigue damage .This paper summarizes the results obtained in a research study whose main objective was to carry out an in-depth analysis of the mechanical performance of crumb-rubber-modified bitumen under severe traffic and climate conditions in real road pavements. For this purpose, cores were extracted on different dates from the surface layers of three highway sections that were constructed using a crumb-rubber-modified bitumen (PMB 45/80-60 C), and they were compared with cores extracted on the same date and at the same location from surface layers constructed with SBS-modified bitumen (PMB 45/80-60). These cores were tested at the laboratory to determine their density (UNE-EN 12697-6), stiffness  and resistance to fatigue (UGR-FACT). From the results obtained in this study, the following conclusions can be drawn:The results obtained in the study presented show that, under real severe traffic and climate conditions, the asphalt mixtures manufactured with crumb-rubber-modified bitumen offer ageing and mechanical performance very similar to that offered by asphalt mixtures manufactured with traditional high-performance SBS-modified bitumen. As future research, it would be interesting to continue this study by adding aspects related to the serviceability of pavements and road safety, such as IRI or skid resistance, and applying a life cycle cost analysis to determine the materials\u2019 real efficiency."}
{"text": "The reception of a patient in the psychiatric ward is an important step that determines the proper course of care. The welcome is the first stage of the relationship, it is essential to take the measure of the importance of this moment.Assess psychiatric inpatients\u2019 knowledge of their rights and obligations.This was a descriptive and cross-sectional study based on a self-administered questionnaire containing about twenty questions (20), which assessed the knowledge of patients hospitalized in the HMPIT psychiatry department about their rights and obligations.Twenty-five (25) patients agreed to answer the questionnaire and two (2) patients refused. Sixty percent (60%) of the patients were unaware of their rights. Sixty-eight percent (68%) of the patients did not know their duties. Forty-eight percent (48%) of the patients did not know the rules and conditions of hospitalization in psychiatry.Patients hospitalized in the psychiatric ward have limited knowledge about their rights and duties and about the conditions and rules governing hospitalization. In addition to the poster on patients\u2019 rights and duties, a welcome leaflet will provide all the information on the rules of hospitalization."}
{"text": "Since the beginning of the COVID-19 pandemic a mental health deterioration has been detected in the general population and especially in people affected by pre-existing psychiatric conditions, and mental health care has moved towards online treatment. Literature studies have been reviewed to gather evidence regarding the impact of the COVID-19 pandemic on people affected by eating disorders (EDs) exploring changes in ED-specific and general psychopathology; mechanisms of vulnerability and resilience; change in treatment delivery service; patients\u2019 perception of online treatment and potential barriers and/or advantages of this method and its effectiveness. A wide variability characterized the response of people with EDs to the COVID-19 pandemic. A trend toward worsening of ED specific psychopathology with respect to the pre-pandemic period was observed as well as a deterioration in general psychiatric symptoms. Feelings of uncertainty and social isolation were the most common vulnerability mechanisms. Resilience factors such as heightened self-care and reduced social pressure also occurred. The treatment has largely switched to online delivering strategies which, despite considered the best alternative to the face-to-face approach, were suffering from some concerns about their quality. The exacerbation of specific and general psychopathology supports the hypothesis of an emotional and post-traumatic nature of EDs and outlines the importance of internalizing symptoms. In front of the great variability observed across ED patients during the pandemic, the identification of risk and resilience variables as well as of subjective factors affecting the perception of online treatment may inform clinicians and promote more targeted and individualized approaches.No significant relationships."}
{"text": "Bioscience Reports at the request of the authors following receipt of a notification from a reader alerting the Editorial Office to western blot bands that appear in both this paper and another paper by different authors (doi: 10.1186/s12935-019-0985-9). The authors wish to retract the article. The Editor-in-Chief and Editorial Board agree with the retraction.This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from"}
{"text": "Burden of disease analyses measure the healthy years of life lost due to living with and dying prematurely from disease and injury. It is now the global standard for comparable policy-relevant evidence on the impact of disease, injuries, and risks on a population. The Australian Burden of Disease Study (ABDS), undertaken by the Australian Institute of Health and Welfare, uses Australian-specific data and methods  to quantify disease burden for Australia. Despite the high quality of deaths registration data in Australia, in burden of disease analyses not all coded causes of death are considered appropriate or valid to estimate years of life lost (YLL). Therefore, these \u2018ill-defined deaths\u2019 are redistributed to one or more diseases on the ABDS disease list according to a more probable underlying cause of death. In the latest ABDS, almost 1 in 10 deaths in 2018 was an ill-defined death. Most of these were redistributed to other diseases using one of three methods developed for the Study:1) direct evidence on more plausible causes of death from data linkage studies or other sources2) redistribution algorithms based on the distribution of underlying causes of death where the ill-defined cause was recorded as an associated cause of death3) reassignment of deaths across a specified range of target diseases according to patterns of causes of death observed in the mortality data for the ABDS disease list.Expert advice was also received on the redistribution of deaths from septicaemia and deaths coded to ICD-10 code X59 Exposure to unspecified factor. Overall, 8.5% of the years of life lost for Australia in 2018 came from ill-defined deaths. These deaths generally followed age-specific all-cause mortality patterns. It is important to consider methods and target diseases when redistributing ill-defined deaths to appropriately quantify their contribution to disease-specific burden."}
{"text": "In this paper, a low-altitude wind speed estimation method based on the fuselage frustum conformal array system is proposed. Firstly, based on the signal model of the fuselage conformal array radar, the four-dimensional joint phase compensation of the echo data in the Doppler domain and three-dimensional space-frequency domain is performed by using the four-dimensional frequency domain compensation method. Secondly, the clutter covariance matrix is estimated by the compensated echo data, and a space-time Adaptive Processing (STAP) processor suitable for low-altitude windshear target is constructed to suppress clutter. Finally, the maximum Doppler value of each distance cell is extracted, and the wind velocity is estimated. Simulation results show that the proposed method can effectively suppress clutter and accurately estimate wind speed. Low-altitude windshear is an atmospheric phenomenon in which the airflow below 600 m in height hits the ground and spreads in all directions . Sudden Airborne weather radar is an important tool for pilots to detect weather phenomena ahead of the aircraft during flight missions, and pilots can avoid severe weather phenomena such as low-altitude windshear on time based on the display and alerts from the airborne weather radar to ensure the safety of the entire mission . With thWhen an airborne weather radar detects a low-altitude windshear target ahead, the widely distributed and strong ground clutter tends to drown out the low-altitude windshear signal, making it difficult to achieve wind speed estimation, so clutter suppression before wind speed estimation is especially important. In the forward-looking working state of airborne weather radar, the clutter distribution characteristics of the echo signal of each distance unit vary with the change of distance unit, especially in the near-ground distance unit performance is more dramatic, this phenomenon is called clutter range dependence. The inhomogeneity of clutter caused by range dependence makes the echo signal data samples of each distance unit no longer satisfy the independent identically distributed condition, which causes the deterioration in the performance of traditional clutter suppression methods and the degradation in target detection performance. At present, the compensation methods used for the clutter inhomogeneity problem are mainly Doppler compensation type methods, such as the DW method , the HODA method is proposed to estimate the wind speed of low-altitude windshear in the fuselage frustum conformal array system for the problem that the useful signal will be affected by strong ground clutter when the low-altitude windshear is detected by fuselage frustum conformal array weather radar. The method is based first on the essential reason for the difficulty of clutter suppression caused by the special array structure of the fuselage frustum conformal array, and then uses the four-dimensional frequency domain compensation method for joint phase compensation of the echo data of each distance unit in the Doppler domain and the three-dimensional space-frequency domain. Secondly, the compensated echo data samples are used to estimate the clutter covariance matrix and construct a Space-Time Adaptive Processing (STAP) processor for low-altitude windshear target to accumulate windshear signals while adaptively suppressing ground clutter. Finally, the maximum Doppler value of each distance unit is extracted to achieve the accurate estimation of wind field velocity. The simulation results show that the method can effectively achieve ground clutter suppression and accurate wind speed estimation.When the fuselage frustum conformal array detects the low-altitude windshear target, the echo mainly consists of three parts: ground clutter signal Assuming that the number of transmitted pulses in one coherent processing time of the radar is K, the space-time two-dimensional data received by the The ground clutter signal rd model  developeFirstly, the width of a single distance unit is determined based on the radar-related parameters of the airborne platform. Then, the horizontal azimuth is divided within the single distance unit, the ground clutter echo signal within the single distance unit is divided into multiple clutter patches, and the echo signal of each clutter patch is calculated. Finally, the echoes of all clutter patches on the single distance unit are summed to obtain the ground clutter echo signal Assuming that the ground clutter signal is undulation-free and unambiguous, the ground clutter signal Supposing that Suppose the radius of the bottom surface of the frustum is rived as :(4)p, it can be seen that the normalized space-frequency For the line array antenna, the geometric distribution of the array elements in space is one-dimensional. Assuming that the line array axis is in line with the positive direction of ion (13) :(15)Fd\u2212lFor the planar array antenna, the geometric distribution of its array elements in space is two-dimensional. Assuming that the length of the planar array is in line with the positive direction of the ion (13) :(16)Fd\u2212pAs for the fuselage frustum conformal array, the antenna array elements are geometrically distributed in space as three-dimensional space, so its clutter distribution characteristic needs to be described in four-dimensional space ion (13) :(17)Fd\u2212fFrom Equation (17), it can be seen that the range of values of The analysis of the clutter characteristics of the fuselage frustum conformal array shows that the clutter characteristics are determined by the four-dimensional frequency The four-dimensional frequency domain compensation method requires joint compensation in the four spaces of Doppler domain In the Doppler domain Assuming that the azimuth of the main beam is The normalized Doppler frequency To make the Then the compensation matrix In the space domain At this point, the normalized space domain frequency The normalized space domain frequency To make the center of the clutter spectrum of the Then the space domain compensation matrix In which In the space domain At this point, the normalized space domain frequency The normalized space domain frequency To make the Then, the space domain compensation matrix In which In the space domain At this point, the normalized space domain frequency The normalized space domain frequency To make the Then, the space domain compensation matrix In which From Equations (21), (25), (29), and (33), the compensation matrix essed as ,27:(34)\u03b2In which Suppose that the echo data of the After compensation, the inhomogeneity of the clutter in the echo data samples caused by the fuselage frustum conformal array structure is improved. The data of the The space-time adaptive processor technique is based on space-time coupling characteristics of the echo to perform clutter suppression and signal matching , and theIn which Taking the estimated By matching the filtering of target signals in different Doppler bands and solving the output signal power value of the optimal processor, the processor can effectively suppress ground clutter and accumulate windshear signals when the output power is maximum. Then, the Doppler frequency of the distance unit under detection is searched in one dimension, and the estimated Doppler frequency Finally, the echo data of all the distance units of the fuselage frustum conformal array are subjected to optimal space-time adaptive processing, and the wind field velocity is estimated, so that the variation of the low-altitude windshear wind speed can be derived for different distance units.Step 1: Compensate the echo data by four-dimensional frequency domain compensation method to remove the inhomogeneity of ground clutter caused by the structure of the fuselage frustum conformal array;Step 2: Estimate the clutter covariance matrix of the distance unit under detection from the echo data samples of the reference distance unit;Step 3: Construct the space-time adaptive processor, solve the optimal weight vector of the processor, complete clutter suppression and signal matching, estimate the center frequency of the low-altitude windshear signal within the present distance unit, then get the wind speed estimation result;Step 4: Update the distance unit under detection and deal with the echo data samples of all distance units within the radar operating range to get the final wind speed estimation result.The values of the main simulation parameters of the radar system are shown in As can be seen from After compensating the echo signal by the four-dimensional frequency domain compensation method proposed in this paper, the clutter range dependence of the near-ground distance unit has been suppressed in For the problem that the useful signal is affected by strong ground clutter when detecting low-altitude windshear, a method for estimating low-altitude windshear wind speed in the fuselage frustum conformal array system is proposed. The method introduces the fuselage frustum conformal array and analyzes the essential reasons for the difficulty of clutter suppression in the fuselage frustum conformal array. Then, it uses a four-dimensional frequency domain compensation method to combine the phase compensation of the echo data of each distance unit in the Doppler domain and the three-dimensional space-frequency domain. After that, it estimates the clutter covariance matrix from the compensated echo data samples and constructs a space-time adaptive processor applicable to the low-altitude windshear target. Finally, it extracts the maximum Doppler value of each distance unit after adaptively suppressing the ground clutter to achieve the accurate estimation of wind field velocity. The simulation results show that the method can effectively suppress the ground clutter and accurately estimate the wind speed in the fuselage frustum conformal array system."}
{"text": "There is no life without cells and there are no cells without membranes. On the other side, there would be no full knowledge of the mechanisms of the actions of a drug without a deeper understanding of its interaction with membranes. In this context, the second edition of the Special Issue on drug\u2013membrane interactions highlights the importance of the interactions of drugs with membranes to better understand a drug\u2019s mechanism of action at the molecular level . The traet al. evaluated the protective effect of two antioxidants, melatonin and indole-3-propionic acid (IPA), against oxidative damage to membrane lipids, induced by high concentrations of iron, in porcine skin. Both antioxidants were shown to be efficient in the reduction of lipid peroxidation. The authors concluded the two compounds are potential therapeutic agents to treat disorders associated with excessive iron accumulation in the skin [Rynkowska Menna and co-workers studied the interaction of dendritic cells (DCs) with the Blood\u2013brain barrier (BBB) in steady-state conditions. The authors observed that transmigrated DCs exhibit an activated phenotype and a stronger T cell-stimulatory capacity when compared to non-migrating DCs. The results obtained are of the utmost importance for the design of novel targeted therapies capable of inhibiting autoimmune inflammation of the central nervous system .in vitro and in vivo studies and, in some cases, molecular docking studies were performed. The findings reported allowed for the prediction of potential herb\u2013drug/drug\u2013drug interactions of garcinol for safe clinical use [The study conducted by Bolla and co-workers reports the inhibitory effect of garcinol formulations in the activity of cytochrome P450 isozymes and P-glycoprotein (P-gP). Both The work reported by Wang describes the effects of potassium ions on surface pressure isotherms, elastic modulus and the stability of DPPC/Cholesterol and DPPC/Cholesterol/Amphotericin B monolayers using Langmuir-Blodgett methodology . The resThe investigation of this enthusiastic topic has just started and a long path needs to be done to develop novel drugs with even more efficacy and safety for the global health benefit."}
{"text": "Public health and social measures (PHSM) are key to reducing the spread of infectious diseases like COVID-19, especially in the early stages of an outbreak. PHSM include non-pharmaceutical actions that individuals, communities, and governments take to reduce person-to-person contact and/or make them safer. PHSM reduce the pressure on the health care system to allow for the continuation of essential services and buy time for the development and dissemination of treatments and vaccines. While a combination of PHSM has proven to be effective in reducing transmission during the COVID-19 pandemic, the evidence on the relative effectiveness and broader health, social and economic impact of individual interventions is still scarce. However, PHSM packages such as lockdowns can have severe unintended consequences for individuals and societies including economic hardship, decreased mental health and wellbeing and exacerbated social and health inequity; therefore, precision in PHSM decisions and implementation is needed. This requires a strengthened evidence base as well as tools that support countries in making balanced decisions about PHSM with the best possible cost-benefit ratio. WHO works with multisectoral partners to achieve effective and context- specific PHSM implementation while maximizing the benefits of PHSM and keeping their health, social and economic burden to a minimum and justifiable. In the WHO Regional Office for Europe, PHSM are a key pillar in the COVID-19 response. The office provides, amongst others, a PHSM monitoring dashboard to track the severity of implementation across all 53 Member States as well as a calibration tool and related capacity building to guide countries in their implementation decisions as the pandemic situation evolves. The WHO has further launched a global initiative in 2021 to measure the effectiveness and impact of PHSM and improve precision in future PHSM decisions and policies. The initiative aims at providing robust data and research evidence on PHSM through a global conceptual model and research agenda, a central research monitoring system and harmonized data collection mechanisms during health emergencies. It further seeks to integrate PHSM into emergency preparedness and response assessments and yield a decision-making tool to facilitate evidence-informed and context-specific PHSM implementation. This workshop will provide an overview of WHO's activities in advancing PHSM research and implementation for better decision-making during future emergencies. Three presentations by the WHO Secretariat at the regional and global levels will focus on the strategic approach and the main deliverables of the respective initiatives so far. The presentation by the University of Munich will provide in-depth insights into the conceptual model on PHSM. The workshop will actively solicit feedback from participants on planned activities and results gathered to-date.\u2022\u2002The lack of evidence on PHSM effectiveness and impact hampered an evidence-driven implementation approach during the COVID-19 pandemic.\u2022\u2002WHO works to achieve effective and context- specific PHSM implementation to maximize the benefits of PHSM while keeping their health, social and economic burden to a minimum and justifiable."}
{"text": "Develop a digital solution for automated data ingestion and rapid update of the large-scale Human Services Dataset (HSDS) which brings together data from across government to take a powerful view of the service usage to improve outcomes of communities.The Centre for Health Record Linkage (CHeReL) hosts a secure, high-performing data linkage system, including a Master Linkage Key (MLK) of administrative health datasets, and generates linked data to inform policy decisions. Since 2018, CHeReL has also been annually linking over 70 frontline datasets to create a large-scale longitudinal linked dataset of over 2.5 billion records.Over the course of 2021, the CHeReL led a project to incrementally improve the currency of the HSDS in compressed timeframes. This provided opportunity to assess value and feasibility of more frequent updates to the dataset within the evaluation and investment context.The automated data Ingestion and validation led to a significant reduction in the data processing timeframes for the Accelerated linkage. We observed 80\\% reduction in Data ingestion and 75\\% reduction in data validation.The digital solution also allows asset owners to register and approve new data providers, monitor their data provision in real-time and report on data sourcing. This provides transparency to the Asset Owner and reduces the need for time-intensive and manual processes to jointly monitor data provision with the Data Linkage Centre.The digital solution also has the capability to support Data Providers automate their data feeds and provide on a regular basis through a secure non- touch process. This reduces on-going workload and ensures on-time provision.The process requires a systematic change in the upstream data source, and we requested participating agencies to send us data in an agreed format. The receipt of files in standard format is pivotal for reducing the overall timeframes of HSDS creation and leverage it for policy and investment purpose."}
{"text": "To the Editor,Mizushima et al. recently published remarkable explorative data on the causes, treatment patterns and outcomes of short bowel syndrome with intestinal failure (SBS-IF) in Japanese adult patients . The obsOverall, the characteristics of these Japanese adults with SBS-IF are very similar to what is observed elsewhere in the world but they notably differ from those of the small population included in a contemporary clinical trial (CT) evaluating the efficacy and safety of a glucagon-like-peptide-2 analog .Observed differences in patients\u2019 characteristics support the discussion raised by Mizushima et al. (1) CD is typically diagnosed in early adulthood; (2) CD surgeries are usually performed in late age and after a long disease duration; and (3) biologics reduce the rate of surgery, preserve the residual bowel and facilitate earlier weaning from PN.SBS is the most common cause of chronic intestinal failure (IF) in CD . Risk faDetailed data about the features of CD and administered treatments  would help to provide a better picture of SBS-IF in Japan.These differences between RW and CT data in Japanese adult patients with SBS also perfectly illustrate how real-world data and randomized control trial data can be mutually complementary and how the first can improve the conclusions of clinical trial by better tackling the variety and heterogeneity of populations."}
{"text": "In this presentation, Dr Orcutt, will outline the health system responses needed to respond effectively to the health needs of forcibly displaced populations - from initial health assessments to the longer term - and the role that research can play in ensuring evidence-informed policies and practice. She will present the main areas of the WHO's new global research agenda on migration and health and outline how translating evidence into implementation is essential to improve the health of migrants."}
{"text": "Hye-Young Kwon was not included a corresponding author in the published article by mistake. As stated, both Jung-Yeol Han and Hye-Young Kwon both equally contributed to the article as corresponding authors.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Introduction: Most studies on the efficacy of psychiatric treatments consider overall scale scores as outcome measures. A focus on individual symptoms would, however, result in a more precise assessment of treatment efficacy and has potential in improving our understanding of the working mechanisms of treatment. Such an approach may also help in improving the identification of patients who are -based on their pretreatment symptomatology- the most likely to benefit from a particular treatment. Objectives: To show the potential of network estimation techniques in a) unraveling the diverse symptom-specific responses to various depression treatments and b) improving the identification of patients who are the most likely to benefit from these treatments. Methods: First, we combined patient-level data of multiple trials considering various depression treatments, such as antidepressant medication and (internet-based) cognitive-behavioral therapy. Network estimation techniques were used to determine the complex patterns in which symptom-specific responses to treatment were related. Results: Individual clinical symptoms differed substantially in their responses to treatment and these symptom-specific responses were related in a complex manner. Patients suffering from symptoms that were directly affected by a particular treatment were -by definition- the most likely to benefit from that treatment. Conclusions: Network estimation techniques were able to unravel the diverse symptom-specific responses to treatment and could help in improving our understanding of the chain of events leading to a clinical response. Information from the networks could also help in improving the identification of patients who were the most likely to benefit from a particular treatment.No significant relationships."}
{"text": "A stratified random sample of participants was interviewed in each region of Pennsylvania during each phase of the implementation. In addition, comparison groups were interviewed from the third implementation region. This allowed us to draw causal inferences regarding the effect of the program on participant quality of life and psychological well-being. The sample was stratified to represent: people age 21-59 and those over age 60 who receive home and community based services (HCBS), plus people age 21 and older who are dually eligible for Medicaid and Medicare but do not use long-term services and supports. We found that engagement in preferred activities both inside and outside the home increased among people who used HCBS and those who did not. In addition, psychological well-being improved slightly while the prevalence of depressive symptoms declined. In general, the implementation of Community HealthChoices appears to have led to improvements in several measures of well-being."}
{"text": "There is little known about the effect of hospice post-disaster. This study utilized exposure to Hurricane Irma (2017) to evaluate the differential mortality effect of the disaster on Florida NH residents  compared to a control group of residents in the same NHs in 2015  by hospice status. We also examine the difference in hospice utilization rates post-storm for short- and long-stay (LS) residents. There was an increase in mortality for those in the cohort not on hospice within 90 days in 2017 compared to 2015 . For the rate of hospice enrollment post-storm among residents previously not on hospice, there was an increase among LS residents within 30 days  and 90 days . It is important to further examine the increase in the rate of hospice enrollment in LS NH residents post-storm."}
{"text": "Nitric Oxide in Plants comprises 12 manuscripts and aims to provide new insights into the molecular networks of NO through both original articles and detailed reviews related to seed and plant development, abiotic stress responses, signaling, and beneficial plant-microbial interactions.Nitric oxide (NO) is a multifunctional gaseous signaling molecule implicated in both physiological and pathological functions in plant systems. Since the first publication accounting for the presence of NO in plants in 1979, numerous milestone discoveries have revealed the complexity of its metabolic and signaling networks. This Research Topic on Ol\u00e1h et al. in an original article where the interplay between NO and strigolactones (SLs) in stress-free Arabidopsis plants is studied. Authors correlate the deficiency in SL synthesis or signaling with decreased S-nitrosoglutathione (GSNO) reductase (GSNOR) protein abundance and activity and conclude underlining the need for functional GSNOR to control NO/S-nitrosothiol levels during SL-induced primary root elongation. However, the authors specify that both SL and karrikin phytohormone signaling could have overlapping roles in their experimental design. Another big challenge for plant biotechnology is the improvement of crop productivity. It is well-established the positive correlation between the supply of nitrogen (N) fertilizers and the seed yield. In this context, the original article of Nejamkin et al. investigates the link between N availability and NO in the promotion of growth and seed production in transgenic tobacco plants transformed with the Ostreococcus tauri NOS gene (OtNOS). They show a severe attenuation in the OtNOS-promoted stimulation of growth and production in transgenic plants under conditions of nitrogen scarcity and emphasize the beneficial effects of the application of nitrate  gene in fresh fruits to demonstrate that NR-derived NO negatively regulated fruit coloration/ripening by suppressing anthocyanin de novo biosynthesis, as well as by redirecting the flavonoid biosynthetic pathway to proanthocyanidins production, a colorless taste factor. They also found the antagonistic effects of NO and abscisic acid (ABA) in the regulation of the coloration of Lycium fruits.In the scope of plant development, the role of NO as a root growth regulator is investigated by Signorelli et al. reviews the current knowledge about the sources and fundamental roles of NO during the different stages of the interaction and discuss the connections between the metabolism of NO and cytokinins, auxin, and ABA signaling pathways. They also report dose- and time-dependent effects of NO on bacterial nitrogenase expression and activity in mature nodules and the protective role of leghemoglobins as reactive oxygen species (ROS)/ reactive nitrogen species (RNS)-scavengers which in turn could inactivate nitrogenase. Following the same thematic, the original article of Berger et al. investigates the contribution of NR, as the main source of NO in plants, for the functioning of the symbiosis. In this paper, a dual role in nodule functioning is attributed to NR: generating NO as a signal for gene regulation and metabolic adaptation, and contributing to the energy supply under the hypoxic conditions prevailing inside the nodule.Two manuscripts go in-depth in the study of the role of NO in the nitrogen fixation by the symbiotic interaction between legume and rhizobium partners. Wang et al. analyze the crosstalk between NO and the inhibitory effects of ABA in releasing potato seed dormancy. Researchers probe in their original article the ABA-dependent decrease of the NO content and the NOS-like and NR activities in potato during sprouting. On the other hand, the promotion by NO of ABA catabolism and the inhibition of ABA biosynthesis ultimately induced dormancy release and tuber sprouting. In the same line, Ciacka et al. summarize in their mini-review the current knowledge on NO and other RNS contribution in the modulation of crucial events related to the preservation of seed vigor and/or regulation of seed longevity during aging. Authors highlight the interest of ROS-RNS cross-talk as NO counteracts ROS generation and stimulates the antioxidant system. Additionally, the authors indicate a concentration- and time-dependent effect of NO on ethylene, polyamines and ABA biosynthesis as well as the implication of the protein modification by S-nitrosylation in the regulation of the deterioration processes in seeds. Another kind of NO-derived modification, consistent with the nitration of unsaturated fatty acids, has been highlighted in the last few years in plant systems. This interaction results in the formation of nitro-fatty acids (NO2-FAs). In this regard, the original article of Mata-P\u00e9rez et al. reports the ability of nitro-linolenic acid (NO2-Ln) to move from roots to leaves in Arabidopsis plants. Moreover, given the potential of NO2-Ln to release NO at physiological pH and temperature, it can modulate the in vitro and in vivo levels of GSNO, the major mobile biological reservoir of NO bioactivity. The manuscript provided by Nabi et al. analyzes the interaction of NO with biological molecules too. In particular, they contribute to this Topic with an original sequencing study aiming at the functional characterization of NO-responsive domains of unknown function (DUF)-containing genes in Arabidopsis leaves. They identified 231 upregulated and 206 down-regulated DUF genes. The study focuses on AtDUF569 given its significant increase in expression and interesting interactions with other proteins. This gene negatively regulates biotic stress responses and differentially regulates plant shoot and root growth under nitro-oxidative stress conditions.Seed germination is another relevant issue for biologists and agriculture and the critical role of NO in breaking dormancy has been extensively demonstrated. In this Topic, Rather et al. highlights in their review the major aspects of copper (Cu)-induced toxicity in plants and summarize two possible strategies for NO to mitigate damages: the upregulation of the enzymatic and non-enzymatic antioxidant systems or defense genes, and the NO-participation in the root exclusion and/or activation of metal-chelating ligands such as metallothioneins and phytochelatins. In the same scope of environmental injuries, Pissolato et al. evidenced in their original article an interesting strategy for alleviating the negative effects of water deficit on sugarcane plants. These researchers demonstrate that the increase in the NO3 supply enhanced NO synthesis through NR which improves sugarcane performance under drought. Another environmental disaster is global warming and ozone layer depletion. Among others, nitrous oxide (N2O) is a potent greenhouse gas. The review of Timilsina et al. describes the mitochondrial reduction of the NR-derived NO to N2O under low oxygen conditions and proposes this route as a way to protect the mitochondrial and cellular integrity from the toxicity of NO accumulation under hypoxia and anoxia.In the context of the implication of NO in the tolerance against abiotic stress situations, In summary, the variety of the work reported here  reinforcAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Dyskeratosis congenita. Autops Case Rep[Internet]. 2020 Jul-Sep;10(3):e2020203. The reason for retracting this image is that, although the authors obtained authorizationfrom the deceased\u2019s next-of-kin to perform the autopsy and use the data for publication,this specific picture should not have been included.This issue was brought to the attention of the journal's Editor-in-chief by the paper'scorresponding author. After exchanging correspondence with the authors and theirinstitution, the Editor-in-chief obtained a formal letter from the Pathology department atSUNY Upstate Medical University requesting the retraction. The letter states that the fourauthors of the paper are in agreement with this decision and also that this issue wasbrought to the attention of the Ethics Committee at the SUNY Upstate Medical University whosupports the image retraction.The Editorial Board and the authors would like to express their most sincere apologies tothe family members for this unintentional oversight by the authors.Prof. Dr. Fernando Peixoto Ferraz de CamposEditor-in-chief"}
{"text": "Drama therapy is a widely acknowledged way to explore life-stories in late life. This presentation will describe a new model for creative interventions, based on the results of four studies that provide multiple perspectives on the integration of life-review and drama therapy for community dwelling older adults. The results of two quantitative studies  suggest that the drama therapy interventions have robust therapeutic potential to enhance mental health while aging. The findings of two qualitative studies with therapists (n=8), participants  and staff (n=13) provide a better understanding of the process, and support the mechanisms that lead to positive effects on mental health. Combining the results yielded a multidimensional model which points to three potential transformative routes: the evolution of the life-story, the evolution of improvised dramatic expression, and the expansion of social engagement."}
{"text": "One of the consequences of long-term exposure to air pollutants is increased mortality and deterioration of life parameters, especially among people diagnosed with cardiovascular diseases (CVD) or impaired respiratory system. Aqueous soluble inorganic components of airborne particulate matter containing redox-active transition metal ions affect the stability of S-nitrosothiols and disrupt the balance in the homeostasis of nitric oxide. Blood plasma\u2019s protective ability against the decomposition of S-nitrosoglutathione (GSNO) under the influence of aqueous PM extract among patients with exacerbation of heart failure and coronary artery disease was studied and compared with a group of healthy volunteers. In the environment of CVD patients\u2019 plasma, NO release from GSNO was facilitated compared to the plasma of healthy controls, and the addition of ascorbic acid boosted this process. Model studies with albumin revealed that the amount of free thiol groups is one of the crucial factors in GSNO decomposition. The correlation between the concentration of NO released and -SH level in blood plasma supports this conclusion. Complementary studies on gamma-glutamyltranspeptidase activity and ICP-MS multielement analysis of CVD patients\u2019 plasma samples in comparison to a healthy control group provide broader insights into the mechanism of cardiovascular risk development induced by air pollution. In addition, it has been proven that air pollution not only initiates the emergence of cardiovascular diseases but also intensifies the course of existing diseases , two-sided. Statistical comparisons between groups were performed by student Numerous epidemiological studies emphasize that exposure to air pollution increases the risk of cardiovascular events. At the same time, the deciphering of the precise mechanisms involved in CVD pathophysiology is still needful. The results of the preliminary case-control studies presented herein demonstrate a novel approach in the investigation of the interplay of aqueous PM extract and CVD progression and are briefly summarized in"}
{"text": "For this project, we are designing and testing the feasibility of employing components of a Faith-based Home Activity Toolbox (Faith-HAT). The goal of this NIH stage 1 intervention development project is to go beyond the four walls of the church to find ways to meet the spiritual needs of persons living with moderate and severe dementia \u201cwhere they are\u201d to help them remain religiously and spiritually engaged. This mixed-methods project is designed in 2 phases: (a) developing a prototype Faith-HAT and (b) testing the feasibility and exploring preliminary effectiveness. To successfully conduct this project, we have included a community advisory board of church leaders, caregivers, and persons living with dementia as members of the research design team to advise on the design and implementation of the Faith-HAT. Brainstorming workshops with the board are used to ensure the research is meeting the needs of the African American families affected by dementia."}
{"text": "We present a case of a 53-year-old female patient with chronic anemia, with no other significant medical history and on no regular medications. The patient was brought to the accident and emergency department following found on the floor of her home after having tripped over a mat and henceforth being unable to mobilize and complaining of pain in her bilateral hip and her right leg. X-rays confirmed bilateral neck of femur fractures and fractures of the distal end of the tibia and fibula. The bones were extremely gracile and osteoporotic. Investigations demonstrated raised parathyroid hormone levels  15-72), with low vitamin D  and adjusted calcium  levels. We have eliminated the diagnosis of myeloma. Calcium and vitamin D were replaced prior to the insertion of bilateral femoral nails."}
{"text": "The purpose of this collaborative study between researchers in Japan and the U.S. was to understand the retirement experience and potential changes in social interactions  among older adults living independently in the community. Specifically, we were interested in individuals\u2019 expectations about retirement and the types of social interactions experienced prior to and post-retirement, situated within the context of the COVID-19 pandemic. Both research teams conducted in-depth one-on-one interviews with community-residing retired older adults in early 2021. In the findings we explore similarities and differences between the retirement experiences of Japanese and American older adults, including methodological differences that transpired; specifically, we evaluate the meaning and experience of the COVID-19 pandemic in each of these cultural contexts and how retired older adults experienced its impact in their social interactions."}
{"text": "Assisted living is generally understood to offer a greater degree of privacy and independence than a nursing home; most residents pay privately, with some receiving support from state subsidies and Medicaid; regulation and oversight are the purview of state agencies. Within these broad parameters, however, one assisted living community may look quite different from another across the country, or down the street, in its resident population and the regulations that govern its operating license. The purpose of this symposium is to explore that variation. The papers leverage an in-depth review of changes in assisted-living regulation from 2007 to 2019 and a methodology to identify Medicare beneficiaries in assisted living using ZIP codes. To set the stage, the first paper examines variation across assisted living licenses to identify six regulatory types and compare their populations\u2019 characteristics and health-care use. The second paper analyzes trends over time in the clinical acuity of assisted living residents associated with changes in nursing home populations. The third paper investigates racial disparities in assisted living associated with memory-care designations and proportions of Medicaid recipients. The fourth investigates how regulation of hospice providers in assisted living affect end-of-life care and place of death. The final paper describes requirements related to care for the residents with mental illness in seven states. The symposium concludes with an expert in long-term care disparities and quality discussing the implications for policymakers, providers, and the population needing long-term care in assisted living."}
{"text": "Assistive robots support persons with disabilities to improve their quality of life and independence. These robots make the life of a physically weak person more comfortable and useful to society. They sense, process sensory information, and execute actions that are helpful to the disabled person. Similarly, these robots carry out rehabilitation by understanding and augmenting the rehabilitation process through a robotic system. These robots are expected to assist different sensorimotor functions, therapeutic training, and assessment of the sensorimotor performance of the patients.Assistive and rehabilitation robotic technologies have developed rapidly expanding the horizon of the field of robotics. These technologies are vital in the society in which around one billion among the growing global population experience some form of physical disability impacting everyday life. Assistive and rehabilitation robotic research, especially exoskeleton robotic research integrates advanced mechatronics and intelligent sensing to restore weak sensorimotor functions. Controlling these robots according to the requirement is one of the challenging tasks. Electromyography (EMG) signals have extensively been used to control assistive robots such as exoskeleton robots so that the wearer is free of actuating any additional device to control the robot. Additionally, many studies have been carried out recently to investigate the possibility of using Electroencephalography (EEG) signals to control robotic devices.This Research Topic is aimed at creating a multidisciplinary forum of discussion on the recent advances in controlling assistive and rehabilitation robots presenting the diversity of the current approaches. It was expected to include Research Topics related to developments of controllers for upper limb/lower limb robotic exoskeletons, biomechanical investigations of robotic exoskeletons and other assistive robots, novel sensors for exoskeleton robots to generate human-like motions, EMG/EEG signals-based exoskeleton robot control, mathematical and physical algorithms for control of exoskeleton robots, assessment and benchmarking of exoskeleton robots' functionality, and clinical studies of assistive robot control. The Research Topic received overwhelming attention from the relevant researchers. Eleven articles have been selected to be published on this Research Topic after carrying out a rigorous peer-review process. Out of 11 articles, seven articles are based on the use of EMG signals for the control of assistive and rehabilitation robots. They areToward Hand Pattern Recognition in Assistive and Rehabilitation Robotics Using EMG and Kinematics of Zhou et al.Multi-Joint Angles Estimation of Forearm Motion Using a Regression Model of Qin et al.A Multi-Information Fusion Method for Gait Phase Classification in Lower Limb Rehabilitation Exoskeleton of Zhang et al.Face-Computer Interface (FCI): Intent Recognition Based on Facial Electromyography (fEMG) and Online Human-Computer Interface with Audiovisual Feedback of Zhu et al.Improved Motion Classification with an Integrated Multimodal Exoskeleton Interface of Langlois et al.Robust Torque Predictions from Electromyography Across Multiple Levels of Active Exoskeleton Assistance Despite Non-linear Reorganization of Locomotor Output of George et al.Control of Newly-Designed Wearable Robotic Hand Exoskeleton Based on Surface Electromyographic Signals of Li et al.Another three articles are based on the use of EEG signals.Engagement Enhancement Based on Human-in-the-Loop Optimization for Neural Rehabilitation of Wang et al.Multi-Feature Input Deep Forest for EEG-Based Emotion Recognition of Fang et al.The Differences Between Motor Attempt and Motor Imagery in Brain-Computer Interface Accuracy and Event-Related Desynchronization of Patients with Hemiplegia of Chen et al.Evaluating Convolutional Neural Networks as a Method of EEG\u2013EMG Fusion\u201d of Tryon and Trejos presented the use of EMG and EEG signals with a hybrid approach to control the assistive and rehabilitation robots.The article titled \u201cOut of seven articles discussed on the EMG signals-based control of assistive and rehabilitation robots, in three articles EMG signals have been used for the control of upper-limb rehabilitation robots. Another two of the articles explained the uses of EMG signals for lower-limb exoskeleton robots and the rest of the articles described the classification of EMG signals to use for rehabilitation purposes.The physiological and neurological differences among individuals can cause divergent responses to the same task, and the responses can further change considerably during training; both of these factors make engagement enhancement a challenge. This challenge can be overcome by training task optimization based on subjects' responses. In one article an engagement enhancement method based on human-in-the-loop optimization is proposed and the performance of the proposed method is demonstrated by the validation and comparison experiments. The results show that both subjects' surface EMG (sEMG) -based motor engagement and electroencephalography based neural engagement can be improved significantly and maintained at a high level.Another article proposes a feature fusion and decision fusion method that combines EMG features and kinematic features for hand pattern recognition toward application in upper limb assistive and rehabilitation robotics. Ten normal subjects and five post-stroke patients participating in the experiments were tested with eight hand patterns of daily activities while EMG and kinematics were recorded simultaneously.A prosthetic hand with high accuracy and robustness are necessary to improve the life quality of forearm amputees. The application of sEMG signals to control a prosthetic hand is challenging. The authors of one of the articles have proposed a time-domain Convolutional Neural Network (CNN) model for the regression prediction of joint angles in three degrees of freedom (DoFs) and 5-fold cross-validation was used to evaluate the correlation coefficient. The 3DOFs includes two wrist joint motion and one finger joint motion. In this study, CNN models were developed using combined EEG\u2013EMG inputs to determine if they have potential as a method of EEG\u2013EMG fusion that automatically extracts relevant information from both signals simultaneously. EEG and EMG signals were recorded during elbow flexion-extension and used to develop CNN models based on time-frequency and time-domain image inputs.It is very important to have a natural, stable, and comfortable human-computer interface for controlling rehabilitation assistance robots to solve problems of patients who have lost limb control ability, such as upper limb amputation and high paraplegia. One article presents a complete limbs-free face-computer interface framework based on facial electromyography including offline analysis and online control of mechanical equipment.One of the studies covered in this Research Topic explored the accuracy of the Brain-Computer-Interface (BCI) and event-related desynchronization between the two tasks. The articles identified the promise and the challenges faced by the field of assistive and rehabilitation robotic technologies and identified the critical need for additional prospective, in the design and control of relevant robots. Another article demonstrated a new wearable robotic hand exoskeleton with multi joints, higher degrees of freedom, and a larger range of motion. The exoskeleton hand comprises six linear actuators and can realize both independent movements of each digit and coordinative movement involving multiple fingers for grasp and pinch. The kinematic parameters of the hand exoskeleton were analyzed by using a motion capture system.EMG/EEG Signals-Based Control of Assistive and Rehabilitation Robots. All articles underlined both the promise and the challenges faced by the field of assistive and rehabilitation robots. The articles further recognized the need for additional perspective, in the control of these robotic devices. In summary, all the articles presented in the Research Topic have set a new trend in EMG/EEG Signals-Based Control of Assistive and Rehabilitation Robots.This Research Topic provides a snapshot of the current status of research on the All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "This Supplement offers four articles addressing current challenges in the management of serious bacterial infections. In the opening article, Mark Wilcox and Matthew Dryden provide an overview of the epidemiology of healthcare-acquired bacterial infections in acute and long-term care facilities. Particular focus is given to assessing the healthcare burden of complicated skin and soft tissue infections (SSTIs) including surgical site infections. The epidemiology and general management of SSTIs is discussed and sets the scene for Christian Eckmann and Paul Tulkens, who review treatment options for SSTIs including a detailed assessment of delafloxacin and the long-acting lipoglycopeptide agents, dalbavancin and oritavancin. Valuable insights are provided into the consequences of under- and over-treatment, economic considerations, and the goal of combining effective treatment with optimal antimicrobial stewardship.The remainder of this Supplement offers a timely review of treatment strategies for multidrug-resistant Gram-negative bacteria. Matteo Bassetti and Javier Garau assess the burden of such infections and outline treatment options for a range of infection types. They discuss in detail the efficacy of old and new antimicrobials and offer a glimpse into the antibiotic pipeline to assess the potential of future treatments. The importance of local epidemiology and rapid diagnostics is also considered. Emilio Bouza continues this theme and focuses on carbapenems combined with \u03b2-lactamase inhibitors. An in-depth assessment of meropenem/vaborbactam is provided that covers pre-clinical and clinical trials as well as \u2018real world\u2019 outcomes for clinically challenging cases and/or extensively drug-resistant bacteria.The Supplement provides a valuable overview of the increasingly complex antibiotic-resistant bacteria in circulation and therapeutic options for the common infections they cause."}
{"text": "This paper presents findings from a University and Community-based Agency collaboration to design and implement a preliminary evaluation of the Elder Abuse Multidisciplinary Team (E-MDT) Intervention. This intervention brings professionals from a variety of fields to investigate and respond to elder abuse. Data from 22 Interviews with staff along with anonymous survey data from E-MDT team members/staff (n=312) sought to establish team successes, challenges in implementation, and ongoing functioning. Themes that emerged in creating successful teams include: Establishing Buy-In and Trust of the team members, The Benefit of sharing experience and practical knowledge with other program sites; and Recognizing the Differences related to Onboarding and Sustaining New programs versus Sustaining Existing Programs. Themes related to responding during COVID revealed challenges such as Adapting to Technology and Inconsistent Access to the Internet. It was noted that remote meetings were easier to attend than face-to-face meetings. Data from the survey found the vast majority of respondents view the E-MDTs as having a positive impact on Clients (93%); while 93% of respondents indicated a positive impact on their Approach to Practice and the service area of their agency. Approximately 80% of the respondents indicated their multidisciplinary teams were Effective. Responses to 3-Open Ended questions included in the survey echoed similar themes from the interviews, as well as comments about their Professional Development and the complexity of responding to elder abuse. The paper will close with a discussion of the strategies used to facilitate the collaboration and complete the evaluation during the COVID-19 pandemic."}
{"text": "Scientific Reports 10.1038/s41598-021-92543-y, published online 23 June 2021Correction to: The original version of this Article contained an error in the Abstract and in the Results section where the beta symbol did not display correctly.This error has now been corrected in the PDF version of the Article; the HTML version was correct from the time of publication."}
{"text": "As widely used instruments to identify risk factors and lay out preliminary plans of how to improve the built environment, home assessment tools play an important role in the process of modifying homes for older adults. Developed by a variety of disciplines and tailored to meet various needs, home assessment tools focus on features in homes and how they meet or hinder an older person\u2019s ability to accomplish tasks \u2014 in other words, person-environment fit. Based on a comprehensive review of ten evidence-based home assessment tools identified by researchers at the USC Leonard Davis School of Gerontology and the National Council on Aging, we found that a common assessment strategy is the use of multidisciplinary teams (MDTs) in developing and testing the assessment tools to ensure the reliability vs validity of different home modification programs. To understand the nature of MDT practice and derive a set of generalizable protocols for developing person-centered home assessment tools, we conducted a systematic analysis of the ten evidence-based home assessment tools and 41 peer-reviewed journal papers about how the tools were developed, used, and modified. In addition, we applied the RE-AIM framework  to examine the use of MDTs in developing the tools and carrying out the programs. Based on our analysis, we propose a set of preliminary protocols for developing home assessment tools and a logic model for conducting person-centered home modification programs."}
{"text": "The current study examines the unique impacts of the ongoing COVID-19 Pandemic on the well-being of middle aged to older women from the 2020 Health and Retirement Study (n = 1252) and how their reports of social contact during the pandemic compare to age-matched women from 2018 (n = 2063). Although up to a third of women across age categories reported changes in social contact due to the pandemic, their rates of communication with friends and family were not significantly different from their counterparts in 2018. Results find expected age patterns in satisfaction with life during the pandemic), where the young-old report the highest levels. However, the association of life satisfaction with the extent to which women reported more loneliness during the pandemic was only significant among the young old and oldest old. Age differences in pandemic-specific experiences in relation to well-being are discussed within a life course developmental framework."}
{"text": "The University of Botswana Public Health Medicine Unit has made significant contributions to the national preparedness and response to COVID-19. The program alumni and Public Health Medicine residents have and continue to provide key technical support to the Ministry of Health and Wellness across the major pillars of COVID-19. This includes key roles in national and subnational coordination and planning, surveillance, case investigations and rapid response teams, points of entry, travel and transportation, infection prevention and control and case management. The unit is thus supporting the country in achieving the World Health Organization (WHO) primary objective of limiting human-to-human transmission, optimal care of the affected and maintaining essential services during the outbreak. The Public Health Medicine Unit has played a key role in capacity building including early rapid COVID-19 training of healthcare workers across the country. Furthermore faculty members and residents are involved in several COVID-19 research projects and collaborations.COVID-19 was declared a Public Health Emergency of International Concern (PHEIC) in January 2020 and a pandemic in March 2020. Botswana reported its first case on 30 A national task force was set up to coordinate the national response. The Ministry of Health and Wellness (MOHW) initially conducted risk assessments of all the district health teams which then informed the response . The couThe Public Health Medicine (PHM) unit is part of the department of Family Medicine and Public Health in the Faculty of Medicine (FOM) at the University of Botswana (UB) with a mandate to train public health physicians through a 4-year residency programme, Master of Medicine (MMed) Public Health Medicine. Its involvement in the national preparedness and response began even before the first cases of COVID-19 were reported in Botswana and it continues to play a key role as the epidemic evolves. WHO under the International Health Regulations requests partners to support state members to achieve the objectives of a coordinated response . The UniTechnical Support for Ministry of Health and Wellness (MOHW): from the onset of the epidemic, the PHM suspended formal didactic teaching and availed its trainees to the national response at national and sub-national levels. Alumni and residents of the programme all played important roles in the overall national coordination including among others, i) analysis of data and preparation of daily situational reports ii) residents played key roles within the national contact tracing, case management teams and testing and management of suspects at points of entry; iii) assessing and repurposing educational facilities for COVID-19 isolation and iv) substantial ongoing support to Greater Gaborone zone through case investigation, case management and testing. Residents' led case investigation teams played key roles in case mapping and identification of chains of transmission. More recently, the unit has had residents being part of the teams which assessed the capacity of the country's points of entry to handle a Public Health Emergency of International Concern.Capacity building: the PHM has worked with MOHW to train healthcare workers in the districts. The unit has excellent relationships with the two mining hospitals in Botswana namely Jwaneng Mine Hospital and Orapa Mine Hospital. The hospitals leveraged on this relationship and requested the unit to train staff in the mining districts. Faculty members and residents conducted training on key COVID-19 topics including surveillance, infection prevention and control, case management and laboratory preparedness and response. Residents and staff also joined the Ministry of Health and Wellness teams in training other districts across the country. Much of this training was done even before the country reported its first case. Additionally, the unit was heavily involved in the weekly national virtual COVID-19 CME sessions. These sessions were organized by MOHW and were supported by local partners. The target audience was doctors and other healthcare workers both in the public and private sector. Public Health Medicine residents made key presentations including infection prevention and control and contact tracing. Furthermore, public health medicine residents supported greater Gaborone in training staff at local private hospitals on COVID-19 and technical support during outbreak investigation at one of the hospitals.Research: the PHM unit is amongst the leaders in COVID-19 research in Botswana. Members are working with MOHW colleagues on the first few cases and contacts (FFX) investigation aimed at describing the clinical presentation and course of COVID-19, and estimating secondary infection and case fatality rates in Botswana. Faculty members and residents are also leading studies investigating the mental health impact of COVID-19 on healthcare workers. The aim of these studies is to determine the magnitude of stress, anxiety and depression among health care workers in the country, and also to shed light upon the protective and risk factors. The findings are expected to help guide interventions that could enable mitigation of mental health challenges during the COVID-19 pandemic in Botswana. Moreover, current literature on COVID-19 and health care workers mental health issues will be augmented. Public Health Medicine Residents are leading COVID-19 outbreak investigations in hospitals including infection prevention and control audits. This includes an outbreak investigation in the largest referral hospital in the country's public health system. This investigation included review of the hospital case reports and an assessment and audit of the hospital structures and processes with the aim of describing the cases in terms of person, place and time, identifying possible sources of infection and factors associated with continued transmission. Furthermore, the weekly journal clubs hosted in the Unit have strongly focused on COVID-19 research in recent months facilitating the sharing of up-to-date COVID-19 information. Undergraduate medical students have been participating in these journal clubs which has allowed faculty members and residents to directly share expertise with them.Safe campus and safe workplaces: when initial restrictions of extreme social distancing were lifted and people returned to work, the PHM unit developed guidelines for safe return to work including guidance on development of workplace preparedness and response plans. These would facilitate implementation of infection and control measures, allow prompt isolation of suspects and enforce effective workplace controls. The unit also led the development of the university\u00b4s COVID-19 preparedness procedures and protocols and provided technical advice to the faculty on preventing workplace transmission of COVID-19.The University of Botswana Public Health Medicine Unit under the Department of Family Medicine and Public Health in the Faculty of Medicine has made significant contributions to the Botswana national COVID-19 preparedness and response. Through active involvement in all the pillars described above, the unit has significantly contributed to minimizing importation of cases, prevention of human-to-human transmission and maintaining essential services."}
{"text": "In the originally published version of this manuscript, there was an error in the title. The title should read: ``Variation in financial protection and its association with health expenditure indicators: an analysis of low- and middle-income countries'', instead of: ``Variation in financial protection and it association with health expenditure indicators: an analysis of low- and middle-income countries''. This error has been corrected online and in print."}
{"text": "Irregular sleep-wake patterns are common in persons living with dementia (PLWD), pose a great burden to caregivers, and are the principal causes of distress and institutionalization of PLWD. A growing body of research supports the importance of activity-based interventions to reduce the frequency and intensity of sleep wake disruption, reduce neuropsychiatric symptoms, and improve quality of life. To date, there are no studies linking sleep disruption and well-being with the nature and timing of activity. This session focuses on lessons learned from the Healthy Patterns Study - a randomized trial of a home-based activity intervention in 200 dyads of PLWD and their caregivers (NCT03682185). Session 1 focuses on the main findings from the clinical trial. Session 2 focuses on the cultural adaptation of the timed activity protocol to improve quality of life (QOL), improve sleep and reduce neuropsychiatric symptoms in older Latinos Session 3 describes the community outreach efforts used over a one-year period to recruit a diverse sample of PLWD and their caregivers for the Healthy Patterns trial. Session 4 examine the relationship between caregiver mastery and neuropsychiatric symptoms in PLWD. Together these findings highlight the complex role of sleep and wake activity in promoting well-being in persons with dementia."}
{"text": "The Editor-in-Chief has retracted this article because after publication concerns were raised regarding multiple errors in the description of the methods and reagents, most notably primer sequences in Table 1. The authors did not provide the methods and the references sequences used to design the primers upon request. Furthermore, errors in the language throughout the text are potentially misleading to the reader. The Editor-in-Chief therefore no longer has confidence in the reliability of the work presented. None of the authors have responded to any correspondence from the editor about this retraction.supplementary informationFormer article version"}
{"text": "In contrast, the AVN increased between-side differences in the sagittal IA (p = 0.01), and sagittal and frontal RCIA during DLS (p < 0.04), leading to bilaterally asymmetrical balance control. Secondary AVN significantly reduced IA and RCIA in the sagittal plane (p < 0.05), and reduced range of RCIA in the frontal plane during initial DLS (p < 0.05). The trend reversed during terminal DLS, indicating a conservative COM-COP control in the sagittal plane and a compromised control in the frontal plane during body weight acceptance, with a compromised COM-COP control in the frontal plane during weight release. The current results suggest that increased between-side differences in the sagittal IA, and sagittal and frontal RCIA during DLS are a sign of AVN secondary to treated unilateral DDH in female juveniles, and should be monitored regularly for early identification of the disease.Avascular necrosis of the hip (AVN) is one of the most severe complications of surgical reduction when treating developmental dysplasia of the hip (DDH). The current study identified the differences in the balance control during walking in terms of the inclination angle (IA) of the center of pressure (COP) to the center of mass (COM), and the rate of change of IA (RCIA) between female juveniles with and without secondary AVN at the hip who were treated for unilateral DDH during toddlerhood as compared to their healthy peers. When compared to female healthy controls, the non-AVN group showed bilaterally similar compromised balance control with significantly decreased IA ( Developmental dysplasia of the hip (DDH) is an abnormal development of the femoral head resulting in subluxation or dislocation of the hip in about 0.1\u20131% of the newborn population . Early tPrevious gait studies on people with treated DDH have focused mainly on the residual gait deviations . AdolescThe body\u2019s dynamic balance control during gait can be evaluated in terms of the motions of the body\u2019s center of mass (COM) in relation to the center of pressure (COP) of the ground reaction forces (GRF) . A commoThe purpose of the current study was to identify the alterations of the whole-body balance control during walking in terms of IA and RCIA in juveniles with treated unilateral DDH who developed secondary AVN at the treated hip and those who did not develop AVN as compared to their healthy peers. It was hypothesized that children with treated DDH, whether with or without secondary AVN, would show altered balance control with increased IA but decreased RCIA during walking when compared to female healthy controls, and that patients with AVN would show a reduced bilateral symmetry in balance control compared to those without AVN.Twenty-four female juvenile patients who had undergone Pemberton\u2019s osteotomy for treating unilateral DDH during toddlerhood participated in the current study. Written informed assents were obtained from the participants as well as from their parents or guardians, as approved by the Institutional Review Board. The patients were divided into two groups: twelve patients in the AVN group  and twelve patients in the non-AVN group  according to the osteonecrosis diagnosis and classification described by Kalamchi and MacEwen . In the In a university hospital gait laboratory, each subject walked at the preferred walking speed on a 10-m walkway while wearing 49 retro-reflective markers to track the motions of the body segments . The marx-axis directed anteriorly, the positive y-axis superiorly and the positive z-axis to the right. An optimization-based method, which has been shown to have better performance than traditional prediction methods . An a priori power analysis using G*POWER  and toe-off (TO), the ranges and time-averages of the IA and RCIA during single-limb support (SLS), initial double-limb support (DLS) and terminal DLS, as well as the peak values of IA and RCIA during DLS, were obtained for each trial and for each subject. Note that initial DLS of one limb is the terminal DLS of the other limb. Data of a total of six trials were averaged for each of the variables, and the differences among non-AVN, AVN and control groups were analyzed using one-way analysis of variance (ANOVA). Once a significant main effect was found, the pair-wise differences were identified  G*POWER  based onNo significant differences were found in any of the spatiotemporal parameters between the non-AVN and Control groups, nor between the AVN and non-AVN groups . HoweverIn the sagittal plane, compared to Control, the non-AVN group showed significantly decreased average IA but significantly increased range of RCIA during SLS of the unaffected side, while the AVN group showed significantly increased average IA during terminal DLS of the affected side . Compared to non-AVN, the AVN group showed significantly decreased RCIA at toe-off, as well as significantly decreased range of RCIA during SLS of the unaffected side, but significantly increased average IA during terminal DLS of the affected side , 3 Figu.In the frontal plane, compared to Control, the non-AVN group showed significantly decreased average IA but significantly increased peak value of RCIA during terminal DLS of the affected side, while the AVN group showed significantly decreased RCIA at toe-off but increased range of RCIA during SLS of the unaffected side. Compared to non-AVN, the AVN group showed significantly decreased RCIA at toe-off and significantly decreased range of RCIA during SLS of the unaffected side , 5 Figu.Compared to the unaffected side, the affected side of the AVN group showed significantly decreased average IA, as well as significantly decreased RCIA at toe-off, peak value of RCIA and range of RCIA during initial DLS in the sagittal plane, but significantly increased RCIA at toe-off and significantly decreased range of RCIA during initial DLS in the frontal plane . No signThe current study aimed to identify the alterations of the whole-body balance control during walking in terms of IA and RCIA of COM relative to COP in juveniles who developed secondary AVN at the hip after treatment for DDH during toddlerhood and those without developing AVN as compared to their healthy peers. When compared to female healthy controls, the non-AVN group showed bilaterally similar compromised balance control with significantly decreased IA but increased RCIA in the sagittal plane during SLS of the unaffected side, and in the frontal plane during terminal DLS of the affected side . In contrast, the secondary AVN increased between-side differences in the sagittal IA and sagittal and frontal RCIA during DLS, leading to altered, bilaterally different balance control in the AVN group. This group showed significantly increased IA but decreased RCIA in the sagittal plane during terminal DLS of the affected side and in the frontal plane during SLS of the unaffected side compared to female healthy controls. Comparisons between the AVN and non-AVN groups showed that AVN secondary to unilateral DDH treatment increased sagittal IA during terminal DLS of the affected side and reduced both the sagittal and frontal RCIA during SLS of the unaffected side. The current results suggest that apart from routine assessment of the morphological changes of the affected hip, it is essential to monitor for any signs of decreased gait speed and cadence or increased between-side differences in the sagittal IA, and sagittal and frontal RCIA during DLS for early identification of AVN subsequent to unilateral DDH osteotomy in juveniles.via compensatory changes.Juveniles without secondary AVN walked with compromised, bilaterally similar balance control showing reduced IA and increased RCIA in the sagittal plane during SLS of the unaffected side, and in the frontal plane during terminal DLS of the affected side at normal gait speed, cadence, stride length, step length and step width. When supported only by the unaffected limb, the COM moved anteriorly at an increased speed while the COP was controlled within a relatively small range, suggesting a compromised velocity control of the COM-COP motion in the sagittal plane. During DLS, on the other hand, the COP moved towards the leading limb during weight transfer; thus, an increased RCIA during terminal DLS of the affected limb indicated a faster weight release to the unaffected side. These changes of the COM-COP control appeared to be a compensation for residual deficits of the hip such as muscle weakness, limited range of motion and modified mechanical properties of the surgically reduced joint . ReducedThe development of AVN secondary to the unilateral DDH treatment degraded or destroyed the hip biomechanics reconstructed by the osteotomy, increasing the difficulties in maintaining balance for the affected limb and in providing compensatory adjustments by the unaffected limb necessary for symmetrical balance control. In the sagittal plane, the juveniles with secondary AVN walked with increased IA but reduced RCIA during terminal DLS of the affected limb, indicating a compromised COM-COP control during weight release to the leading unaffected limb at a reduced speed. A plausible reason for this phenomenon is that AVN of the femoral head affects the biomechanics of the hip joint and the surrounding muscles, reducing the unresisted range of motion of the joint and the ability for generating power necessary for body-weight transfer from the trailing limb (affected side) to the leading limb (unaffected side). Reduced speed in weight transfer to the leading limb as a result of reduced forward propulsion of the affected trailing limb during terminal DLS further affects the balance control with reduced frontal RCIA during the subsequent SLS of the unaffected side.In the frontal plane, the patients with AVN also showed a compromised COM-COP control with increased IA but reduced RCIA during SLS of the unaffected limb. During this period the control of the COM motion relative to the COP vector can be considered as an inverted pendulum with the COP controlled within a small range. However, the COM moved beyond the unaffected foot while the affected limb swung from the trailing to the leading position. With the increased IA an increase in the corresponding RCIA would be needed for stable balance control . The patThe non-AVN group walked with similar COM-COP balance control strategies between affected and unaffected side, while those for the AVN group were bilaterally different mainly in the sagittal IA, and sagittal and frontal RCIA during DLS. Secondary AVN significantly reduced IA and RCIA in the sagittal plane, and reduced the range of RCIA in the frontal plane during initial DLS, with a reversed trend during terminal DLS as the trailing limb became the leading limb. These results indicate a conservative COM-COP control in the sagittal plane and a compromised control in the frontal plane during body-weight transfer to the leading affected limb, and a compromised COM-COP control in the frontal plane during weight release to the unaffected limb. These strategies were most likely related to the altered biomechanical conditions of the affected hip, including the changes in the shape and orientation of the femoral head and the neck-shaft angle, as well as the lines of action and lever-arm lengths of the surrounding muscles . TherefoThe current study was the first to identify the effects of AVN secondary to surgically treated unilateral DDH on the whole-body balance control and bilateral asymmetry of such control during walking in terms of IA and RCIA in juveniles. The bilateral asymmetry as a result of secondary AVN was found to occur mainly in the sagittal IA, and sagittal and frontal RCIA during DLS, while the COM-COP control remained symmetrical during SLS. A recent study showed that the loading rates on both the affected and unaffected sides were strongly correlated to the morphology of both the affected and unaffected hips . TherefoWithout secondary AVN, female juveniles who were treated for unilateral DDH during toddlerhood walked with bilaterally similar compromised balance control, showing significantly decreased IA but increased RCIA in the sagittal plane during SLS of the unaffected side, and in the frontal plane during terminal DLS of the affected side. Secondary AVN significantly reduced IA and RCIA in the sagittal plane, and reduced range of RCIA in the frontal plane during initial DLS, with a reversal during terminal DLS, indicating a conservative COM-COP control in the sagittal plane and a compromised control in the frontal plane during body-weight acceptance, and a compromised COM-COP control in the frontal plane during weight release. These strategies were most likely related to the altered biomechanical conditions of the affected hip, including the changes in the shape and orientation of the femoral head and the neck-shaft angle, as well as the lines of action and lever-arm lengths of the surrounding muscles. The current results suggest that increased between-side differences in the sagittal IA, and sagittal and frontal RCIA during DLS of level walking are a sign of AVN secondary to unilateral DDH osteotomy in female juveniles. These differences should be monitored for early identification of AVN secondary to treated unilateral DDH in this patient population."}
{"text": "The ongoing COVID-19 pandemic and subsequent economic recession have wreaked havoc on the United States\u2019 economy and brought to the forefront stark racial and ethnic inequalities in our society. Older Black and Latinx adults are particularly hard hit by the pandemic as they have relatively lower levels of income and wealth to protect against crises. This study used data from the 2020 COVID-19 module of the Health and Retirement Study, to highlight how the COVID-19 pandemic has economically impacted older Black, U.S.-born Latinx and foreign-born Latinx adults. Results show the pandemic has economically devastated older Black and Latinx adults across a host of economic factors, with foreign-born Latinx experiencing greater economic hardships relative to other groups. Our findings document stark inequalities that are being exacerbated by the pandemic. We discuss the implications of the economic shocks of the pandemic for the health and well-being of older Black and Latinx adults."}
{"text": "This vesicular trafficking flows along highly organized, balanced and directional routes from the ER toward the Golgi apparatus and cell surface or toward lysosomes (the biosynthetic-secretory pathway) and from the plasma membrane to early endosomes and recycle them back to the surface to be reused or sort them to degradation , nucleotides, lipids, and short peptides to monitor the close environment  is a constituent of hepatocyte-generated EVs. Using FN1 knock-out cells, the authors characterize the role of FN1 hepatocyte-EVs. FN1 facilitates the integrin-dependent EV binding and EV uptake by endocytosis of target cells such as hepatocytes and hepatic stellate cells (HSC) but is dispensable for EV-mediated anti-fibrotic activity in vivo. A fascinating role in the use of EVs in the improvement of therapy strategy for the type 1 dyabete mellitus (T1DM) is highlighted by the work of Bai et al. The authors improved a previously characterized protocol for beta cell generation from iPSCs using miR-212/132-enriched EVs secreted by beta cells. Functional analysis defined the role of the miRNAs 212 and 132 in the regulation of target mRNAs important to promote differentiation of endocrine cells from induced iPSCs. Importantly, the generated beta cells from miR-212/132-enriched EVs are also able to secrete insulin under glucose stimulation and ameliorated hyperglycemia in vivo. All together these original works support the importance of the application of EVs both in physiology and pathological contexts due to their pivotal roles in cross-talk intercellular communication. Accordingly, Bergamelli et al. investigated the expression of surface markers of placental EVs after optimization of their isolation from a histoculture model of first trimester placental explants in normal conditions and after human cytomegalovirus (hCMV) infection. The authors found that a number of molecules changed in the surface of EVs after infection. This paper paves the way for downstream functional characterization of these non-invasive biomarkers that could be relevant for the outcome of the viral infection during pregnancy.In a multi-omics study of cell-to-cell communication, Finetti et al. brings to light to the identification of the intraflagellar transport protein IFT20 as a new regulator of the autophagic system. In particular, the authors found that IFT20 plays a direct role in autophagy as an adaptor that targets ATG16L1 and downstream autophagy regulators to a specific endomembrane compartment, resulting in autophagosome biogenesis. This discovery confers a new role for IFT20 in T cells beyond its implication in lysosome biogenesis, as recently demonstrated from the same group. In the original article submitted by Wen et al., another new player well-known for vesicular transport, the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) protein, was also identified to play a role in autophagy in bone-resorbing osteoclasts (OCs). In particular, the authors show that the GBF1 inhibition impairs not only in vitro differentiation of osteoclasts but also causes ER stress and autophagy through alterations of different signaling molecules. Bodakuntla et al. summarize the crucial role of two important structural components of the vesicular trafficking (cytoskeleton and membranes) in axonal branches in which the local machinery dynamically controls and regulates the axonal growth to ensure a high degree of interconnectivity for neural network. The dysfunction of the endosomal-lysosomal system is nicely illustrated in the context of atherosclerosis, a disease whose etiology and pathogenesis are strictly dependent from defective lysosome functions. The review of Marques et al. fully describes the origin and impact of the malfunctioning of lysosomes in plaque cells in cardiovascular diseases. Moreover, they also reviewed the field of Lysosomal Storage Diseases (LSDs) research to point up how therapeutic approaches that target lysosomes in LSDs might hamper atherosclerosis progression and its high associated mortality.The main form of intracellular communication occurs through the trafficking of vesicles between several compartments, as exemplified by the endosomal-lysosomal system. Interestingly, the latter intersects the autophagic system thus increasing the complexity of the cross-talks between these cellular processes. Unraveling these pathways, the original article by Notwithstanding the continuous growth within the field of vesicles in cell communication, many unanswered questions remain that hold still several future perspectives. For example, what are the biological implications and functions of the extra- and intracellular vesicles size diversity? How can we generate a more comprehensive understanding of the molecular machinery and events of protein trafficking? Does the variety of vesicles produced or released by a defined cell type change over time? How do vesicles are spatiotemporally coordinated? How can modulate vesicle targeting to improve therapeutic strategies? These are important future challenges that we hope will bring light to our understanding of new functional and structural properties of cell communication through vesicles with a significant impact not only on translational medicine but also on more general fields, such as cell biology, virology and immunology.We would like to thank the authors and reviewers for their substantial contribution in participating on this Research Topic. Altogether, these studies significantly improve our knowledge on cellular communication and we hope they could encourage the birth of future works in this field to provide an ever better understanding on how the communication in-and-out of the cells occurs and how its dysregulation may be affected in disease.AO conceived and wrote the Editorial. AC reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
{"text": "The workforce in residential long-term care (LTC) is key in providing high-quality, person-centered care for residents. However, low staffing and adverse staffing outcomes such as turnover or job dissatisfaction hinder the provision of high-quality care. International research can add valuable insights for policy and practice by learning from different settings and cultures. The initiative \u201cTo Harmonize Research In long-term care liVing Environments (WE-THRIVE)\u201d, is led by an international group of LTC researchers to identify common data elements (CDE) for cross-comparative research that support older adults thriving in LTC. In this symposium, we will present an overview of the WE-THRIVE initiative with a specific focus on CDEs and measurement. The first talk will provide the context for the WE-THRIVE initiative, and discuss the collaborative and iterative processes required to develop the initial CDEs in the area of workforce and staffing. In the second talk, we will discuss which staff should be \u201cin the house\u201d to meet the needs of residents during and after a pandemic, and what type of workforce data system should be available to ensure the best quality outcomes for residents and carers. Next, current issues in the measurement of staffing in LTC based on a review of reviews of staffing\u2019s relationship to quality of care will be discussed. Finally, we extend the debate to consider theoretical and empirical explanations for the relationship between staffing and quality in LTC and the promotion of person-centred care outcomes."}
{"text": "Understanding patterns in the types of activities older adults engage in during physical activity and sedentary time could help shape intervention designs. Few studies have adequately described the physical activity and sedentary pursuits older adults undertake, including during the COVID-19 pandemic. To answer these questions, this symposium uses data from three recent studies: Adult Changes in Thought (ACT),an epidemiologic study with self-reported and device-based measures of physical activity and sedentary time including time spent in various domains of activity; Objective Physical Activity and Cardiovascular Disease Health in Older Women (OPACH), an epidemiologic study with device and self-report measures of sedentary behavior; and an ongoing clinical trial, the Healthy Aging Resources to Thrive (HART) study with device and self-reported data on sitting time and patterns as well as physical activity. The first session in this symposium will present a description of the rates of meeting the aerobic, strength, and balance recommendations among older adults in the ACT study. Next, we will have a presentation describing sedentary activities in older adults by age, sex and device-based sitting patterns in the ACT study. In the third presentation we will use OPACH data to examine patterns and context of sedentary in relation to aging-related outcomes. Finally, we will describe changes in physical activity and sedentary time in the HART trial in the cohort enrolled prior to the COVID-19 pandemic vs. those enrolled during the pandemic. Our Discussant will provide new insights on the roles of sedentary behavior and physical activity in aging and health."}
{"text": "Due to the small Huang\u2013Rhys factor, the GeV\u2212-center zero-phonon line emission is expected to be very intensive and spectrally narrow. However, structural defects and the inhomogeneous distribution of local strains in the nanodiamonds result in the essential broadening of the ZPL. Therefore, clarification and elimination of the reasons for the broadening of the GeV\u2212 center ZPL is an important problem. We report on the effect of reactive ion etching in oxygen plasma on the structure and luminescence properties of nanodiamonds grown by hot filament chemical vapor deposition. Emission of GeV\u2212 color centers ensembles at about 602 nm in as-grown and etched nanodiamonds is probed using micro-photoluminescence and micro-Raman spectroscopy at room and liquid nitrogen temperature. We show that the etching removes the nanodiamond surface sp2-induced defects resulting in a reduction in the broad luminescence background and a narrowing of the diamond Raman band. The zero-phonon luminescence band of the ensemble of the GeV\u2212 centers is a superposition of narrow lines originated most likely from the GeV\u2212 center sub-ensembles under different uniaxial local strain conditions.The negatively charged germanium-vacancy GeV In ZPL 11 direct\u2212 centers in the NDs, hydrostatic-type pressure results in a blue shift of the ZPL. In contrast, uniaxial strain causes a larger redshift with different magnitudes depending on the direction of the strain [\u2212 centers, having the same structure as SiV\u2212 centers. Comparative analysis of the ZPL spectra in \u2212 centers is significantly more likely than a blue-shift. We believe that analogously to the SiV\u2212 case in HFCVD NDs, the distribution of uniaxial strains induces the shifts of ZPLs of sub-ensembles of GeV\u2212 centers. A blue-shift of the ZPL in the spectrum in The main mechanisms that lead to the color center wavelength shift are hydrostatic pressure and uniaxial strain. It was found by Lindner et al. that for SiVe strain . The sam\u2212 centers. The NDs with GeV\u2212 color centers were produced by the hot filament chemical vapor deposition (HFCVD) technique on silicon followed by reactive ion etching in oxygen plasma. We showed that the reactive ion etching in oxygen reduces the number of structural defects localized in the surface area of the NDs; this resulted in the Raman line of diamond narrowing to 5.5 cm\u22121 and increased the luminescence intensity, corresponding to neutral nitrogen-vacancy color center NV0. The cooling of the samples to the liquid nitrogen temperature enables us to observe the fine structure of the inhomogeneously broadened ZPL of ensembles of the GeV\u2212 centers in the strained nanodiamonds, using the high-resolution micro-photoluminescence technique. The origin of inhomogeneous broadening of the ZPL is speculated to be due to the fact that the observed ZPL spectra of the GeV\u2212 are overlapped with ZPLs of color center sub-ensembles under different strain conditions. At the same time, the color centers belonging to the one sub-ensemble experience practically the same local strain field. The strain response of ZPL spectra of the ensembles of GeV\u2212 at T = 80 K and its analysis provides a way to image the strain distribution in CVD nanodiamonds optically.We realized a top-down method to fabricate NDs with embedded GeV"}
{"text": "Drama therapy is a widely acknowledged way to explore life-stories in late life. This presentation will describe a new model for creative interventions, based on the results of four studies that provide multiple perspectives on the integration of life-review and drama therapy for community dwelling older adults. The results of two quantitative studies  suggest that the drama therapy interventions have robust therapeutic potential to enhance mental health while aging. The findings of two qualitative studies with therapists (n=8), participants  and staff (n=13) provide a better understanding of the process, and support the mechanisms that lead to positive effects on mental health. Combining the results yielded a multidimensional model which points to three potential transformative routes: the evolution of the life-story, the evolution of improvised dramatic expression, and the expansion of social engagement."}
{"text": "The University of Massachusetts 5-campus system was the first university system to receive the Age-Friendly University designation in the AFU Global Network . Simultaneously, the town of Dartmouth and city of New Bedford became Age-Friendly Communities. This allowed for dynamic collaboration between our university and communities. This presentation highlights several examples. The Ora M. DeJesus Gerontology Center faculty and student researchers developed the original age-friendly survey items for New Bedford\u2019s initial community assessment; and the College of Nursing and Health Sciences faculty and student researchers compiled data for Dartmouth\u2019s survey. Community service during the pandemic has flourished. The Community Companions program, which matches students with community members in social need, went virtual. Nursing students and faculty have been on the frontline in the vaccination efforts in the town of Dartmouth. These partnerships will be presented as examples of potential opportunities for other age-friendly communities. Community-university partnerships are encouraged."}
{"text": "The global health system is facing a serious challenge after the recent outbreak of COVID-19 coronavirus infection which was first identified in Wuhan, China in November 2019 and declared as a pandemic in March 2020 by WHO. There is a wide consensus that this pandemic has negative psychosocial consequences as well as unforeseeable provision of mental health care services and just not on physical health alone. The aim of this research study is to determine the prevalence of psychological distress and to identify the sociodemographic variables with the main attributable factors associated with the psychological distress among healthcare workers and suggestions on how to reduce the impact on the mental health of healthcare workers during the COVID-19 pandemic in different regions of the world.We performed a cross-sectional study from September-November 2020. We used a self-administered survey tool which was distributed electronically to healthcare workers across the globe. The data were stored on an online database with password protected devices where survey responses were restricted to investigators exclusively.Data collected were: 1) Socio-demographic data ; 2) Psychological General Well-Being Index (PGWBI) questionnaire which contains 22 standardized items. This is a subjective assessment to score the degree of psychological well-being by focusing on 6 domains: depression; anxiety; positive-well-being; self-control; vitality and general health; 3) Subjective assessment from respondents of the main attributable factors causing psychological distress and suggested methods to help reduce the impact on mental health on health care workers.Majority out of the 217 respondents were from a younger age group; females and married/domestic partnership, mainly from Western Pacific Region, South East Asian and the African Region. More than half the respondents were moderate-severely psychologically distressed and the three main attributable factors causing psychological distress were: fear of family/friends contracting COVID-19 followed by lack of PPE and discomfort caused by wearing PPE for long hours. Respondents suggested that the distress would be reduced if: more resources were provided in hospital; protocols and guidelines were implemented and counselling facilities with recreational activities were available to frontline workers.This study showed that the COVID-19 pandemic has affected the mental health of healthcare workers and more support or strategies need to come in place to protect frontline workers at the time of crises."}
{"text": "LED (Light-Emitting Diode) presents advantages such as luminescence, reliability, durability compared with conventional lighting. It has been widely applied for life, healthcare, smart farm, industry, and lighting from indoor to the automotive headlamp. However, the LED is vulnerable to thermal damage originated from the high junction temperature, especially in high power applications. Hence, it requires precise qualification on the optical power and the junction temperature from the pilot line to secure reliability. In this study, the photo-thermal sensor is proposed by employing a sheet-type thermocouple composed of photo-absorbent metal film and thermocouple. This sensor aims low-cost qualification in pilot line for high-power luminous devices and optical monitoring of costly luminaire such as automobile LED headlamp. The sensor is designed to detect the increased temperature response of LED hot spots from the transferred thermal power and absorbed optical power. The temperature response of each sheet-type thermocouple is utilized as a signal output of the absorbed optical power and hot spot temperature based on the introduced sensor equation. The proposed thermal sensor is evaluated by comparing the experiment with the measured reference value from the integrating sphere and the attached thermocouple at a junction. The experiment result reveals 3% of the maximum error for the optical power of 645 mW. The LED has significantly been developed based on its advantages such as small volume, impact resistance, high reliability, long life, and low power consumption, and it became a remarkable measure for convenient use, energy-saving, and environmental protection. Recently, the high-power LED industry has widened its application from indoor lighting to the health care, display, architectural industry, and even automotive headlights; however, thermal reliability of high-power LED is required more than ever due to the high integration and miniaturization of the package. The optical power and the hot spot temperature of the LED must be qualified in the pilot line and tested robustly to secure the functions without failure. In terms of its optical performance, however, the total optical power must be increased with higher input power and integration of the light source, which results in instability of the thermal system and reduction in lifetime and lighting performance . Recent The hot spot temperature was also compared with an infrared thermal imaging camera measurement, but the result is still questionable due to the additional light loss on the phosphor layer, which can cause measuring error. Christensen and Zhao present a thermal network model integrated with a sub-model of a structure of LED in finite element to predict the die temperatures ,5. Cheng2 nanoparticles of average particle size with 10 nm to the adhesive layer as an enhancer of refractive index and light scattering additives to increase the luminous efficacy and luminous flux of the white-LED in the form of polymer matrix nanocomposites.The energy and optical efficiency of the lighting application using luminous devices also have been researched to enhance their advantages on green technology. Wang et al. investigate a design of aluminum nitride (AlN) based substrate for high-power LED to improve heat dissipation and its efficiency of multi-chip LED by taking advantage from hybrid substrate design, such as simple assembly on a printed circuit board, providing the subsidiary protection of ceramic and decrease of production cost . Lee et In this study, a new type of photo-thermal sensor is introduced, aiming low-cost qualification in pilot line for high-power luminous devices and optical monitoring of costly luminaire such as automobile LED headlamp, and a compact method of both optical power and temperature measurement is achieved by employing the photo-thermal sensor. The principle of the introduced photo-thermal sensor is based on photo-absorbent heat from the optical power of the luminous device. The photo-thermal sensor consists of a couple of sheet-type thermocouples which can measure the temperature increase from the transferred thermal energy and absorbed optical energy on the hot spot of the luminous devices. Because two sheet-type thermocouples are designed to have the same thermal property and different optical absorbance coefficients, measured temperature responses of each sensor provide temperature difference which contains information of actual optical energy term. This net temperature between two sheet-type thermocouples is utilized as an output of a photo-thermal sensor which can measure the optical power and estimate the actual hot spot temperature of the luminous device. The proposed measuring method is evaluated by the measured optical power using the commercial integrating sphere and the actual temperature of the LED hot spot from an attached thermocouple.The temperature measurement of the LED is significantly affected by the optical power absorption, and it leads to over-estimated temperature originated from additional thermal power input of the absorbed optical power. Eventually, the measurement error from light absorption makes it harder to manage the thermal system of the LEDs. To reduce the over-estimating error in indirect measurement and achieve the optical power measurement for the thermal management, the novel concept of the photo-thermal sensor is introduced with a couple of same sheet-type thermocouples that have a different light absorption coefficient each other. The difference of responses between two thermocouples is utilized as the sensor output of the photo-thermal sensor, which can present optical power history.The configuration of a photo-thermal sensor is depicted in As shown in The implementation of the photo-thermal sensor is based on the assumption that the sensor can be modeled as a lumped system accompanying the light absorption term. The dynamic thermal model with the lumped capacitance  is emploThe dimensional and thermal variables of the photo-thermal sensor are presented in The thermal model of a single thermocouple in Radiation term can be linearized by introducing characteristic temperature, As a result, the entire heat equation for a photo-thermal sensor is derived by subtracting Equation (6) from Equation (5) based on the assumption that two thermocouples have the same thermal properties and boundaries except for the light absorption coefficient as The three different experiments on the photo-thermal sensor were carried out to characterize the thermal behavior of each thermocouple and to evaluate the performance of its measurement on the optical power and the LED surface temperature. In In the sensor response test, as shown in As described in Equations (7) and (8), the introduced photo-thermal sensor employs thermal behavior of temperature response in thermocouple during the measurement, which is originated from the exchange of thermal energy between the sensor and the LED surface. The measurement of optical power is based on the difference in sensor response between thermocouples resulting from the difference in thermal input caused by the amount of light absorption only. The introduced photo-thermal sensor also shows a unique concave steady-state temperature distribution along with the sensor distance. As described in the derivation of the heat equation, it can be explained that the distribution is originated from the changes in thermal resistance (The evaluation of the proposed photo-thermal sensor was carried out based on the comparisons of the optical power measurement and the LED surface temperature estimation from a photo-thermal sensor with the pre-measured optical power and surface temperature result from an integrating sphere and attached thermocouple by the junction. As shown in In this study, the compact measurements of the LED optical power and the hot spot temperature of the LED are introduced by employing a photo-thermal sensor based on the photo-absorbent power of the thermocouple. For this purpose, a pair of sheet-type thermocouples are designed and fabricated to compose a photo-thermal sensor realizing real-time measurement with the simplified sensor equation and minimized ambient effect. The modeling of the sensor equation is established based on the lumped capacitance model of each sheet-type thermocouples with consideration of the view factor and additional optical power absorption term. The fabricated photo-thermal sensor was calibrated and evaluated by measuring the optical power and the surface temperature of the LED. From the results, the following achievements are obtained.First, the response of stepped input power shows high linearity with the regression  fashion ."}
{"text": "The global health system is facing a serious challenge after the recent outbreak of COVID-19 coronavirus infection which was first identified in Wuhan, China in November 2019 and declared as a pandemic in March 2020 by WHO. There is a wide consensus that this pandemic has negative psychosocial consequences as well as unforeseeable provision of mental health care services and just not on physical health alone. The aim of this research study is to determine the prevalence of psychological distress and to identify the sociodemographic variables with the main attributable factors associated with the psychological distress among healthcare workers and suggestions on how to reduce the impact on the mental health of healthcare workers during the COVID-19 pandemic in different regions of the world.We performed a cross-sectional study from September-November 2020. We used a self-administered survey tool which was distributed electronically to healthcare workers across the globe. The data were stored on an online database with password protected devices where survey responses were restricted to investigators exclusively.Data collected were: 1) Socio-demographic data ; 2) Psychological General Well-Being Index (PGWBI) questionnaire which contains 22 standardized items. This is a subjective assessment to score the degree of psychological well-being by focusing on 6 domains: depression; anxiety; positive-well-being; self-control; vitality and general health; 3) Subjective assessment from respondents of the main attributable factors causing psychological distress and suggested methods to help reduce the impact on mental health on health care workers.Majority out of the 217 respondents were from a younger age group; females and married/domestic partnership, mainly from Western Pacific Region, South East Asian and the African Region. More than half the respondents were moderate-severely psychologically distressed and the three main attributable factors causing psychological distress were: fear of family/friends contracting COVID-19 followed by lack of PPE and discomfort caused by wearing PPE for long hours. Respondents suggested that the distress would be reduced if: more resources were provided in hospital; protocols and guidelines were implemented and counselling facilities with recreational activities were available to frontline workers.This study showed that the COVID-19 pandemic has affected the mental health of healthcare workers and more support or strategies need to come in place to protect frontline workers at the time of crises."}
{"text": "In the current pandemic of COVID-19 affecting countries across the globe, there are wide variations on how each country is handling the crisis. World leadership, economic status of the country, health care infrastructure, established public health foundations and various other factors play a role in it. Hence it becomes imperative to understand how the current pandemic, the biggest public health crisis, was handled in the UAE from a public health perspective.The World Health Organization (WHO) has released recommendations on strategic preparedness and handling of the COVID-19 pandemic [The emergency response system of the UAE is managed by National Crisis and Emergency Management Authority (NCEMA) and the UAE government was vigilant in issuing the first alert of the new coronavirus outbreak, even before it was declared by WHO as a public health emergency of international concern .The UAE has a comprehensive, government-funded health service as well as private health facilities which delivers a high standard of health care to the population.During this pandemic, the entire health care system was prepared and alerted with protocols in place for efficient handling of the crisisRisk communication is a key factor during a pandemic and the UAE government executed a detailed awareness campaign that targeted different groups of the community and provided a daily update about the status of the disease locally and internationally. UAE adopted the mandatory use of face masks in March 2020 well ahead of the WHO recommending this policy . Smart tThe ALHOSN UAE app is the official integrated digital platform for COVID-19 tests in the UAE through which individuals can receive COVID-19 test results on their smartphones. Similarly, the StayHome app supported quarantine and isolation of patients .The coronavirus helpline was established by the Ministry of Health and Prevention (MoHAP), as well as a dedicated hotline for mental health counselling to respond to psychological concerns and anxiety of people during the pandemic .The government of the UAE made remarkable progress in testing for the SARS-CoV-2 virus and in the management of cases. Algorithms for segregation, isolation, and treatment were released to guide health care professionals in handling COVID-19 cases  has set up similar field hospitals at various locations and apart from these, a quarantine facility called Complex 3, with a capacity to quarantine 10000 patients was set up. The government vigorously worked to establish this in only 9 days .All these facilities followed rigid COVID -19 protocols in handling and management of cases.Circulars were released for all health care professionals and a series of training workshops were conducted to educate health care professionals about the disease diagnosis, reporting, and management to strengthen epidemiological surveillance and enhancing prompt reporting of all suspected COVID-19 cases to Abu Dhabi Public Health Centre (ADPHC). In addition, active surveillance was established to identify Severe Acute Respiratory Infections (SARI) admitted to different hospitals there are required to be tested for COVID-19  for COVID-19 inactivated vaccine in July 2020 by G42 Healthcare in collaboration with Sinopharm CNBG, Department of Health, Abu Dhabi and UAE Ministry of Health and Prevention. This is a vivid example of national initiatives to foster population health and to enhance the UAE's medical research and development capabilities . The vacSEHA plays a vital role in getting the residents vaccinated and it has vaccination centers established in various other Emirates for effective functioning and reach.The final priority work area for preparedness in dealing with this pandemic would be to develop all-of-society and business continuity plans. The UAE government is already leading the way in restarting business and announced a two-phase recovery plan to rebuild the economy . The twoThe United Arab Emirates, as of 27 December 2020, has a COVID- 19 cases recovery rate of almost 89% and has recorded 669 COVID-19 deaths since the epidemic began . The casThe UAE moves forward with successfully reopening the economy and addressing the newer challenges of the pandemic like the newer variants of the virus.The UAE government encourages research and development of newer technologies with regards to COVID-19 pandemic and aligned to the nation's objectives, G42 Healthcare introduced the LamPORE technology with strategic global partnerships that is now integral to the UAE national testing program .G42 Healthcare has implemented a COVID-19 virus genomic sequencing study aimed at monitoring the pattern of spread and evolution of the virus since the start of the pandemic. This sequencing will also identify the emergence of new strains. Studies have already been published from the UAE on genomic sequencing of COVID-19 virus which has contributed to the understanding of the global transmission network of SARS-CoV-2 .Thus, the UAE has been efficient and effective in handling the crisis of COVID-19. It continues to pioneer in health care and serves as a leading example in the Middle East in comprehensively protecting the population and responsibly reopening the economy."}
{"text": "Cervical cancer is one of the fourth most common gynecological malignancies and has been identified as the fourth leading cause of cancer death in women worldwide. MicroRNAs (miRNAs) are single-stranded sequences of noncoding RNAs that are approximately 22-24 nucleotides in length. They modulate posttranscriptional mRNA expression and play critical roles in cervical cancer. Single nucleotide polymorphisms (SNPs) in miRNA genes may alter miRNA expression and maturation and have been associated with various cancers. This review mainly focuses on the roles of SNPs in miRNA genes in the development of cervical cancer and summarizes the research progress of miRNA SNPs in cervical cancer and their molecular regulation mechanisms. For example, miRNAs may function as oncogenes or tumor suppressors to regulate the occurrence and development of cervical cancer through special signaling pathways, including the PI3K-AKT pathway Studies have reported that SNPs in pri-miRNA and pre-miRNA genes may interfere with the maturation process or degradation of miRNAs by destroying the secondary structure, reducing the number of mature miRNAs and affecting the expression of mature miRNAs et al. reported that the SNP rs4938723 in the promoter of pri-miR-34b/c was significantly associated with cervical cancer, and the C allele was a risk factor for cervical cancer in a Chinese Han population. In addition, the CT genotype was significantly associated with the clinical staging and poor prognosis of patients MiR-34 is considered to be the first miRNA that is directly regulated by p53, and it has been reported to be dysregulated in many types of cancer et al. found that the SNP rs11134527 in miR-218 was associated with cervical cancer in a Chinese Han population, and the GG genotype can reduce the risk of cervical cancer et al. showed that the SNP rs11134527 was associated with the development of CIN in cervical cancer in a Chinese Han population, and the A allele of rs11134527 was associated with a lower risk of CIN MiR-218 is encoded by the intron of the SLIT2 tumor suppressor gene et al.'s study found that the SNP rs895819 located in the promoter of pre-miR-27a has a significant association with the risk of cervical cancer in a southern Chinese Han population et al. reported that the SNP rs895819 was associated with cervical cancer in a dominant genetic model in a southern Chinese Han population et al. reported that overexpression of miR-27a upregulates the expression of B4GALT3, promotes carcinogenic activity through the \u03b21-integrin pathway, and may be a potential biomarker for cervical cancer Previous study found that miR-27a was highly expressed in cervical cancer tissues and in HeLa and C33A cells et al. reported that the G allele of the SNP rs531564 in the promoter of miR-124-1 was a protective factor in cervical cancer in a Chinese Han population et al. showed that the C allele of rs531564 was the risk allele of cervical cancer in a Chinese Han population, and this SNP was related to the progression from CIN to cervical cancer et al. found that miR-124 can inhibit the mimicry and cell movement of angiogenesis by targeting amotL1 et al. found that miR-124 negatively regulates the target lncRNA NEAT1 and affects the migration and invasion of HeLa cells, EMT and activation of the NF-\u03baB pathway Mature miR-124 is processed by pre-miR-124-1, pre-miR-124-2 and pre-miR-124-3, all of which have reduced expression in a variety of tumor tissue types et al. reported that rs4636297 in miR-126, which was located 12 bp downstream of the pre-miR-126 sequence, was associated with CIN and cervical cancer in a Chinese Han population et al. indicated that the T allele confers a higher risk of developing CIN and cervical cancer Several studies have found that miR-126 is usually underexpressed in human colorectal cancer et al. reported that the SNP rs1625579 in the intron of pre-miR-137 was associated with a significant reduction in the risk of cervical cancer in a Sourthern Chinese population. Compared with the TT genotype, the TG and GG genotypes had a better protective effect on cervical cancer patients MiR-137 is underexpressed in cervical cancer tissues and cell lines and can inhibit the development of tumors et al. detected the expression of miRNAs in six types of cervical cancer cell lines and normal cervical samples, and they found that cancer samples can repeatedly show increased miR-21 expression et al. reported that there were significant differences in the alleles and genotypes of rs1292037, which is located 210 bps from the 3' end of pre-miR-21, in cervical cancer patients in the sensitive and resistant groups. The rs1292037 locus with the G allele in the miR-21 gene may increase the resistance of cervical cancer patients to cisplatin plus paclitaxel l in a Northern Chinese population et al. confirmed that miR-21 was significantly overexpressed in human cervical squamous cell carcinoma tissues and cell lines and found that miR-21 regulates the proliferation, apoptosis and migration of HPV16-positive cervical squamous cells by regulating the expression of the target gene CCL20et al. reported that the overexpression of miR-21 inhibited the expression of the mRNA of the target gene PTEN in cervical cancer cell lines to promote the proliferation, migration and invasion of cervical cancer cells et al. detected the sensitivity of cervical cancer cells to paclitaxel and found that the inhibited expression of miR-21 can inhibit cell proliferation and colony formation by regulating the PTEN/AKT pathway and improve the PTX sensitivity of cervical cancer cells Lui et al. reported that for the polymorphic site rs2292832 of miR-149 in cervical cancer tissues and HeLa and SiHa cells, the TC and CC genotypes increased the risk of cervical cancer compared with the TT genotype The expression of miR-149 is upregulated in cervical cancer tissues and cells The reason behind the association of SNPs with cervical cancer could be because SNPs located in pre-miRNAs may affect the expression of mature miRNAs and be involved in the binding of certain nuclear factors to miRNAs during miRNA processing.et al. found that the expression of miR-146a was upregulated in HeLa cervical cancer cells and C33A cells, and the rs2910164 SNP increased the amount of mature miRNAs in cervical cancer cells. Similarly, Li et al. reported that miR-146a can act as an oncogene, affect the expression of the target gene TRAF6 and regulate the differentiation of Th17 cells through NF-\u03baB signaling to regulate the growth and apoptosis of cervical cancer cells MiR-146a is abnormally expressed in a variety of cancers et al showed that the T allele in the SNP rs11614913 was associated with a reduced risk of cervical cancer development in an Indian population et al. in a Chinese Han population were consistent with those of Nisha et al. Previous studies reported that the expression of miR-196a in human cervical cancer tissues and cell lines was significantly upregulated Therefore, the abnormal expression of miRNAs may directly or indirectly affect the expression of many target genes, and the expression levels of these target genes will also dynamically change under various cell and environmental stimulations. Combining these changes with SNP-related miRNA-level regulation can provide important internal mechanisms for disease development.The occurrence of tumors is the result of the abnormal regulation of signaling pathways related to cell proliferation, differentiation, apoptosis, and the cell cycle. Mutations in the genes that affect different cell signaling pathways could play important roles in the mechanisms of the occurrence and development of cervical cancer. Many studies have found that mutations in miRNA genes may affect the combination of mature miRNAs and downstream target genes by affecting miRNA expression, thereby affecting the regulation of signaling pathways and playing an important role in the occurrence and development of cervical cancer. This review summarizes the SNP sites of miRNAs related to cervical cancer, lays a foundation for in-depth research on the pathogenesis of cervical cancer and identifies new targets for the diagnosis and treatment of cervical cancer."}
{"text": "Homing peptides and cell-penetrating peptides allow for systemic targeting of diseased tissues and/or efficient intracellular delivery of payloads. The translational potential of peptides as targeting ligands is strengthened by their small size, low immunogenicity, and biocompatibility. Whereas early studies on homing and cell-penetrating peptides focused on cancer delivery, a number of other disease indications have been demonstrated to be targetable with the peptides for improved diagnosis and therapy.The original contributions in this Special Issue address the development of internalizing peptides as facilitators of intracellular cargo uptake ,2,3 as wThe field of peptide-guided drug delivery is a vibrant multidisciplinary research area and this Special Issue serves to present a number of important advances in as outlined below.An intriguing study from the laboratory of Dr. Hongbo Pang at University of Minnesota (USA) investigated whether a co-incubation with the cell-penetrating peptide transportan can facilitate cellular uptake of cargo compounds . This moA study by Dr. Rafael Mor\u00e1n-Torres et al. at National Autonomous University of Mexico deals with development of short selective cell-penetrating peptides, referred to as \u201cmoonlighting peptides\u201d . The autIn another original report in the current Special Issue , the teaTwo studies in this Special Issue deal with applications of homing peptide called CAR (amino acid sequence: CARSKNKDC), which was originally reported to target neovasculature in injured regenerating tissues. CAR recognizes the unique sulfation pattern of heparan sulfate proteoglycans on the target cells. The first study  coordinaIn the second study on CAR-mediated systemic targeting, Iqbal et al. used the peptide for precision delivery of therapeutic antifibrotic TGF-\u03b2 modulator Decorin to skeletal muscle to slow progression of a mouse model of muscular dystrophy .Development of contrast agents remains challenging due to lack of sensitivity, low signal to noise ratio, and/or difficulty in tissue penetration in the case of optical imaging agents. The work by the team of Dr. Juliana Hamzah and colleagues from the Harry Perkins Institute of Medical Research and Curtin University  reported development of iron oxide nanoparticles functionalized with CSG peptide to detect tumor stroma, based on the over-expression of laminin-nidogen-1 complex that is recognized specifically by the CSG peptide . The autIn a paper by Hingorani et al., the authors report development of activatable cell-penetrating peptide conjugate for delivery of resiquimod, a TLR 7/8 agonist that has antitumor efficacy [In the study by Saghaeidehkordi et al., the authors targeted breast cancer cells with homing peptide 18-4 that targets cell surface Keratin 1 [The reports in this Special Issue are important advances that illustrate the multifaceted and interdisciplinary efforts on development of peptide-based strategies for precision-guided therapy and diagnosis of disease. We wish to thank all the authors of this Special Issue for contributing their high-quality research and for the critical evaluation of their manuscripts."}
{"text": "Most intervention programs in the dementia domain have exclusively focused on the caregiver (CG) or the patient (CR), despite evidence of a reciprocal interaction between the dyad. This presentation will describe a randomized controlled trial that is evaluating the feasibility and efficacy of an innovative dyadic intervention (DT) that is delivered through an interactive technology that includes an evidenced-based CG component, an evidenced-based cognitive training component for the CR and a dyadic component. The program is designed to: be synergistic and emphasize issues important to CGs in the earlier stages of caregiving. The sample involves 200 informal CGs and CRs with early-stage dementia. Data will be presented regarding factors influencing the feasibility of implementing a dyadic intervention such as recruitment challenges , and mutual engagement of both the CG and CR. Strategies implemented to maintain the trial during the COVID-19 pandemic will also be discussed."}
{"text": "A 9-year-old male child was brought by his father to the emergency department of the hospital with chief complaints of swelling on the left half of the abdomen since birth. The father of the child told that he had swelling of small size at birth which started gradually increasing in size for 18 months and then it was static up to 6 years of age. Later it again started increasing in size and now it has occupied the entire left abdomen. On clinical examination, the swelling was soft in consistency, non-tender with mild reddish-blue discolouration of overlying skin and no local rise of temperature. There was no pus discharge and itching over the swelling. For further investigation child was referred to the department of radiodiagnosis for contrast-enhanced computed tomography and ultrasonography of the abdomen. On computed tomography multiple varied size hypodense areas, most of them communicating with each other seen in the subcutaneous plane of anterior abdominal wall more on left side extending from left hypochondrium to left lumbar region inferiorly and crossing midline reaching right hypochondrium laterally on the posterolateral aspect of the abdominal wall. Few areas showed hyperdense content within with no significant enhancement on all post-contrast phases. On ultrasound, multiple cystic anechoic areas with internal debris independent part and showing no vascularity were noted."}
{"text": "The original version of the article contained inaccuracies in the Ethics declarations.The Ethical approval and the Statement of human rights are replaced by the following disclosure.Ethical approvalAll procedures performed in the case report involving human participant were in accordance with the ethical standards of Soonchunhyang University Cheonan Hospital and with Helsinki Declaration (1964) and its later amendments or comparable ethical standards. This study was approved by the Institutional Reviewer Board (IRB) of Soonchunhyang University Cheonan Hospital (IRB No. 2020-07-043).Also the article reports on findings that were presented at the\u00a0ISCEV Symposium in Miami in 2017 and published in our journal ("}
{"text": "This article has been corrected to remove images of the BREAST-Q scales . Permission to use the BREAST-Q is granted by way of a license agreement, signed by the intended users. The license agreement prohibits the reproduction of the BREAST-Q in publications or any other public documents. The authors of this article violated the license agreement by reproducing the BREAST-Q scales in the Appendix of this article. As a result these images have now been removed."}
{"text": "Al Mandhari, Regional Director, WHO Regional Office for the Eastern MediterraneanWHO defines self-care interventions as a variety of tools which can be accessed and used by individuals with or without the direct supervision of a health worker. Advances in evidence-based health information, medicines, diagnostics, products and technologies have increased the potential for self-care\u00a0interventions to increase health coverage for promotive, protective, preventive, curative, rehabilitative and palliative needs of individuals, families and communities. The increasing demand for sexual and reproductive health (SRH) services in the Eastern Mediterranean Region (EMR) and the importance of ensuring universal health coverage (UHC) including coverage, quality and financial protection for SRH also highlights the need for engagement of WHO Member States in the EMR.The 2019 WHO consolidated guideline on self-care interventions for health (\u201cGuideline\u201d) contains evidence-based recommendations and good practice statements on Sexual and reproductive health and rights (SRHR) [Successful introduction and uptake of self-care interventions at the country level will depend on an interplay of factors linking these two pathways, but also on elements that lie beyond the control of individuals and the traditional scope of the health sector. Translating these complex, multilevel and critical changes into effective policy measures requires high levels of commitment and engagement from diverse and relevant partners. Experiences from regions and countries are also needed to make clear what public goods are available to policy-makers, programme managers, health workers and laypersons for harnessing the potential contribution of self-care interventions.The work undertaken by the WHO Regional Office for the Eastern Mediterranean (EMRO) is an example of how this process can be approached. In 2019, WHO EMRO held several regional- and national-level discussions to disseminate the Guideline and consultative meetings and workshops on integrating self-care interventions for SRH in national health policies, programmes and practices in the EMR. Access to health is undermined by critical shortages of human and financial resources as well as lack of security of SRH essential medicine and commodities in many countries of the region, in addition to tangible physical and logistical barriers and the disruption and insecurity caused by humanitarian emergencies . FollowiSeveral themes appear across the papers and outline three priority steps for a dynamic approach to national-level policy changes that can ultimately accelerate strengthening and advancing SRHR Fig.\u00a0. While aFirstly, political will and leadership and multi-stakeholder partnerships are required. One example of how catalyzing the political will to act can lead to effective, positive change is shown in the key role played by parliamentarians  to promote innovative self-care interventions through their legislative, budget allocation, oversight and advocacy roles. Public sector ownership and patronage  in advocating for better national policies has also been shown to be effective in enabling introduction of self-care interventions.A second step towards effectively enabling self-care interventions is protecting people\u2019s human rights irrespective of their socioeconomic background, gender, sexual orientation or age in ensuring quality of care. The work of community pharmacists  in increasing coverage of self-care interventions through counselling and over-the-counter access to essential medicines demonstrates how accessing services in pharmacies and outside of traditional health facilities can expand the reach of health services to even the most vulnerable populations. Moreover, even during the pandemic, rights-based approaches to healthcare delivery can improve health outcomes of men who have sex with men , and point to the need to further support policy changes in task-shifting. From a public health perspective, it is advantageous for licensed products to be available over the counter, and the readiness of national regulatory guidelines could lead to increased access, availability and usage of essential self-care interventions . This in turn contributes to ensuring a rights-based foundation for the introduction of self-care interventions.Thirdly, the papers highlight the importance of evidence-based normative guidance, because they provide trustworthy, reliable sources to inform health decision-making for policy-makers, health workers and laypersons. Results from the regional component  of a global cross-sectional values and preferences survey give a glimpse of the knowledge and priorities of laypersons and health workers around access, use and uptake of self-care interventions for SRH. Policy-makers can consider the participant narratives regarding the need to consider both the heterogeneity of self-care interventions and the needs and lived experiences of diverse populations to ensure that the policies reflect the priorities and needs of people .The papers included in this supplement provide concrete examples of how policy action leading to implementation of self-care interventions in the EMR can lead to tangible, positive shifts in healthcare delivery. This starts with a constructive policy debate to understand how self-care interventions fit in the context of health, community and policy systems . Policy-Evidence on the patterns of use and uptake of health services and on the effectiveness of specific self-care interventions is not enough to develop effective policies. It must come with better evidence on what strategies work to enhance the capacities of individuals and communities to access quality self-care interventions. A structure to support further research that includes stakeholder values and identification of core gender, equity and human rights standards and principles can strengthen the evidence base . Strong Several of the papers in this supplement highlight the importance of training health workers to promote and counsel on the use of self-care interventions . This will involve training and development of competencies that go beyond biomedical approaches or a disease focus to a more empathetic and compassionate mindset which considers the person at the centre of care and leverages and understands the need for demonstrable supportive attitudes, adequate knowledge and skills; and codes of conducts and specific trainings to eliminate the current power dynamics between health workers and clients. People in different settings and circumstances have varying abilities to access health services, and the ability to promote self-care interventions in populations who may be stigmatized or marginalized and/or lack trust in existing health systems, and to support them as needed with quality care, has the potential to improve health and equitable distribution of healthcare.Another area of importance is facilitating the linkages between digital and self-care interventions. Although digital health technologies are growing rapidly, access is likely to be unequal due to the digital divide. Closing this gap will require action from policy-makers to ensure sustainable, safe and ethical use of technology in the health sector. Evidence-based, high-quality self-care interventions can be delivered via digital technologies and can offer effective alternatives to some face-to-face interactions with providers. During the COVID-19 pandemic, for instance, such innovative approaches using digital platforms allow health systems to better maintain the delivery of essential SRH services .The experience provided in the papers from this supplement can help other countries accelerate progress on self-care interventions in SRHR. Rapid introduction and scale-up of self-care interventions can be a game-changer for accelerating positive health impact through sustainable action at the local level that is driven by the health needs of people. The examples highlighted from the EMR show how individuals can be are enabled to play an active role in improving their own health , engage successfully with community action for health , and push governments to meet their responsibilities in addressing health and health equity . For policy-makers, self-care interventions are important for responding to people\u2019s priorities, needs and rights with regard to health. Ensuring availability of quality, regulated self-care interventions is part of the duty of policy-makers to protect their constituencies against harmful or exploitative practices. Despite the diversity of the countries in the EMR, the opportunities and challenges in the regional examples show the need for quality data  to inform how the public health community and policy-makers could not just improve health outcomes, but also transform health systems through self-care interventions. Self-care interventions for SRH is crucial component of health systems and their availability is a pre-requisite to ensure SRH service delivery responds to people\u2019s needs and rights to reach UHC."}
{"text": "The activity of the left and right central pattern generators (CPGs) is efficiently coordinated during locomotion. To achieve this coordination, the interplay between the CPG controlling one leg and that controlling another must be present. Previous findings in aquatic vertebrates and mammalians suggest that the alternate activation of the left and right CPGs is mediated by the commissural interneurons crossing the midline of the spinal cord. Especially, V0 commissural interneurons mediate crossed inhibition during the alternative activity of the left and right CPGs. Even in humans, phase-dependent modulation of the crossed afferent inhibition during gait has been reported. Based on those previous findings, crossed inhibition of the CPG in one leg side caused by the activation of the contralateral CPG is a possible mechanism underlying the coordination of the anti-phase rhythmic movement of the legs. It has been hypothesized that the activity of the flexor half center in the CPG inhibits the contralateral flexor half center, but crossed inhibition of the extensor half center is not present because of the existence of the double limb support during gait. Nevertheless, previous findings on the phase-dependent crossed inhibition during anti-phase bilateral movement of the legs are not in line with this hypothesis. For example, extensor activity caused crossed inhibition of the flexor half center during bilateral cycling of the legs. In another study, the ankle extensor was inhibited at the period switching from extension to flexion during anti-phase rhythmic movement of the ankles. In this review article, I provide a critical discussion about crossed inhibition mediating the coordination of the anti-phase bilateral rhythmic movement of the legs. Anti-phase bilateral rhythmic movement is produced during locomotion in mammals. The central pattern generators (CPGs) produce the rhythmic movement of the limbs Guertin, . PreviouThe CPGs in the spinal cord produce locomotion in mammals Brown, . Even inIn rats, locomotor activity in each side of the limb was produced even the spinal cord was separated with a midline cut (Kudo and Yamada, Even though the CPG on each side of the spinal cord is possible to produce rhythmic movement in each leg separately, activity of the left and right CPGs must be coordinated during locomotion in humans, according to an observation that humans move the legs coordinately during gait Perry, . PreviouV interneurons, and inhibitory V0D interneurons. The role of the V0 commissural interneurons on the left-right alternation of the motor output is dependent on the frequency of the locomotion cycle (Talpalar et al., V interneurons maintained an alternate activity at low-frequency cycle of locomotion, but switched to a synchronized activity at high-frequency cycle of locomotion (Talpalar et al., V commissural interneurons play a role in the left-right alternation during the high-frequency cycle of the locomotion. In contrast, ablation of the inhibitory V0D interneurons eliminated the left-right alternation at low-frequency cycle of the locomotion, but maintained it at high-frequency cycle of the locomotion (Talpalar et al., D interneurons play a role in the low-left-right coordination of the low-frequency locomotion.V0\u2013V3 commissural interneurons represent the classes of the postmitotic spinal interneurons based on the transcription factor expression (Butt et al., D interneurons receive exaction from the ipsilateral flexor centers and inhibit the contralateral flexor half center (V commissural interneurons are involved in two possible connections. One is that the excitatory V2a interneurons receive excitation from the ipsilateral flexor center and excite V0V interneurons but inhibit contralateral flexor half center through the inhibitory interneurons (V interneurons, and then, V0V interneurons excite the contralateral flexor half center (The pathways mediating the alternate activity of the half centers during locomotion have been proposed by a computational model (Rybak et al., f center . On the rneurons . Anotherf center . Taken tAccording to the discussion above, the alternate activity of the left and right CPGs is likely mediated by crossed inhibition between the CPGs; activity of the half center on one side inhibits the contralateral half center. Crossed inhibition induced by the activity of the CPG in one leg has been examined by observing the effect of the rhythmic movement of one leg on the soleus H-reflex in the contralateral leg at rest in humans. The soleus H-reflex at rest was suppressed by the contralateral leg cycling in the flexion phase and the end of the extension phase (McIllroy et al., However, those previous findings on the unilateral rhythmic movement are not direct evidences indicating the mechanism underlying the coordination of the leg movements during the anti-phase bilateral rhythmic movement during which both left and right half centers are alternately activated. In addition, we have to note supraspinal influence on crossed inhibition during unilateral movement. Unimanual activation of one finger muscle increases interhemispheric inhibition from the active hemisphere to the resting hemisphere (Vercauteren et al., In humans, one important neural event indicating the existence of the inhibitory pathways crossing the midline of the spinal cord is crossed afferent inhibition. The soleus H-reflex in the leg at rest was suppressed by the conditioning stimulation of the tibial nerve in the contralateral leg given 3\u201333 ms after the test stimulus (Stubbs et al., Soleus H-reflex amplitude is suppressed by the contralateral cutaneous stimulation of the dorsum of the foot in the early stance phase of gait (Suzuki et al., Such crossed afferent inhibition is possible to be induced by passive movement of the contralateral leg. For example, passive rhythmic movement of one leg suppressed the contralateral soleus H-reflex at rest (McIllroy et al., Based on those findings, the activity of one half center is inhibited not only by the active rhythmic movement of the contralateral leg, but also by the passive rhythmic movement of that. The somatosensation is induced, but the CPG is inactive during passive movement. It has been stated that the CPG is capable of reorganizing the sensory input to reconfigure itself to evoke the appropriate pattern Frigon, . AccordiAs discussed above, crossed inhibition of the contralateral CPG is a possible mechanism underlying the anti-phase bilateral rhythmic movement. Crossed inhibition is supposed to be achieved through mutual inhibition between the extensor half centers, between the flexor half centers, or between the extensor half center and contralateral flexor half center (see \u201cCrossed Pathways\u201d section and D commissure interneurons proposed by Rybak et al. and Danner et al. (Rybak et al., This hypothesis by Dietz was supported by a previous finding on the split-treadmill gait (Yang et al., In human experiments, crossed inhibition of the CPG during activity of the contralateral CPG has been examined by comparing the motor output between the unilateral and bilateral rhythmic movements. For example, peak power during unilateral cycling was greater than that during the anti-phase bilateral cycling (Dunstheimer et al., V commissural interneurons (Previous findings on the phase-dependent inhibition of the rhythmically moving one leg induced by the rhythmic movement of the contralateral leg were not in line with the hypothesis proposed by Dietz. For example, during bilateral anti-phase cycling, the activity of the tibialis anterior, biceps femoris, and rectus femoris muscles in the flexion phase was less than that during the unilateral cycling of the tested leg (Ting et al., rneurons . HoweverAnother previous study had tested the soleus H-reflex of the rhythmically moving ankle with and without rhythmic movement of the contralateral ankle (Hiraoka et al., A previous study reported that the soleus H-reflex during bilateral leg cycling was not significantly different from that during the unilateral cycling of the leg contralateral to the tested side (McIllroy et al., An important finding in the previous study by Hiraoka and colleagues is that such phase-dependent inhibition was not present during the in-phase movement of the ankles. This finding suggests that crossed inhibition during the switching period of bilateral rhythmic movement is particularly present during the anti-phase bilateral movement. It has been suggested that the control process of the in-phase bilateral movement of the hands is different from that of the anti-phase movement (Shih et al., Because pre-stimulus background muscle activity level was equivalent between the conditions in this previous study by Hiraoka and colleagues, suppression of the soleus H-reflex during bilateral rhythmic movement observed is likely presynaptic origin. In humans, rhythmic leg activation during gait was greatly controlled by presynaptic inhibition (Stein and Capaday, The conflict between the finding by Hiraoka and colleagues and the finding by Ting and colleagues may be due to the difference in the measurement of the motor status. The experiment by Ting and colleagues observed the EMG and force. Thus, the finding indicates the direct inhibition of the motoneurons causing the decrease in the motor output. In contrast, the experiment by Hiraoka and colleagues observed the suppression of the H-reflex with equal EMG activity. Thus, the finding in the study by Hiraoka and colleagues indicates the inhibition of the excitatory synaptic transmission to the motoneurons. This process is not direct inhibition of the motoneurons, and thus, does not indicate the change in the motor output. Such difference may be related to the conflicting findings between the studies.In the studies on bilateral coordination in humans, as introduced in the present study, actual locomotion is not performed; pedaling movement (Ting et al., The mesencephalic locomotor region and the lateral hypothalamus project to the reticulospinal neurons, and those neurons project to the spinal cord for activating the CPGs (Jordan et al., In this article, previous studies on the phase-dependent crossed inhibition underlying the anti-phase coordination of the rhythmic movement of the legs were reviewed. V0 commissural interneurons mediating crossed inhibition of the contralateral half center likely contribute to the alternate activity of the left and right CPGs. Crossed inhibition of the contralateral leg motor system has been reported in previous studies in humans. Accordingly, alternate activity between the left and right CPGs may be coordinated by crossed inhibition of the spinal cord in humans. On the one hand, a previous finding suggested that the flexor half center is inhibited during the activity of the contralateral extensor half center. On the other hand, another recent study indicated that the extensor half center is inhibited at the period switching the activity from the extensor to flexor half center while the contralateral limb is at the period switching the activity from the flexor to extensor half center. Future studies are needed for further insight into those findings.KH wrote this article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Since Nd is the most abundant lanthanide element with a magnetic moment, the Nd-Fe-B magnet was considered as the final solution in the permanent magnet industry. However, this material had a poor high-temperature performance, particularly low coercivity. To deal with this weakness, heavy rare earth elements (HREE) such as Tb and Dy have been used to improve the coercivity, which raised another issue arising from the criticality of HREE. This raised worldwide attention about a decade ago, and the development of advanced permanent magnets with less critical metals have become active all over the world. As a result, new knowledge and technologies concerning the material science of the high-performance rare earth magnets have been acquired in the last decade.Permanent magnet is one of the most important industrial materials in modern society and its function is to generate magnetic flux in a space without any supply of energy. The most powerful and commercially important permanent magnet today is the Nd-Fe-B magnet that appeared in 1983. This material is composed of an iron-based hard magnetic compound, Nd2Fe14B. A blind search with only human experiences over numerous compositional and processing parameters has been proved to be insufficient after decades of research.The science and technology of permanent magnets contain a wide spectrum of disciplines from physics of magnetism, phase equilibria and process sciences. The functionality of a permanent magnet comes from the large hysteresis of magnetization, which is a typical structure-dependent phenomenon. Permanent magnets are normally used in the second quadrant of the hysteresis below the external field called \u2018coercivity\u2019 at which magnetization reversal occurs. So, the major issue in the development of permanent magnets has been how to achieve high coercivity by controlling the microstructure of the alloys that contain a hard magnetic compound as a major constituent phase. Another important activity in permanent magnetism is the search for new hard magnetic compounds whose intrinsic hard magnetic properties are comparable or superior to those of NdToday, the science and technology of permanent magnet materials is in a totally different stage as compared to the situation a decade ago. The first-principles calculations of the ground state magnetism of rare earth magnetic compounds are now possible with great precision and finite-temperature magnetic behaviors are now handled considering the contributions of phonons in the electronic calculations on one hand and by using effective atomistic spin models in mesoscopic scales combined with micromagnetic stochastic simulations or thermodynamic Monte Carlo simulations on the other. The fundamental understandings of microstructures and local magnetic properties have been completely renewed in the case of the Nd-Fe-B magnet by the use of advanced analytical technologies for atomic-resolution structural, chemical, and magnetic properties.The selection of authors in this Focus Issue is biased to Japanese institutes. Instead of trying to take an international balance, this Focus Issue attempted to update the activities in two decade-long national projects in Japan, namely, Elements Strategy Initiative Center for Magnetic Materials (ESICMM) under the subsidy of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Technology Research Association of Magnetic Materials for High-Efficiency Motors (MagHEM) under the subsidy of the Ministry of Economy, Trade and Industry (METI). The majority of contributions to this Focus Issue are from ESICMM, which has been given the role of laying out the scientific bases of permanent magnets rather than industrial developments.12-type rare earth magnets which are attracting attention due to their intrinsic magnetic properties superior to those of Nd2Fe14B. The paper by Trinh et al. from Kyoto University reviews the synthesis of mesoscopic particles of rare-earth permanent magnet compounds via a chemical route from nano-sized precursors. One area that has shown marked advances in the past decade is the theoretical understandings of coercivity on the basis of atomistic spin models of the rare earth permanent magnets constructed from information obtained by the first-principles calculations. Ghoda from Tokyo Institute of Technology summarizes the recent advances in the large-scale first-principles computation of atomistic structure and magnetic properties of near grain-boundary interfaces in Nd-Fe-B and SmFe12-SmCu systems. The paper by Tsuchiura et al. from Tohoku University reviews finite temperature magnetic properties in equilibrium and the switching field of the magnetization of particles, based on an atomistic spin model. The paper by Miyashita et al. from The University of Tokyo describes advances in the theoretical computation of finite-temperature dynamics of magnetization process and thermodynamics associated with coercivity phenomena in the spin model. The paper by Okamoto from Tohoku University summarizes the advances in experimental approaches for micromagnetic measurements and analysis of the coercivity mechanism. The paper by Miyake et al. from AIST is a review of the high-precision first-principles calculation of the stability and magnetic properties of the rare earth permanent magnet compounds. The paper by Abe et al. is a brief summary of combined studies of equilibria experiments and theoretical calculations for the construction of a prototype database for thermodynamic assessments using the Calphad-type methods to describe important features of production processes of the multi-component Nd-Fe-B-type permanent magnets.The paper by Li et al. from NIMS addresses the most frequently asked questions about the coercivities of Nd-Fe-B permanent magnets by summarizing the advances in the understanding of microstructure\u2013coercivity relationships of Nd-Fe-B based permanent magnets. The paper by Koyama and Tsukada from Nagoya University and Abe from NIMS describe the recent understandings of the thermodynamics of formation of the thin intergranular phase, which is necessary to achieve a high coercivity in Nd-Fe-B magnets. The paper by Takahashi, Sepehri-Amin and Ohkubo from NIMS reviews the development of the Fe-rich ThMn2Fe17N3 and related materials.The invited paper by Hioki from Daido Steel Co. Ltd. provides an account of the development of hot-deformed Nd-Fe-B magnets that pioneered installment of the Dy-free Nd-Fe-B magnet in hybrid electric vehicles in 2016. The paper by Horikawa et al. of Aichi Steel Corporation is a review of recent advancements of anisotropic bonded magnets based on Nd-Fe-B and Sm-Fe-N partly conducted under MagHEM and ESICMM. Another paper by Takagi et al. from AIST reports recent results of their activities on powder materials processing for SmAs guest editors, we are confident that this Focus Issue provides a concise summary of the advancements in the science and technology of permanent magnets in Japan during the past decade and perspectives of the future direction of R&D in this field of research."}
{"text": "Assisted living is generally understood to offer a greater degree of privacy and independence than a nursing home; most residents pay privately, with some receiving support from state subsidies and Medicaid; regulation and oversight are the purview of state agencies. Within these broad parameters, however, one assisted living community may look quite different from another across the country, or down the street, in its resident population and the regulations that govern its operating license. The purpose of this symposium is to explore that variation. The papers leverage an in-depth review of changes in assisted-living regulation from 2007 to 2019 and a methodology to identify Medicare beneficiaries in assisted living using ZIP codes. To set the stage, the first paper examines variation across assisted living licenses to identify six regulatory types and compare their populations\u2019 characteristics and health-care use. The second paper analyzes trends over time in the clinical acuity of assisted living residents associated with changes in nursing home populations. The third paper investigates racial disparities in assisted living associated with memory-care designations and proportions of Medicaid recipients. The fourth investigates how regulation of hospice providers in assisted living affect end-of-life care and place of death. The final paper describes requirements related to care for the residents with mental illness in seven states. The symposium concludes with an expert in long-term care disparities and quality discussing the implications for policymakers, providers, and the population needing long-term care in assisted living."}
{"text": "The objective of the Symposium is to expand familiarity of the application of advanced methods of modern statistical modeling and data management, to administrative health data by combining methodological innovations with practical hands-on demonstrations. Topics will cover a range of methodological and substantive topics including: i) decomposition and partitioning approaches in analysis of disparities and time trends in AD/ADRD; ii) new artificial intelligence technologies that allow us to enrich electronic health record datasets with self-report scores in geriatrics; iii) using administrative data to model adherence to disease management and health-related behavior; iv) the use of longitudinal extension of the average attributable fraction to study health disparities and multimorbidity; and v) the geographic and racial disparities in total and remaining life expectancies after diagnoses of AD/ADRD and other chronic conditions. The increasing availability of large-scale datasets based on electronic health records and administrative claims records provide an unprecedented opportunity for obtaining nationally representative results based on individual-level measures that reflect the real care-related and epidemiological processes. This makes the reduction of barriers to entry to the use of such data of vital importance to the community of geriatrics and health researchers."}
{"text": "Psychosis disorder is a debilitating disorder characterized by multiple admissions to psychiatric care facilities, higher unemployment rates, and decreased life expectancy. All of which create a high burden on the patient, their family, and the healthcare system. Understanding the basic mechanisms of psychotic disorder is essential for early discovery and facilitating better care for those suffering from it .The dopamine hypothesis of schizophrenia  suggestseNeuro paper by A recent eNeuro paper by Increased functional connectivity of VTA with the hippocampus and decreased functional connectivity of the same brain structure with the striatum were also found in individuals at high risk for psychosis in a task-based paradigm . In the Studies in individuals at later stages of psychotic disorders show some differences in the pattern of results. A recent study by This recent paper presents a promising and interesting direction in understanding the mechanisms associated with psychosis, by evaluating resting-state functional connectivity in first-episode psychosis. The alignment of these resting-state findings with task-based results could point toward a possible direction for further investigation. Future studies may focus on longitudinal data, using the previous findings as a model to predict the onset, risk, and course of psychosis based on both task-based and resting-state connectivity. Such a model will enable us to promote better care for individuals suffering from psychosis and their families."}
{"text": "ABSTRACT IMPACT: This work reveals the influence of a season of American football-related head impact exposure on two functional outcome measures in a cohort of adolescent boys, shedding light on the chronic effects of 'subconcussive head impacts.' OBJECTIVES/GOALS: To examine the influence of a season of exposure to head impacts in American football on changes in neurocognitive and oculomotor function in adolescent male athletes. METHODS/STUDY POPULATION: Participants were recruited from a local high school: the football group  was instrumented with sensor-installed mouthguards to track impact exposure during games and practices, and members of the men\u2019s cross-country team were recruited to the control group . All participants were administered Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) and were assessed for near point of convergence (NPC) at pre- and post-season. Linear models will be fit for changes in the five ImPACT composite scores and NPC values, with group and one of the head impact variables as predictors for each model. In a secondary within-group analysis, correlation coefficients will be calculated for the relationships between the head impact variables and the functional change scores for the FB group. RESULTS/ANTICIPATED RESULTS: The two groups did not differ significantly on age or number of previous concussions; the CON group had significantly lower BMI. Group assignment was significantly associated with change in NPC ; no significant associations were observed for any of the head impact variables with change in NPC. Group and each of the head impact variables  were not significantly associated with change in any of the five ImPACT composite scores. Change in visual memory composite score was negatively correlated with total impacts  and sum of PRA . DISCUSSION/SIGNIFICANCE OF FINDINGS: Significant, albeit relatively weak, correlations between change in visual memory composite score and two head impact kinematic variables, coupled with significant increases in NPC in the FB group compared to the CON group, suggest that a season of exposure to football-related head impacts has the potential to elicit minor functional impairments."}
{"text": "The COVID-19 pandemic has generated awareness of the value of the direct care workforce to provide care in settings serving those most at risk from the disease. However, few studies have gauged the impact of COVID-19 on this workforce and their pandemic-related challenges. The purpose of this study was to examine the challenges and stress experienced by direct care workers  and their perceptions of preparation and quality of employer communication during this health crisis. Nursing home (NH) workers reported separation from family members and understaffing as the top external and work-related challenges. They felt adequately prepared and gave their employers high marks for communicating with them during the pandemic. NH direct care workers were more likely to report increased workload and understaffing as a challenge compared to workers in home and community-based settings. They also experienced a significantly higher number of work-related challenges compared to workers in assisted living."}
{"text": "Increasing requirements of medical aid given to children with infectious-inflammatory diseases of the urinary system stipulate the necessity to improve its quality using evidence-based therapeutic-diagnostic and organization technologies. The aim of the work \u2013 to substantiate, develop the improved model of the specialized nephrology care for children with infectious inflammatory diseases of the urinary system at the regional level. The official statistical data have been studied (2006 to 2017); information-analytical and statistical methods have been used. A bacteriological study (2009\u20132016) of urine samples was carried out for 3089 children (0\u201317 years old) in the Chernivtsi region. They formed the foundation for substantiation and development of an improved functional-organizational model of the system. In addition to the existing and functionally changed elements contains new elements: regional/inter-regional center of specialized medical aid to children with infectious-inflammatory diseases of the urinary system. Implementation of the elements of the suggested improved model in a part of a rational approach in distribution of functions concerning medical observation of patients at the stages of giving medical aid enabled to make the period of hospitalization of nephrological patients 11,40% shorter and an average period of treatment of patients with infectious-inflammatory diseases of the urinary system 2,93% shorter. Infectious-inflammatory diseases of the urinary system organs are considered an urgent issue in pediatrics due to a high rate of occurrence among the children population and a considerable variation rate of the pathology in the structure of the total sickness of children from various regions of Ukraine \u20133.Increasing requirements of medical aid given to children with infectious-inflammatory diseases of the urinary system stipulate the necessity to improve its quality using evidence-based therapeutic, diagnostic and organization technologies, an appropriate supply of resources including highly technological interventions in particular \u20137.The aim of this study was to substantiate, develop the improved model of specialized nephrology care for children with infectious inflammatory diseases of the urinary system at the regional level. The official statistical data have been studied , information-analytical and statistical methods have been used. The modern etiological structure of uropathogens \u2013 urinary tract infection (UTI) pathogens among the children of the Chernivtsi region (2009\u20132016) was studied. A bacteriological study of urine samples was carried out for 3089 children (0\u201317 years old) in the Chernivtsi region; the regional spectrum of sensitivity to antibacterial drugs was determined among the main groups of UTI pathogens; age, gender, and administrative-territorial differences among the children\u2019s population of the region were analyzed. This work is a fragment of the scientific and research paper entitled \u201cScientific support, monitoring and evaluation of models of health care development in Ukraine at the regional level\u201d (due date 2015\u20132017), state registration no. 0115U002852.The approval for this study was obtained from the Ethics Committee of the HSEEU \u201cBukovinian State Medical University\u201d and Chernivtsi Regional Endocrinology Center, Ukraine .Imperfect normative-legal regulation of the organization of medical aid given to children with urinary tract infection (UTI); lack of clear mechanisms of interaction between health care institutions including the primary, secondary and tertiary aid, out-patient and in-patient stages in giving specialized medical aid to children with infectious-inflammatory diseases of the urinary system in the region -11; inadConceptual areas to improve the standard of giving specialized medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level have been substantiated by the results of the study .On the basis of the existing normative-legal documents regulating standardization of medical aid, clinical recommendations of the European Association of Urology , and the data of our study, a clinical route of a patient aged from 0 to 17 years with infectious-inflammatory diseases of the urinary system is developed and implemented at the regional level into the work of health care institutions in Chernivtsi region which determine stages of giving medical aid .A central element of the system and, in fact, an innovation element of the improved model is a regional/inter-regional center of specialized and highly specialized medical aid given to children with infectious-inflammatory diseases of the urinary system. Its medical staff provides the implementation of information, methodical, therapeutic, medical-organizational work with monitoring of indicators to complete the regional program and other functions through comprehensive therapeutic-preventive, social-economical, hygienic, medical-social, information-educational measures. Thus, they provide completely organizational work depending on the determined area of the region.The center\u2019s medical structure has several units to provide children with infectious-inflammatory diseases of the urinary system with available and effective evidence-based medical aid corresponding to the best world patterns, keeping to the stages of giving medical aid according to the improved clinical route. Functional distribution of the center is the following: out-patient consulting rooms of doctors ; in-patient nephrological department with the priority of day-time in-patient departments with intensive care units and dialysis; specialized microbiological laboratory; department of information-methodical supply and monitoring.The following main tasks of the regional/inter-regional center of specialized medical aid given to children with infectious-inflammatory diseases of the urinary system are determined:\u2022achievement of final diagnosis, choosing the tactics of treatment, its correction, if necessary, rehabilitation and further out-patient care of children with UTI; \u2022organizational-methodical, clinical dynamic control over the results of the therapeutic and rehabilitation technologies used while giving medical aid to children with UTI in the region; hemodialysis of newly organized beds, referring to the Institute of Nephrology, National Academy of Medical Sciences of Ukraine, (a state institution) if highly specialized in-patient medical aid is necessary;\u2022to monitor changes of the regional spectrum peculiarities of bacterial causative agents in the urine of patients with UTI in various groups of children considering their gender and age; to organize the continuous treatment of children in case of relapses and exacerbations, to refer patients to be examined by medical-social experts if necessary, sanitary-resort treatment; to obtain epidemiological remarks by sickness rates of children suffering from UTI, their occurrence, and efficiency of medical aid they got ;\u2022achievement of organizational-methodical, informative, communicative functions of the center in work with medical professionals in the region, public organizations, mass media concerning prevention and early finding of children with UTI.The functions of the center include its organizational interaction with regional health care institutions giving medical aid to children and teenagers. The stages of this interaction are presented in Therefore, the improved functional-organizational model of giving medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level is based on a reformed medical aid system for the population. It consists of the following elements:1.Already existing elements of the health care system giving medical aid to children with infectious-inflammatory urinary system diseases;2.Existing but partially changed elements at the expense of their functional optimization such as pediatric service of the secondary health care institutions, microbiological laboratories of the health care institutions (HCI); interaction of HCI in giving various medical aid according to the improved clinical route; clinical and scientific base for the system of continuous postgraduate education of medical professionals giving medical aid to children with infectious-inflammatory diseases of the urinary system; first of all \u2013 general practitioners or family doctors, pediatricians, pediatric nephrologists and urologists;3.The elements of new quality \u2013 the foundation of a regional/inter-regional center of specialized medical aid given to children with infectious-inflammatory diseases of the urinary system, introduction, and provision of work of the electronic register of patients, the electronic-information system as elements of the regional target comprehensive program for saving health of children in the Chernivtsi region. Results of the expert evaluation of the suggested innovations made by qualified independent experts were indicative of their importance in order to improve medical aid given to children with infectious-inflammatory diseases of the urinary system at the regional level by the major directions: systematic, comprehensive, stage-by-stage, successive approaches, and rational use of resources. On the whole, the suggested model was evaluated by the independent experts in the total sum of 9.26\u00b10.08 points out of 10.0 possible, and coordinated agreement of the experts in making their decision (CV (%) = 2.50\u20135.07).Therefore, under conditions of the current and prognosticated threats  , 26, disImplementation of the elements of the suggested improved model in a part of a rational approach in distribution of functions concerning the medical observation of patients at the stages of giving medical aid allowed making the period of hospitalization of nephrological patients and the average period of treatment of patients with infectious-inflammatory diseases of the urinary system shorter by 11.40% and 2.93%, respectively.The efficiency of implementation of certain elements of the suggested model with its positive evaluation by independent experts and its compliance with the strategy of branch reforms enables to recommend the improved functional-organization model of giving medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level to be introduced into the health care system of Ukraine.The approval for this study was obtained from the Ethics Committee of the Bukovinian State Medical University and Chernivtsi Regional Endocrinology Center, Ukraine .The authors declare that there is no conflict of interest."}
{"text": "Although the magnitude and rate of aging in Japan and the United States differ, the drastic change in population structure has resulted in common challenges in both countries. One challenge is assisting older people in staying in the community. Enhancement of home- and community-based care allows older people to remain in their homes or spaces of their choice without moving into an institution to receive necessary care. This symposium includes four presentations (two from Japan and two from the U.S.) examining various efforts surrounding home- and community-based care designed to strengthen older people\u2019s abilities to stay in the community. The presenters will cover a wide range of strategies that have been implemented in both countries. The first presenter will describe the development and delivery of a project to expand Arizona\u2019s dementia capable system. The second presenter will describe initiatives of a professional association of geriatrics to promote the concept of aging in place. The third presenter will discuss the Home Hazard Removal Program (HARP), a new home hazard removal and fall risk self-management program delivered in the home by occupational therapists. The fourth presenter will discuss Japan\u2019s national policy priority of promoting the use of home health care within the community-based integrated care system. The symposium will conclude with a review of similarities and differences of various efforts, summarize common goals and challenges, and identify best practices."}
{"text": "In the original article, there was an error in the Funding statement as published. Some of the funders were missing from the original statement.The corrected Funding statement is shown below.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant AGL2013-45339R), the Spanish Ministry of Science, Innovation and Universities (MCIU), State Bureau of Investigation (AIE), and European Regional Development Fund (FEDER) (grant PGC2018-096958- B-I00), and the Catalonian Government (grant 2017SGR499). YE was recipient of an APIF fellowship from the University of Barcelona.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "This paper focuses on whether stronger relationships with parents early in the family lifecycle results in adult children providing more support to them 45 years later, and whether this association is contingent on parents\u2019 remaining years of life. We test time-to-death of parents as an indicator of vulnerability, an easy to ascertain and potentially powerful predictor of support. Data derived from the Longitudinal Study of Generations, a panel of three-generation families, originally fielded in 1971 and continuing to 2016. Focusing on the youngest generation (mean age = 19 in 1971), the analytic sample consists of 356 child-father relationships 473 child-mother relationships. We examined trajectories of instrumental support provided to parents over four waves between 1997 and 2016 as a function of each parent\u2019s remaining years of life . We also examined variation in those trajectories based on frequency of shared activities and intensity of emotional closeness in 1971. Ordinal multi-level growth curve analysis revealed that proximity to death was a significant predictor of instrumental support provided over time. Only in child-father relationships did greater emotional closeness, as expressed in 1971, produce stronger associations between remaining years of life and provision of instrumental support. Findings are discussed in terms of understanding intergenerational dynamics that unfold over many decades and the utility of time-to-death as an alternative metric for assessing vulnerability. This research is timely in light of growing uncertainty about the family as a reliable source of care in later life, particularly for older men."}
{"text": "Communicable diseases including COVID-19 pose a major threat to public health worldwide. To curb the spread of communicable diseases effectively, timely surveillance and prediction of the risk of pandemics are essential. The aim of this study is to analyze free and publicly available data to construct useful travel data records for network statistics other than common descriptive statistics. This study describes analytical findings of time-series plots and spatial-temporal maps to illustrate or visualize pandemic connectedness. We analyzed data retrieved from the web-based Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation dashboard, which contains up-to-date and comprehensive meta-information on civil flights from 193 national governments in accordance with the airport, country, city, latitude, and the longitude of flight origin and the destination. We used the database to visualize pandemic connectedness through the workflow of travel data collection, network construction, data aggregation, travel statistics calculation, and visualization with time-series plots and spatial-temporal maps. We observed similar patterns in the time-series plots of worldwide daily flights from January to early-March of 2019 and 2020. A sharp reduction in the number of daily flights recorded in mid-March 2020 was likely related to large-scale air travel restrictions owing to the COVID-19 pandemic. The levels of connectedness between places are strong indicators of the risk of a pandemic. Since the initial reports of COVID-19 cases worldwide, a high network density and reciprocity in early-March 2020 served as early signals of the COVID-19 pandemic and were associated with the rapid increase in COVID-19 cases in mid-March 2020. The spatial-temporal map of connectedness in Europe on March 13, 2020, shows the highest level of connectedness among European countries, which reflected severe outbreaks of COVID-19 in late March and early April of 2020. As a quality control measure, we used the aggregated numbers of international flights from April to October 2020 to compare the number of international flights officially reported by the International Civil Aviation Organization with the data collected from the Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation dashboard, and we observed high consistency between the 2 data sets. The flexible design of the database provides users access to network connectedness at different periods, places, and spatial levels through various network statistics calculation methods in accordance with their needs. The analysis can facilitate early recognition of the risk of a current communicable disease pandemic and newly emerging communicable diseases in the future. Communicable diseases remain a major public health threat worldwide. The COVID-19 pandemic is a stark reminder of the ongoing challenge posed by communicable diseases on human health . The conThe risk of in-flight communicable disease transmission has been a global health concern well before the emergence of COVID-19 . A numbeWe previously analyzed travel data retrieved from the web-based Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation (CAPSCA) dashboard , which cFlexible analysis of travel data can be performed through in-database processing. Specifically, users can analyze travel data through various network statistics calculations, including network analysis , networkThe CAPSCA dashboard allows us to create a spatial-temporal database by integrating the travel data from different airports to illustrate connectedness at the city, country, or regional levels in accordance with the users' preference. The database can facilitate research and policymaking at local and global levels and provide a spatial outlook of the evolution of the pandemic network for predicting and assessing the risk of a communicable disease pandemic.The database enables the visualization of pandemic connectedness through the workflow of travel data collection, network construction, data aggregation, travel statistics calculation, and visualization with time-series plots and spatial-temporal maps. The workflow of data collection and analysis is summarized in Travel data and meta-information were retrieved from the CAPSCA dashboard through two separate procedures:Extracting the airport meta-information from the rendered JavaScript object \u201cairportData\u201d through a HyperText Transfer Protocol request.Downloading and extracting the flight numbers of civil flights, including both passenger and cargo flights, from the JavaScript Object Notation responses through multiple Asynchronous JavaScript and Extensible Markup Language requests.The collected travel data were filtered for valid International Civil Aviation Organization (ICAO)\u2013formatted airport codes. Raw JavaScript Object Notation responses contain formatted airport codes from various data sources such as the ICAO, IATA, and FAA. Each type of formatted airport code has its specific format. Valid ICAO codes start only with a letter and have 4 letters or digits, valid IATA codes consist of 3 letters, while valid FAA codes are 3-5\u2013character alphanumeric codes. Each format type helps develop a filtering system to extract travel data with specific codes.A live version of the data record, which is maintained up-to-date with the latest data, can be downloaded from our travel database project repository . The datThe aggregated raw inputs are location metadata that contain data at multiple levels\u2014country, city, airport, and geolocation (latitude and longitude)\u2014and travel data, which contain daily information regarding flight origin and the destination, starting from January 2019. These data encompass >200 countries and regions worldwide.The data records (details) are structured into the following 3 comma-separated value (CSV) files:[ICAO_airport_meta.csv] Table of the location metadata (ICAO-CAPSCA airport meta). The fields of the table are as follows:countryName is the name of the countrycountryCode is the International Organization for Standardization (ISO)-3166 alpha-3 code of the countryairportName is the name of the airportairportCode is the ICAO code of the airportcityName is the name of the citylatitude is the geolocation (latitude) of the airportlongitude is the geolocation (longitude) of the airport[flight_2019-01-01_2020-12-03.csv] Table of travel data (daily flight numbers from origin to destination). The fields of the table are as follows:date is the record datenum_flight is the number of flights from the origin airport to the destination airportorig_airportCode is the ICAO code of the origin airportorig_airportName is the name of the origin airportorig_countryCode is the ISO-3166 alpha-3 country code of the origin airportorig_countryName is the country name of the origin airportorig_cityName is the city name of the origin airportorig_latitude is the geolocation (latitude) of the destination airportorig_longitude is the geolocation (longitude) of the destination airportdest_airportCode is the ICAO code of the destination airportdest_airportName is the name of the destination airportdest_countryCode is the ISO-3166 alpha-3 country code of the destination airportdest_countryName is the name of the country where the destination airport is locateddest_cityName is the name of the city were the destination airport is locateddest_latitude is the geolocation (latitude) of the destination airportdest_longitude is the geolocation (longitude) of the destination airport[network_statistics.csv] Table of the calculated network statistics. The fields of the table are as follows:date is the reference date of the network statistics at time ttV is the number of vertices (Vt) at time ttE is the number of edges (Et) at time ttD is the edge density (Dt) at time ttR is the reciprocity (Rt) at time tThe travel data can be used to construct the travel network structure . The basFor example, if we focus on global analysis, we aggregate the airport data at the country level and input the country data as a new set of nodes to form travel subnetworks, which are represented by the country-country\u2013origin-destination matrix with entries being the flight frequencies between 2 countries.We can further aggregate the travel data to obtain overall worldwide flight information. t is the number of vertices of the dynamic network at time t, and Et is the number of edges of the dynamic network at time t, network statistics such as Dt  and Rt  density ) can be t.which refers to the ratio of the number of connections with respect to the maximum possible connections among countries. This equation illustrates how dense the connections in the dynamic network are at time t is based on a directed network structure and is defined as follows:Reciprocity Rt is the ratio of the number of links pointing in both directions, Et<-> , to the total number of links, Lt. In other words, the value of Rt represents the average possibility that a link is reciprocated.where RNetwork statistics data were visualized using time-series plots. In addition, data records of the origin-destination and degree matrices can be visualized using spatial-temporal maps.The time-series plots of network density and reciprocity shown in For example, to analyze the connectedness in Europe during the first wave of the COVID-19 pandemic in early 2020, spatial-temporal maps of Europe at 14-day intervals between March and April 2020 were generated A. Maps dt  or software facilitating network visualization, such as Gephi (The Gephi Consortium).CAPSCA is a voluntary cross-sectorial and multi-organizational collaborative program managed by the ICAO with support from the WHO. The quality of the data on the dashboard should be guaranteed. As a quality control measure, we used the aggregated number of international flights from April to October 2020 to compare the number of COVID-19 cases at hub airports officially reported by the ICAO  with theOngoing systematic surveillance is important to help detect early outbreaks and to evaluate the effectiveness of public health measures and programs ,28. In tOur study provides a clear workflow for data collection and analysis and the suggested software for analysis. Because air transportation is highly relevant to the dissemination of communicable diseases, the database and the analysis can also be applied to investigate the risk of other communicable disease pandemics occurring currently or emerging in the future. In addition, researchers may replicate our workflow for assessing pandemic connectedness by using the same database or other databases.For data quality assurance, we conducted correlation analysis and validated the database. We compared the number of aggregated international flights officially reported by the ICAO for 7 regions from April to October 2020 with corresponding data we collected from the CAPSCA dashboard. We found only minor differences probably owing to data synchronization performed by the ICAO after collecting the daily raw counts of COVID-19 cases. We expect that our findings may help researchers explore and validate freely available health-related databases to conduct ongoing and systematic analysis and interpretation to identify early warning signals, such that necessary action can be taken to prevent and control the spread of communicable diseases.In this study, we demonstrated a workflow to analyze freely available travel data retrieved from the CAPSCA dashboard, together with data on confirmed COVID-19 cases reported by the WHO, for systematic surveillance. Flexible analysis of the travel data can be performed through in-database processing, which allows us to visualize and analyze the risk of a pandemic and pandemic connectedness by using different tools such as time-series plots and spatial-temporal maps. This analysis facilitates early recognition of the risk of pandemics of current communicable diseases and newly emerged communicable diseases in the future."}
{"text": "Agricultural systems all over the world are key for supplying vital goods such as food, fibre and energy from biomass. These agricultural systems form the foundation of human material well-being. However, increasing intensification, monocultures and overexploitation have often led to the serious degradation of the ecosystems upon which agricultural systems are embedded. Therefore, the functioning of these systems and their constituent biodiversity are at risk  what kind of land use trade-offs and synergies among agricultural production, ecosystem services and biodiversity can be identified at the landscape scale; and (b) how can the influence of agricultural land use on ecosystem services and biodiversity be monitored and evaluated at the landscape scale? The idea for this Special Issue emerged at the Landscape 2018 - Frontiers of agricultural landscape research Conference in Berlin, from where the individual contributions were drawn. The aim of the Conference was to present recent advances in landscape research to promote the development of sustainable agricultural land use and landscape strategies in an interdisciplinary and application-oriented manner.In this Special IssueThe research in this Special Issue addresses these landscape-related issues: (a) a general approach to enhance the indication of the supply of provisioning ecosystem services in agricultural landscapes is introduced by Bethwell et al. ; (b) asp"}
{"text": "There were errors in the Funding statement. The corrected funding statement is below:This research was funded by the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia. The project number is PNU-DRI- Targeted-20-019.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "In the original article, we inaccurately cited the report of Sun et al. . The autGenome Editing for CNS Disorders, Alzheimer's Disease, Paragraph 1. The corrected paragraph is shown below.A correction has been made to in vivo studies in adult mice, the CRISPR-APP system was split into two AAV9 vectors and delivered to the dentate gyrus of WT mouse brains. The injection of CRISPR-APP reduces the level of the processed C-terminal fragments (CTFs) by half while having no or minimal impact on the total APP protein. No additional in vivo tests were performed to evaluate treatment efficacy in the context of AD  is the main cause of dementia, affecting millions of people worldwide (Winblad et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Objective: This project report outlines the development and implementation of digital tutorials  by peer tutors (TUTs) based on previously established in-person tutorials, as well as the subsequent combination of both approaches. The TUTs' objective, in spite of corona-related restrictions and strict hygiene requirements during the pandemic, was to provide fellow students with the opportunity to learn, practice and reflect on clinical-practical skills.Methodology: In a collaborative undertaking, the TUTs first analyzed the learning objectives of the in-person tutorials in order to be able to design content-matched digital tutorials without entirely abandoning the practical aspect. The Moodle learning management platform was selected as the appropriate tool for delivery of the relevant theoretical knowledge. Practical exercises are embedded in the digital tutorials during online meetings. The participants (PTs) create their own models in the sense of a home skills station based on instructions provided via Moodle. Acceptance was systematically documented via questionnaires.Results: The digital tutorials were well accepted by the PTs (n=64). Evaluation (response rate: 37.5%) outcomes were consistently positive. Both course implementation and the PTs' own progress were rated \u201cgood\u201d to \u201cvery good\u201d. Nevertheless, the PTs do not yet feel well-prepared to carry out the various activities practiced independently.In the winter semester of 2020/21, the in-person tutorials were also reintroduced in a combined format. The marked demand for the tutorials may indicate the PT preference for practice on the simulation center models.Conclusion: The systematic combination of digital and in-person tutorials using the flipped classroom approach would appear to make sense in the long run. The effectiveness and sustainability of this approach in comparison with in-person tutorials only should be further investigated. The long-term plan, even once the pandemic has passed, is to combine them with the digital tutorials. For example, the Moodle course could be serve as the flipped classroom by providing information materials and forums as theoretical preparation for practical application during in-person tutorials [Starting from the winter semester 2020/21, in-person tutorials can again take place in compliance with the hygiene regulations of the Faculty of Medicine at the Klinikum rechts der Isar, see [utorials . In addiThe hybrid form of the course now envisaged should be assessed in terms of effectiveness and sustainability as part of accompanying research with the initial presence-only event. It is already clear that the still fledgling student tutorial program \u201cHow to... train your skills!\u201d has undergone significant and promising further development. This is the result not only of the combination of digital and in-person tutorials, but also of the situational change of perspective and being constrained to apply practical skills at a distance and with the simplest improvised means.The authors declare that they have no competing interests."}
{"text": "The ballasted track superstructure is characterized by a relative quick deterioration of track geometry due to ballast settlements and the accumulation of sleeper voids. The track zones with the sleeper voids differ from the geometrical irregularities with increased dynamic loading, high vibration, and unfavorable ballast-bed and sleeper contact conditions. This causes the accelerated growth of the inhomogeneous settlements, resulting in maintenance-expensive local instabilities that influence transportation reliability and availability. The recent identification and evaluation of the sleeper support conditions using track-side and on-board monitoring methods can help planning prevention activities to avoid or delay the development of local instabilities such as ballast breakdown, white spots, subgrade defects, etc. The paper presents theoretical and experimental studies that are directed at the development of the methods for sleeper support identification. The distinctive features of the dynamic behavior in the void zone compared to the equivalent geometrical irregularity are identified by numeric simulation using a three-beam dynamic model, taking into account superstructure and rolling stock dynamic interaction. The spectral features in time domain in scalograms and scattergrams are analyzed. Additionally, the theoretical research enabled to determine the similarities and differences of the dynamic interaction from the viewpoint of track-side and on-board measurements. The method of experimental investigation is presented by multipoint track-side measurements of rail-dynamic displacements using high-speed video records and digital imaging correlation (DIC) methods. The method is used to collect the statistical information from different-extent voided zones and the corresponding reference zones without voids. The applied machine learning methods enable the exact recent void identification using the wavelet scattering feature extraction from track-side measurements. A case study of the method application for an on-board measurement shows the moderate results of the recent void identification as well as the potential ways of its improvement. The ballasted track superstructure is the most-used superstructure worldwide due to its low construction costs, flexibility of application, automated maintenance, etc. However, it has significant disadvantages due to the relatively quick deterioration of its geometric quality. The ballast layer has the highest influence on track geometry quality, which causes high maintenance costs. The costs consist of track inspection and corrective maintenance costs that, despite the high automation, still reach up to 30% of the overall maintenance costs ,2. The fNowadays, subgrade and sleeper support condition monitoring and estimation is presented by different on-board and track-side methods. The existing on-board monitoring methods , left arThe present track-side methods for void identification on, more generally, stiffness measurement , center Another concept of track sleeper support monitoring is on-board measurement from regular trains , right. -Mechanical modelling of track and vehicle interaction for cases of void and the equivalent geometrical irregularities;-Exploration of differences in time and frequency domain between both cases of the irregularity;-Wavelet scattering feature extraction and selection of the significant features from modelled recordings of axle-box acceleration;-Development of the method for vertical rail deflection extraction from high-speed video recordings;-Signal processing of the collected track-side measurements to extract the vibration features of wheel and rail oscillations in the void and reference zone;-Statistical processing and void severity classification using machine learning methods;-A case study of void identification on a common crossing from on-board measurements on regular trains.The present paper demonstrates an approach for the identification of the sleeper support condition. The aim of the study is the development of the methods that allow to differentiate between the void and geometrical irregularity based on track-side and on-board measurements. Different to other reviewed studies, the present research includes both mechanical modelling and a data-driven approach based on the developed method for efficient data acquisition from many void defect zones. The study is produced in the following steps:The objective of the section is the exploration of the dynamic behavior of the railway track with sleeper voids, its influence on track-side and on-board measurements using mathematical modelling and its principal differences to the behavior in a geometrical irregularity. There have been many papers published over the last decades devoted to modelling of track dynamic behavior in the void zone.A theoretical study of the sleeper contact impact due to unsupported sleepers is presented in the study  using FEThe presented literature review shows many studies on modelling the dynamic track behavior considering the sleeper support conditions. Most of the studies are based on more or less detailed FEM models with or without coupled MBS vehicle models. However, many studies over the last years show an increase of interest in robust models based on 2D beam models and even on analytical approaches. Such models can be better fitted to the description of complex short-time nonlinear and long-term interaction processes in track rather than the redundant geometrical dimension of the FEM models. Nevertheless, all models suffer from the lack of good experimental validation of the effects of the dynamic behavior in the voided zone.The modeling in the present study is based on a three-beam model, whicht is coupled with a two-mass discrete model. The model is similar to that in the previous studies of the authors . However\u03b72(x) depend on the void parameters. The interaction force between the beams is presented in The voids under the sleeper with length xn elements of a beam over the length L corresponds to the system of ordinary differential equations that in matrix form is written as follows:M] is the matrix of element masses; [C] is the matrix of damping in connecting layers; [K] is the matrix of stiffness taking into account the bending rigidity of the beam; The numeric model of M] has a diagonal form with a non-zero main diagonal. It consists of two scalars MU and MB corresponding to unsprung and sprung masses and three square blocks [M1], [M2] and [M3] with dimensions N \u00d7 N corresponding to the number of elements into which each beam is divided (3). The matrix of damping [C] (4) takes into account the interaction between the neighbor beams and the system of two vehicle masses. The contact interaction is introduced by the matrix The finite difference method was used for the differential equation solution. The mass matrix [The stiffness matrix The vector column of external loading The model parameters presented in Experimental measurements  show thaThe simulated geometrical irregularity is chosen considering the research aim of the void identification from the other irregularities. Therefore, the case of the equivalent to void geometrical irregularity is determined using the quasistatic passing of the model for the void case. The equivalent to void geometrical irregularity corresponds to the wheel trajectory line and is shown in The simulation results are presented as the track deflection and accelerations corresponding to on-board and track-side measurements. The wheel trajectory has a similar process as the rail deflection one for the track section in the middle side of the void. The similarities of wheel and rail dynamic behavior in the voided zone are clearly presented on the acceleration diagrams, explained by the mutual oscillation of wheel and rail while passing the void zone. Thus, the dynamic behavior due to the voided zone is present in both track-side and on-board measurements, which can be used for void monitoring and identification.The simulation results for the equivalent to void geometric irregularity are presented in To provide a consistent analysis of the dynamic behavior, a comparison of the wheel trajectory and accelerations for different depths of void and the equivalent geometrical irregularities is presented in The wheel dynamic behavior in the equivalent geometric irregularities for the different void depth is different to the void case. The wheel oscillations are formed by the wave of the irregularity and some similarity to the impact interaction is caused by the applied equivalent irregularity derived from the void irregularity.The presented analysis of the dynamic behavior in the void zone shows the differences to the similar geometric irregularity both from the viewpoint of the track-side and on-board measurements. Different to the track-side measurements, the on-board measurements do not allow to determine the deflection of the rail elastic wave. However, the wheel trajectory variation due to the rail deflection within the void depth can be theoretically identified using the features of the dynamic interaction in the void zone. The similarities of the track-side and on-board measurements enable to use the track-side measurements for the identification of the voids from on-board ones after filtering the low frequency part of rail elastic wave deflection.To explore the time-frequency differences of the simulated accelerations, wavelet scattering analysis is used. The research approaches in mechanical and railway engineering over the recent decades are characterized by a growing interest in applying wavelet frameworks to signal processing. The continuous wavelet transform method and global wavelet power spectra were used for evaluating degradation at railway crossings using axle-box acceleration measurements in . A data-The wavelet analysis has the benefit of multilevel and flexible time frequency resolution that results in the advantage of time localization and stability over Fourier transforms. However, it has more computational complexity and discrete wavelet transform or wavelet packet decomposition do not separate the carrier and modulated frequency on amplitude modulation . The ensThe wavelet scattering transform (WST), applied in the present study, forms translation and time-invariant, stable, and informative signal representations. It is stable to deformations and preserves class discriminability, which makes it particularly effective for classification. The WST has wavelet advantages with the application of a scaling window and a complex wavelet operator cascaded by averaging convolution to extract information. Moreover, it requires less computation, signal energy can be concentrated at a low bandwidth, features can be extracted at any layer.The overall process of WST consists of three main operations: convolution, nonlinearity and averaging, as described in s to the , top: thThe Matlab wavelet scattering tools  were useBefore extracting the features from the modelled signals, the signals are oversampled to correspond to the experimentally determined signal length. The features of wavelet scattering coefficients are extracted for the number of resolutions across all orders of the scattering transform and the resolution of the scattering coefficients. The wavelet time scattering decomposition is constructed with the two filter banks: eight wavelets per octave in the first filter bank and one wavelet per octave in the second filter bank. The overall number of extracted features is 1232 for the signal length 2100, which corresponds to the measured signal sets. The diagrams of extracted features for the cases of void irregularities and the geometrical one as well as their significance are presented in The region of interest for the void detection are features 10 to 25 and 122 to 128, where the difference between the 2-, 3-, 4-mm lines are the lowest, which can be used as a common void indicator. The aim of the section is the development of an efficient method for in situ measurements and the collection of the statistical information to use for the development of the method for void identification and classification using track-side and on-board measurements. The in situ information collection from many different void zones is based on high efficiency multipoint photogrammetric measurements with low-cost, high-speed cameras. Additionally, control measurements with conventional methods were applied for the photogrammetric method validation.Image and video processing methods in the photogrammetric measurements are often used for railway and civil engineering applications. The application of a system of synchronized high-speed cameras to measure absolute longitudinal and vertical rail displacements using DIC is presented in . The DICThe application of the photogrammetric method for the diagnostic of transition zones is presented in ,69. The Another trend in the application of image and video-processing methods is related to deep-learning computer vision algorithms such as YOLO3 and others ,73,74,75Most of the presented photogrammetric measurements studies are usually directed on a deflection measurement of a single point at one object with one camera. However, analysis of multiple points of relative motion could provide promising results, such as those presented in the studies ,77. The One of the most significant limitations of the reviewed studies is the low time-resolution of the used cameras that does not allow to acquire information about the dynamic impact of the sleepers on the ballast in the void zones. Additionally, most of the studies were used for a limited number of measurements due to the method complexity, which did not allow to collect the statistical information. The limitations are taken into account in the present study. The proposed method for the sleeper void identification is based on experimental information collected in track-side measurements of multipoint rail deflection. The high-speed video recording measurements were carried out in 15 different problem zones of Swiss railways (SBB) by infrastructure managers. The measurement evaluations were produced by ETH Z\u00fcrich  and TU DThe measurement of rail deflection using high-speed video recordings is a cost-effective alternative to the LVDT  measurement, which enabled the collection of statistical information. The application of the DIC method increases the accuracy of marker tracking from 0.61 mm/pixels to about \u00b10.05 mm, which makes the accuracy of the video method sufficient for low rail-deflections in the reference zones , top. AdThe typical measurement cases for different void damage from low to high are shown in A data-driven approach is used to recover the relation of the measured rail accelerations and sleeper support conditions. The relation is used for the development of the method for sleeper void detection and quantification using track-side and on-board measurements.Various data-driven approaches were proposed in numerous studies on railway infrastructure diagnostics over the last years. A one-dimensional convolutional neural network was proposed in the study  for damaThe study  exploresMost of the presented studies are based on data-driven deep-learning approaches, spectral signal processing for feature extraction and either experimental or simulation-based sources of statistical information. However, only a few studies present both data-driven and model-based approaches together. The application of mathematical modelling and numerical simulation could potentially improve the data-driven approach. On the other side, some studies replace real measurements with the simulated ones without comparison to experimental measurements.The present statistical investigation is based on experimental data collected from 15 damage zones using the developed high-speed photogrammetrical tool for rail deflection measurements. Thereby, the simulation results of the track\u2013train dynamic interaction in voided and reference zones as well as their time-frequency analysis are used to improve the data-driven approach. The improvement consists of the additional model-based feature selection. The flowchart of the statistical processing is presented in The acceleration time series dataset is in the second step processes to extract time-frequency domain features using the previously constructed wavelet scattering network. After the feature extraction, the dimension is reduced from 2000 time-series variables for the input data to 154 wavelet scattering features. After the following model-based feature selection, the number of features is reduced to 88. In the next step, two supervised machine learning approaches were used: support vector machine (SVM) and k-nearest neighbor classifier (KNN). The main reason why the machine learning methods were preferred to the popular deep learning ones is the relatively small dataset of the experimental measurements. Additionally, the machine learning models are simpler in interpretation.The rail deflection dataset consists of two groups: the first for the measurements in the various ballast damage zones and the second for the simultaneous measurement in the reference zone, 10 outside the void zone. Each measurement zone is equipped by three markers for rail deflection measurements. The measurements were carried out in each measurement zone for about 12 train passages of different train types with velocities in range the of 100 to 160 km/h. The overall dataset of successful measurements is 652 time series. The comparison of the time-series datasets for the void and reference zone is presented in The histograms of maximal rail deflection distribution in the voided and reference zone are depicted in The acceleration datasets derived from deflections are presented in he paper , where tIn order to carry out on-board monitoring of voided sleepers, the decision rules should be obtained that enable, based on the acceleration measurement as input, to decide the severity degree of the void damage as the output. Here, we present a way to establish a decision rule. Three levels of severity are considered: void-free zone, void with depth less 3 mm, and void with more than 3 mm depth. The data are labelled in the corresponding classes: REF, HL1 and HL2. The data are randomly split in 70/30 training and test datasets and a fivefold cross-validation scheme was used.The cubic SVM and fine KNN classifiers were used to obtain the optimal decision boundaries between classes of sleeper support state. The KNN algorithm is a robust and simple classifier . It is bThe SVM classifier finds the optimal decision boundary with regard to the bias variance trade-off. It stays accurate to the training points and makes an accurate prediction with new points. The SVM presents the advantages, compared to other machine learning techniques, that it can make both linear and non-linear classifications and can better deal with outliers than KNN. The classification results for cubic SVM is presented in To prove the applicability of the developed method of void identification, the trained statistical models were applied for a real on-board measurement. The sleeper support conditions on a common crossing were estimated using on-board inertial measurements on a regular train , left 1. TherebyThe classification results for the SVM and KNN classifiers are presented in The research review presents many approaches on track-side and on-board track conditions identification. However, only on-board inertial measurements could be a cost-effective and frequent method for the sleeper support condition estimation. Many studies demonstrate that the on-board measurements from regular trains can provide the comparable condition estimation as the exact but expensive measurement trains. Thereby, the main difficulty is the correct interpretation of the inertial measurements. Other studies present a successful application of artificial intelligence methods for railway engineering applications.The mechanical modeling shows that the track dynamic behavior in the void zone was different to the equivalent geometrical irregularity specific pattern. The pattern is related to one or more dynamic impacts of the rail-sleepers grid to the ballast bed during void closure. The impacts appear in the zone before the wheel reaches it. The applied wavelet scattering to modelled on-board accelerations allowed to create the framework for the automatic extraction of significant features of the voided zone. Additionally, modelling shows that the dynamic behavior due to the voided zone is present in both track-side and on-board measurements.The statistical data about the dynamic behavior of railway track in many voided zones were collected using high-speed video cameras. The developed computer vision software allowed to extract exact and free-from-interference multipoint information about the rail vibrations. The method is simpler and more efficient than the conventional LVDT method, which allowed quick and cost-effective information collection from many problem zones.The collected statistical information was used to train the machine learning classifier models. The time series is separated in two independent variables: the vector of maximal sleeper void and the corresponding rail acceleration series dataset. Thereby, the Winkler-line rail deflections process is removed from rail deflections to avoid the bias to the predictor variable. An additional reason for the high-pass filtering is the intention to investigate the vibration information that is the same both for the track-side and on-board measurements. The model testing using a fully independent dataset demonstrated good enough classification results.However, the classification with the real on-board measurements of an axle-box acceleration on a common crossing was not so optimistic. There are many explanations for the insufficient good classification results of the on-board axle-box measurements on the common crossing. The mechanical explanation is that the measurements on the common crossing have the influence of the complicated geometrical irregularities that influence the wheel trajectory. The wheel accelerations depend on the long-wave structural irregularity, short-wave wear irregularity under the influence of lateral wheel position and the wheel profile irregularities itself ,53,96. TThe statistical reason of insufficient classification results is that only three measurements were used for the void estimation. Many experimental studies on wheel and rail common crossing interaction show that the axle-box acceleration measurements are subjected to high random variation due to many influencing factors. Thus, sleeper condition estimation with many different on-board measurements would bring more certainty to the classification results. The bad differentiation between the HL1 and HL2 for both classes can also be explained with unknown true state of the sleeper support condition for 4.7 Mt and 26.8 Mt since the tamping works produced are not known. The good support condition with the low void can be assumed for the measurement 0.07 Mt. However, even in this case, an insignificant void cannot be excluded due to impact interaction in the crossing zone that causes quick differential settlements.(1)One or more dynamic impacts of the rail-sleepers grid to the ballast bed occurs while void closure happens.(2)The track dynamic behavior in the void zone is different to the geometrical irregularity-specific pattern.(3)The similar dynamic behavior due to the voided zone is present in both track-side and on-board measurements.(4)The developed framework for the wavelet scattering feature extraction together with mechanical modeling allow to select the significant features for the void zone.(5)The application of machine learning methods allows good enough automatic recognition of the void zones.(6)The pre-trained model testing for on-board measurements from a common crossing zone shows a moderate result of the void identification.The presented research shows the possibility to identify the void irregularity and classify its severity using both track-side and on-board measurements. The research is based on the data-driven approach supported by a mechanical model feature selection. The classification using simple machine learning methods shows good enough results for isolated void irregularities. However, the identification results at switch locations are less convincing due to the multiple other interactions taking place. The classification results could be further improved by using more advanced deep-learning methods. On the other hand, the application of the mechanical model for multiple irregularities could improve the data-driven classification. The following partial conclusions of the research can be proposed:"}
{"text": "Multiple myeloma is characterized by malignant proliferation of clonal plasma cells. Usually, appears as a generalized disease but it can present as solitary bone plasmacytoma or a solitary soft tissue mass or extramedullary plasmacytoma. In the case of extramedullary involvement, it could present as soft tissue plasmacytomas and the prognosis is poor. The 18F-FDG PET/CT could be a valuable tool for characterization of the medullary and extramedullary involvement. We present a case of F18-FDG PET/CT with extramedullary involvement with soft tissue plasmacytomas in the setting of MM. This showed multiple soft tissue masses in extremities, abdomen, and thorax wall with high FDG uptake and hypermetabolic lytic bone lesions  is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment (Palumbo and Anderson The role of imaging in the work-up of patients with MM is aimed at allowing the recognition of both the effects of myeloma cells on the skeletal system and the presence of extramedullary disease (Nanni and Zamagni F18-FDG PET/CT can help to identify areas of metabolic activity in whole body that represent clonal plasma cell proliferation while MRI is particularly well suited for the imaging of bone marrow (Ferraro et al. This case represents an unusual presentation of multiple myeloma in 18F-FDG PET/CT and emphasizes on the value of whole-body images for characterization of the medullary and extramedullary involvement."}
{"text": "The positions of the transmission spectra maxima in a one-component film are different for different film thicknesses. The best correlation of the maxima positions of the dye transmission spectra in solid and liquid solutions was observed for thicknesses of films close to a few (up to 10) monolayers. On the other hand, the absorption spectra maxima positions of one-component dye films (upper 10 nm) and composite films with high concentration, did not match the corresponding positions of absorption spectra maxima recorded in solutions. Comparison of the absorption spectra in one-component dye films and in solutions indicates the presence of both monomers and their aggregates in one-component films . Simultaneously with aggregation manifestation in the absorption spectra, the intensity of fluorescence of one-component dye films dramatically decreases. A quantum chemical simulation of the possible relative arrangement of two dye molecules indicates that the most possible of the simplest types of aggregates are physical dimers. Films of practical importance  possess a high quantum yield of fluorescence when reaching an impurity concentration of a few percent (aggregation does not take place yet).The spectral properties of new boron-containing dyes were studied. One-component (pure dyes) and composite \u201cAlq This similarity indicates that, mainly, the dye molecules are involved in the film formation and there is no spectral manifestation of their fragments . The recorded absorption spectra of one-component films of all dye samples were compared with the absorption spectra of dyes in solution and in the solid matrix Alqifferent . Moreove3 matrix, which is not observed in composite films at low concentrations of dye. Therefore, in our opinion, the most probable explanation for the difference in the absorption spectra of dyes in solutions and one-component films is the presence of both monomers and dimers in the films.As can be seen from 3) molecules can be neglected). The parameters of the four lowest electron transitions in possible dimers of the dyes studied were calculated using the TD/DFT/ WB97XD method  for different configurations are shown in Scheme A corresponds to dimers of H-type (H-type dimer is the first stage of H-aggregate formation). In the case of The calculated dimer parameters (data of the first and higher excited states) were compared with data of the experimentally obtained absorption spectra see , Table 23 films. It was found that the dimers of such a type form involving guest dye molecules in the Alq3 matrix, starting at their concentration near 1\u20133%. The following increase in impurity concentration leads to a dramatically decreasing in a film\u2019s fluorescence intensity. This effect should be taken into account in the process of luminescent materials development based on the studied dyes.In summary, we can conclude that it is most likely that the structure of one-component films of the abovementioned dyes is formed due to both monomers and dimers that do not take place in liquid solutions. The absorption, fluorescence spectra, and quantum chemical calculations indicate that these dimers are dimers of H-type. These dimers form in one-component thin films of dyes as well as in their solid solutions in Alq"}
{"text": "The Editorial Office has been unable to confirm such findings directly with authorities at the institution in accordance with standard practice. Given the nature of the concerns raised, the Editor-in-Chief wishes to alert the readers to interpret the results presented here with caution.Corresponding authors Insug Kang and Eui-Ju Yeo stated on behalf of all co-authors that they agree to this Expression of Concern."}
{"text": "The objectives of this study were to investigate burnout in a sample of Irish Hospital Consultants and its association with psychopathology (symptoms of depression and anxiety). We examined the effect of personality factors on the development of psychopathology in response to burnout and in relation to work-related stress among the participants.This is a cross-sectional survey, utilising validated psychometric measures. Self-reported online questionnaires were distributed to all hospital consultants registered with the Irish Hospital Consultants Association distribution list and were completed between September to December 2016. Questionnaires sought to determine demographic information; work-related characteristics; burnout related phenomena: emotional exhaustion, depersonalization, and a reduced sense of personal effectiveness (Maslach Burnout Inventory [MBI-GS]); symptoms of depression and anxiety .A total of 477 hospital consultants  from hospitals in Ireland took part in the study. Of those studied, 42% reported high levels of burnout. The Depression and Anxiety Stress Scale revealed that Consultants were experiencing high levels of stress symptoms but comparatively low levels of anxiety symptoms. The study population scored highest on the conscientiousness and agreeableness subscales and lowest on the neuroticism subscale. Those who scored higher in the neuroticism subtype appeared to be at an increased risk of burnout.The prevalence of work-related burnout in consultants is of concern. The psychological burden of burnout is reflected in reported symptoms of stress and depression. Personality, particularly conscientiousness and agreeableness appears to impact the development of physician burnout. Strategies that modulate the relationship between personality and burnout may be beneficial for optimal health care delivery. Further research is needed to identify appropriate short and long-term strategies to ensure physician wellbeing and optimal delivery of patient care."}
{"text": "This study indicated the effect of the latent classes of stress on the physical and psychological health outcomes in Korea. Using the 2010 Korea Health Panel Study, 1,689 middle-aged adults  were analyzed to identify the latent classes of stress by gender using Latent Profile Analysis (LPA). After the determination of the number of latent classes, health outcomes  were also regressed on the latent classes including covariates . The perceived stresses  are classified as the 2-class model for women and the 3-class model for men. The classes of women are named 'high stress and 'low stress; however, the classes of men are named 'family-related stress', 'disease stress', and 'low stress.' The different combinations of stress are associated with anxiety/depression and health status respectively. This study will discuss the difference of latent stress classes by gender and extend the understanding of stress groups and health outcomes."}
{"text": "Following publication, concerns were raised regarding image manipulation. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiers' guidelines.This retraction was approved by the Chief Editors of Frontiers in Cellular and Development and the Editor-in-Chief of Frontiers. The authors [did] agree to this retraction."}
{"text": "A multimodality approach is often used in the management of high-grade soft tissue sarcoma of the extremity (eSTS). Limb-sparing surgery is the keystone of eSTS management, often accompanied with radiotherapy (RTX) and/or chemotherapy (CTX). The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guideline recommend RTX and CTX in selected groups of high-risk patients.Our cross-sectional study aimed to acquire insight into the variation of eSTS management across the world and to assess the importance of several clinicopathologic risk factors for the indication of multimodality therapy.The optimal management of patients with eSTS remains an important field of research. Recent developments of prediction tools and advances in genomics and proteomics may allow for better patient selection for multimodality therapy. Because in recent years some retrospective studies have been performed to assess the use of these tools for the indication of multimodality therapy, further studies are needed to improve patient selection for the indication of multimodality therapy, with a special focus on perioperative CTX and new perioperative modalities. Also, the cost-effectiveness of chest CT scan versus chest X-ray and the use of prognostic tools for patient-tailored follow-up regimen should be explored. Given the rarity and heterogeneity of eSTS, large collaborative efforts of international sarcoma centers are crucial to further improve patient-tailored management of eSTS."}
{"text": "Flavone acetic acid (FAA) is a novel antitumour agent that has a profound effect on the vasculature in murine tumour models. Previously we have shown that FAA induces a coagulopathy and thrombocytopaenia in tumour-bearing mice, and the purpose of the present study was to determine the significance of the FAA-induced intravascular coagulation in the antitumour action of FAA. Several anticoagulant agents were tested for their effectiveness in altering ex vivo coagulation of murine plasma; heparin and ancrod were found to be most effective. These agents were administered to tumour-bearing mice prior to FAA and TNF treatment with little effect on the induced regrowth delay. However: the FAA-induced consumption of platelets in tumour-bearing mice was not blocked by anticoagulant treatment. These data suggest that platelet consumption occurs independently of the normal coagulation pathway, and further that fibrin deposition may not be a major factor in the antitumour action of FAA."}
{"text": "We have analysed 174 gastric carcinomas from the United Kingdom and from Japan for the presence of Epstein-Barr virus (EBV) using in situ hybridisation for the small EBV-encoded nuclear RNAs (EBERs). EBV was detected in the tumour cells in all of six undifferentiated gastric carcinomas with prominent lymphoid stroma  but only in three of the remaining 168 typical gastric adenocarcinomas (1.8%). No differences were observed between the British and the Japanese cases. One case with an EBV-positive UCNT showed adjacent areas of EBV-negative typical adenocarcinoma. It is uncertain whether these patterns represent two independent carcinomas or whether they are the result of heterogeneous EBV infection in a single tumour. In the remaining EBV-positive carcinomas, viral transcripts were detected in virtually all tumour cells, indicating that EBV infection must have taken place early in the neoplastic process and suggesting that the virus is likely to be of pathogenetic significance for the virus-associated tumours. Immunohistology demonstrated absence of detectable levels of the EBV-encoded latent membrane protein, LMP1, and nuclear antigen, EBNA2. The BZLF1 protein which induces the switch from latent to lytic infection was demonstrated in a small proportion of the tumour cells in three cases. The close association of EBV with undifferentiated gastric carcinomas compared to the variable association with gastric adenocarcinomas suggests fundamentally different roles for the virus in the aetiology of these two malignancies."}
{"text": "Using the breast carcinoma cell line MDA-MB 468 as immunogen, we have produced six new rat monoclonal antibodies (mAbs) against the human EGF receptor (EGFR) and are investigating their use for diagnostic and therapeutic applications in cancer patients whose tumours overexpress these receptors. The mAbs  were selected on the basis that they bound to the extracellular domain of the EGFR and blocked growth factor-receptor interaction. Competitive assays showed that, with the exception of antibody ICR65, the mAbs bound to one of two distinct epitopes on the external domain of the EGFR. ICR65, however, cross-reacted with mAbs binding to both epitopes. All of the mAbs immunoprecipitated the 170 kDa glycoprotein from cells expressing the EGFR but not the 185 kDa product of the related c-erbB-2 proto-oncogene. Unlike EGF and TGF alpha none of the mAbs stimulated the growth of quiescent human foreskin fibroblasts but they inhibited the EGF and TGF alpha induced growth stimulation of these cells in vitro. When tested for their effect on tumour cells the mAbs were found to inhibit the growth in vitro of a number of human tumours that overexpressed the EGFR  but they were without effect on tumour cell lines expressing low or undetectable amounts of the receptor. Our initial results indicate that this new generation of antibodies which bind with high affinity to the EGFR, block growth factor-receptor interaction and inhibit the growth of human squamous carcinoma cell lines overexpressing the receptor have potential for clinical application."}
{"text": "A retrospective population-based case-control interview study has been conducted in three distinct areas in the north of England where local excesses of children with leukaemia have been reported. A total of 109 cases of childhood (0-14 years at diagnosis) leukaemia and non-Hodgkin's lymphoma who were born in one of the study areas and diagnosed there between 1974 and 1988 were included in the study. One control per case was matched on sex, date-of-birth and health district of birth. The objective was to compare residential histories of cases and controls and in particular to determine whether case children had lived in the same place at the same time more often than controls. The residential distance between two children was taken to be the smallest geographical distance between homes they had 'occupied' simultaneously for a period of at least 6 months between conception and diagnosis. Case children were more likely than expected to have other cases as their nearest neighbours by residential distance . A detailed examination of the nearest neighbour pattern permits the generation of further specific hypotheses. These suggest that persistent infection established in utero or early infancy may be involved in the development of some cases of childhood leukaemia. Horizontal transmission of the agent(s) within small communities may occur but there is no evidence of direct contact between cases."}
{"text": "Small-cell neuroendocrine carcinoma of the lung is known to express products related to the vasopressin gene, although these products have been reported to sometimes differ from those generated by neurones of the hypothalamo-neurohypophyseal system. To further investigate vasopressin gene expression in neuroendocrine carcinomas, we performed immunohistochemistry on 24 histologically classified small-cell carcinomas using antibodies directed against different regions of the vasopressin precursor. All of the tumours examined contained at least two parts of the vasopressin precursor, suggesting that vasopressin might have a biological role in these tumours and indicating a role for these products in tumour diagnosis and treatment. Sixty-seven per cent of the tumours contained immunoreactivity for all major regions of the precursor: vasopressin, vasopressin-associated human neurophysin, the bridging region between the hormone and the neurophysin, and vasopressin-associated human glycopeptide. However, 33% of the tumours examined appeared to express only part of the vasopressin precursor, as evidenced by the absence of immunoreactivity for the neurophysin and/or the glycopeptide. These results support the proposition that both normal and abnormal vasopressin gene expression occurs in small-cell carcinoma of the lung."}
{"text": "The provision of education, training and pedagogy, its associated science is being radically impacted by technological developments and changing methodologies in the imparting and acquisition of knowledge. This is resulting in the thrust and focus of higher education moving from a traditional university centred process to a more student-orientated one. The Internet's propensity for real-time interaction makes computer-based training, or distance learning, viable for accommodating medical education needs. In medicine many concepts are visual or structural and in many cases clinical reasoning is based on spatial abstraction of structures. Incorporating these principles, the Institute developed the concept of the Virtual Study Centre (VSC), utilising methodologies which take advantage of the developments in web based computing and communication infrastructures to specifically address the difficulties associated with existing methods of distance learning.The VSC is a 'hypermedia' learning environment, which offers a more flexible approach to learning for both producers and users of educational material. It is achieved through distributed student access to networked learning resources. A project team was established to define the specific models of learning scenarios where synchronous interaction played an important role. Utilising an assessment matrix based on the requirement outcomes of the learning scenarios, it evaluated products available in the web-based training area for quality, extent and complexity in respect to multimedia design, interactivity and overall ease of use. Each product had to comply with their criteria under the following headings: technical composition, infra-structural design, regional and cultural constraints. A compromise in the quality and speed of audio and video was not an option. To provide the best we expected the best from the products so that we could provide a well-crafted teaching system, which could be used throughout the medical profession.We have identified the optimal model based standards required in software tool-sets to develop and support multimedia web-based training.A fundamental element in the provision of distance education is interaction. This paper illustrates the considerable deficit in the availability of quality media-rich tool-sets on the market, which enables optimum interaction. It details the research undertaken in the provision of the levels of interaction necessary to provide a fully integrated web-based education facility and the difficulties of tailoring a traditionally taught course for the web. It develops and explores the issues surrounding the monitoring, examination and identification of students and defines an approach to underpin optimum tool-set assessment and utilisation."}
{"text": "S. cerevisiae and point out the value of this relatively untapped source of information.The recently emerged protein interaction network paradigm can provide novel and important insights into the innerworkings of a cell. Yet, the heavy burden of both false positive and false negative protein-protein interaction data casts doubt on the broader usefulness of these interaction sets. Approaches focusing on one-protein-at-a-time have been powerfully employed to demonstrate the high degree of conservation of proteins participating in numerous interactions; here, we expand his 'node' focused paradigm to investigate the relative persistence of 'link' based evolutionary signals in a protein interaction network of P. falciparum /Yeast orthologs, as proof-of-principle that high-order network topology can be used comparatively to deduce local network structure in non-model organisms.The trend for highly connected proteins to be preferably conserved in evolution is stable, even in the context of tremendous noise in the underlying protein interactions as well as in the assignment of orthology among five higher eukaryotes. We find that local clustering around interactions correlates with preferred evolutionary conservation of the participating proteins; furthermore the correlation between high local clustering and evolutionary conservation is accompanied by a stable elevated degree of coexpression of the interacting proteins. We use this conserved interaction data, combined with High local clustering is a criterion for the reliability of an interaction and coincides with preferred evolutionary conservation and significant coexpression. These strong and stable correlations indicate that evolutionary units go beyond a single protein to include the interactions among them. In particular, the stability of these signals in the face of extreme noise suggests that empirical protein interaction data can be integrated with orthologous clustering around these protein interactions to reliably infer local network structures in non-model organisms. H. pylori  reflects the number of the bin we assign a data point with a xi coordinate. Representing the nith bin on the x-axis, we place On a logarithmic scale, we define the bin size The advantage of logarithmic binning is an elevated degree of noise reduction which is dependent on the bin size ,43. Althcontains detailed statistical measurements of presented correlations. Furthermore, we show results of the perturbation analysis of coexpression coefficients as briefly addressed in the main paper.Click here for file"}
{"text": "Using in vitro techniques, bone marrow (BM) function has been studied in 25 patients in complete remission and at least one year after the completion of MVPP chemotherapy for Hodgkin's disease. The numbers of granulocyte/macrophage (GM-CFC) and fibroblastoid (CFU-F) progenitors were significantly lower than controls and there was no evidence of any improvement with time (median months off treatment was 30 for GM-CFC and 34 for CFU-F). In long-term BM culture production of haemopoietic cells were strikingly lower in the post-MVPP group and the development of adherent stromal cell populations was also significantly less. In addition, the yield of GM-CFC in adherent layers after four weeks of culture was significantly lower than in controls. We conclude that following MVPP chemotherapy and in apparently disease free and haematologically normal individuals there is evidence of impaired BM function up to nine years after the completion of treatment. These abnormalities may be relevant to the known increased risk of acute non-lymphocytic leukaemias in this group of patients and are likely to render the BM less able to withstand subsequent insults such as further chemotherapy or infection. The eventual development of BM failure is also a possibility and long-term follow-up of these patients is essential."}
{"text": "The clinical use of anti-oestrogens in breast cancer therapy has traditionally been restricted to tumours that contain measurable oestrogen receptor protein. However, it is now widely recognised that the clinical response to adjuvant anti-oestrogen therapy appears to be independent of the oestrogen receptor content of the primary tumour. The study reported here was designed to investigate the possibility that human stromal cells can respond to anti-oestrogens by an increased synthesis of the inhibitory growth factor, transforming growth factor beta (TGF-beta). Two established human fetal fibroblast strains were used as models for the breast cancer stromal fibroblasts. These cells were found to respond to the addition of anti-oestrogens by a large increase in their synthesis of biologically active TGF-beta. Despite the application of ligand binding, immunoassay and Northern analysis, no oestrogen receptor or oestrogen receptor mRNA was detected in either of the human fetal fibroblasts strains. These observations may provide a mechanism of action of anti-oestrogens that is independent of the presence of oestrogen receptor in the tumour epithelial cells, and thus provide an explantation for the counter-intuitive results of adjuvant anti-oestrogen action."}
{"text": "The Hospital Anxiety and Depression Scale (HADS) is a widely used screening tool designed as a case detector for clinically relevant anxiety and depression. Recent studies of the HADS in coronary heart disease (CHD) patients in European countries suggest it comprises three, rather than two, underlying sub-scale dimensions. The factor structure of the Chinese version of the HADS was evaluated in patients with CHD in mainland China.Confirmatory factor analysis (CFA) was conducted on self-report HADS forms from 154 Chinese CHD patients.Little difference was observed in model fit between best performing three-factor and two-factor models.The current observations are inconsistent with recent studies highlighting a dominant underlying tri-dimensional structure to the HADS in CHD patients. The Chinese version of the HADS may perform differently to European language versions of the instrument in patients with CHD. In China, economic transition, urbanization, industrialization and an aging population have quickly increased the incidence and prevalence of coronary heart disease (CHD) in the past decades . CHD hasThe Hospital Anxiety and Depression Scale (HADS)  is a widThe original English version has been translated into and validated in many languages, including Chinese -12. The A recent review  of the HIn Europe, the HADS has been applied extensively in the studies of patients with CHD as an index of both outcome and the effect of therapeutic intervention -23. TherThe study used a cross-sectional design. To address the research question confirmatory factor analysis methods were used on a pooled HADS data set from mainland Mandarin-speaking patients admitted to hospital with CHD.The factor structure of the HADS was determined using confirmatory factor analysis using Mplus version 3 . The weiThe first author administered the Chinese version of HADS to patients for self-completion. Demographic data and medical history were also obtained from patients and medical charts.One hundred and sixty patients with CHD were initially enrolled into the study of which 154 completed the questionnaires. The patients ranged in age from 38 to 86 years with a mean age of 60 years (SD = 10.37). One hundred and twenty (77.9%) patients were males. In terms of the clinical data, over two thirds of subjects were angina patients. The study was conducted in the general cardiovascular wards of two large university-based teaching hospitals in Xi'an City of China. Inclusion criteria were diagnoses of angina pectoris or myocardial infarction, no known psychiatric problems, and could understand Chinese. The study was conducted over a four-month period. The clinical ethical committee of the two university affiliated hospitals in Xi'an approved the study. Informed consent was obtained from all patients prior to commencement of the study.The mean HADS anxiety (HADS-A) sub-scale score was 6.16 (SD 3.86) and the mean HADS depression (HADS-D) sub-scale score was 6.43 SD 4.12). Based on Snaith and Zigmond's  interpre. Based oThe finding of high proportions of Chinese CHD patients screening positive with anxiety and depression using the HADS is consistent with previous studies conducted in China or in western countries ,5,34,35The CFA findings are in many respects, rather surprising. It has been suggested that the bi-dimensional underlying factor structure of the HADS observed in many early psychometric evaluations of this instrument is an artifact of the factor extraction method  and that the instrument is indeed tri-dimensional, a perspective supportive by more recent studies using CFA . In studGiven the observation that tri-dimensional models offered a similar fit to the data as bi-dimensional models, the issue of scoring the instrument as a tri-dimensional instrument is worthy of discussion. It has been previously suggested that the HADS could be scored as a three sub-scale instrument . HoweverThe finding of virtually identical fit characteristics of the best performing two and three-factor models also raises the issue of conclusively defining the underlying factor structure of the HADS. The HADS clearly cannot be both bi-dimensional and tri-dimensional within the same data set and further clarification of the structure of the instrument is desirable since this may provide additional evidence not only on the limitations of the HADS, but also the development, enhancement and possible future revision of this widely used measure. The current study was limited by sample size and this may be an important factor in clarifying the relative performance of the competing models tested. It is worthy of note that a number of studies that have utilised factor analysis with large sample sizes have found a clear advantage in model fit of tri-dimensional models over the traditional anxiety/depression bi-dimensional model of the HADS ,18,26. LPrevious findings of the factor structure of the Chinese version of the HADS in Cantonese-speaking Chinese CHD patients in Hong Kong indicates clear and consistent superiority of three-factor models in fits to data . One posThe original validation of the Chinese version of the HADS  identifiIt should be acknowledged that the current study had a number of limitations, in particular, the modest sample size and the absence of a comparison to a 'gold standard' such as a structured clinical interview to assess for anxiety and depressive disorder. Further research addressing these limitations is recommended.WW participated in the design of the study and assisted in the drafting of the manuscript. VL participated in the design of the study and assisted in the drafting of the manuscript. CM participated in the design of the study, performed the statistical analysis and assisted in the drafting of the manuscript."}
{"text": "Multiple primary tumours occurring in a three-year population-based series of patients with histopathologically peer-reviewed sarcomas from North West England were ascertained in order to look at the patterns of neoplasms seen. A total of 30 out of the 310 patients entered in the study had additional primary tumours. Very few patients were aged under 60 years at diagnosis of both their malignancies. The youngest was a known case of neurofibromatosis and, although seven patients were diagnosed with a sarcoma and carcinoma of the breast--a combination of cancers characteristic of the Li-Fraumeni cancer family syndrome--no other patients could directly be identified as suffering from any other cancer predisposition syndrome."}
{"text": "We quantified and examined the kinetics of DNA interstrand cross links (DNA-ISC) caused by Cis dichlorodiammine platinum (DDP) using the method of alkaline elution in 58 highly purified human ovarian tumours growing in primary culture. A large heterogeneity in both the quantity and kinetics of DDP induced DNA-ISC was observed in cultures derived from neoplasms of different patients and from different lesions of the same patient. In the majority of cases. DNA-ISC lasted for prolonged time intervals after 1 h drug exposure, being significantly repaired only 48 or 72 h following drug washout. The persistence of DNA-ISC is probably due to a prolonged formation of these lesions for up to 24 h as assessed by the change in the repair kinetics that occurred after preventing new DNA-ISC formation by quenching of monoadducts with thiourea. The inefficient repair of DDP monoadducts appears therefore to be a possible reason for the permanence of DNA-ISC. These studies suggest that the long permanence of DNA-ISC in human ovarian cancer could be the basis for the high selectivity of DDP for this human malignancy."}
{"text": "The prevalence of nausea and emesis among a series of out-patients (n = 95) receiving mainly mild-to moderately-emetic cytotoxics, was assessed, along with levels of psychological morbidity. Particular focus was given to the rates of psychologically-based (anticipatory) nausea and emesis. Results indicated that 23% of patients experienced anticipatory nausea and the majority reported that this occurred before at least half of the previous treatment cycles. Both emetic challenge of chemotherapy regimen and younger age were linked to this anticipatory effect. The data clearly indicated that nausea and emesis, both post-treatment and in anticipation of treatment, carried a psychological cost with anxiety being highest in those experiencing anticipatory nausea and/or emesis. The role of anxiety in the aetiology of psychologically-based nausea and emesis was not evaluated and it is considered that a prospective study is needed to clarify the exact contribution of psychological factors in the incidence of both post-treatment and anticipatory side-effects."}
{"text": "Samples of colorectal carcinoma, adenoma and normal colorectal mucosa were examined for the expression of TGF-beta by immunohistochemistry. Immunoreactivity for TGF-beta was present in 52 out of a total of 58 samples of normal mucosa examined. In adenomas and carcinomas TGF-beta expression was observed in eight out of ten and 46 out of 48 samples respectively and was largely restricted to epithelial cells. In normal mucosa differential expression of TGF-beta was present within epithelial cells, those in the upper parts of the crypts showing enhanced immunoreactivity compared to cells in the proliferative compartment. This pattern of differential staining is consistent with TGF-beta having an important role in the control of growth and differentiation in colonic mucosa."}
{"text": "Initial classifications of 1009 testicular tumours were reviewed as part of a population based survey of all testicular neoplasms in Victoria, Australia, between 1950 and 1978. All reviews were made by one of two pathologists at the Peter MacCallum Cancer Institute, using the system of the British Testicular Tumour Panel. Accuracy of diagnosis varied markedly over the time period and with pathological category. Seven cases were initially designated malignancies but were determined to be non-malignant conditions upon review. In each decade, review reduced the proportion of seminomas and increased the proportion of non-seminoma germ cell tumours (NSGCT) and non germ cell tumours. Reclassification resulted in changed age specific incidences of seminoma and NSGCT, most noticeably in 1950-59. Trends in age standardised incidence of seminoma and NSGCT were not affected by reclassification although the values were. The trend in age standardised incidence of non germ cell tumours was affected by reclassification. The implications of the changes in classification for epidemiological studies and clinical management are discussed."}
{"text": "The mutagenic and cytotoxic activity of two newly synthesized doxorubicin derivatives and of one daunorubicin derivative were studied in V79 Chinese hamster cells and bacteria . The results showed that all the compounds tested were cytotoxic and mutagenic for both prokaryotic and eukaryotic cells. However, in both systems, the two 4-desmethoxy- and the 4'-desoxy-derivatives were more active than the parent compounds, indicating that modifications in the aglycone or in the sugar moiety can produce appreciable changes in the biological properties of the anthracycline antibiotics. The in vitro activities observed in this study correlated with the in vivo antitumour potency."}
{"text": "Multiple sclerosis is a chronic disease of uncertain aetiology. Variations in its disease course make it difficult to impossible to accurately determine the prognosis of individual patients. The Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) developed an \"online analytical processing (OLAP)\" tool that takes advantage of extant clinical trials data and allows one to model the near term future course of this chronic disease for an individual patient.For a given patient the most similar patients of the SLCMSR database are intelligently selected by a model-based matching algorithm integrated into an OLAP-tool to enable real time, web-based statistical analyses. The underlying database (last update April 2005) contains 1,059 patients derived from 30 placebo arms of controlled clinical trials. Demographic information on the entire database and the portion selected for comparison are displayed. The result of the statistical comparison is provided as a display of the course of Expanded Disability Status Scale (EDSS) for individuals in the database with regions of probable progression over time, along with their mean relapse rate. Kaplan-Meier curves for time to sustained progression in the EDSS and time to requirement of constant assistance to walk (EDSS 6) are also displayed. The software-application OLAP anticipates the input MS patient's course on the basis of baseline values and the known course of disease for similar patients who have been followed in clinical trials.This simulation could be useful for physicians, researchers and other professionals who counsel patients on therapeutic options. The application can be modified for studying the natural history of other chronic diseases, if and when similar datasets on which the OLAP operates exist. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. Currently there is no cure for MS, but there are treatments for its relapsing forms that reduce the short and mid-range impact of the disease. It remains impossible to accurately predict the prognosis of individual patients, which could be important for patient counselling and in weighing therapeutic options. The Sylvia Lawry Centre for MS Research in Munich (SLCMSR) uses data from clinical trials and natural history studies to develop mathematical models for the course of the disease which might assist in the efforts to accurately determine short, mid and long-range prognosis. The \"individual risk profile\" project makes the Centre's large database available to health care professionals via access to a representative part of the database.The SLCMSR database consist of data from most natural history studies and the placebo arms of nearly all randomised controlled clinical trials in MS patients from the last decade. The data are anonymised, homogenized and pooled from the academic and corporate sources. As of April 2005, 45 separate data sets and 81,000 patient-years of data from 20,000 patients were included. The database is divided into so-called \"open\" and \"closed\" parts. The \"open\" database is accessible by researchers  at their discretion. The \"closed\" database is accessible only to authorized staff on behalf of the Validation Committee of the Centre as part of the validation policy of the SLCMSR [An interdisciplinary team of neurologists, information technology specialists, and biostatisticians developed a Java-based OLAP tool using the statistical software package R 2.0.1 . The souRegistered OLAP users access the database via their internet browser, select values for patient characteristics of their interest and get displays of the observed disease course for placebo patients from the database with matching characteristics.The essential component of the OLAP is a matching algorithm. A given patient of interest is \"identified\" by a set of covariates which are widely accepted to be potential prognostic factors -7: the nThis descriptive report is based on 1,059 patients from placebo arms of controlled clinical trials available from release 1.0 of the SLCMSR database (April 2005).The patient baseline characteristics of the database are summarized in table The advantages of OLAP-tools based on a unified database (\"data warehousing\") are widely applied in business and increasingly used in medical research and medical decision-making. In this report we describe a tool for investigating the course of MS based on specific clinical data and using that information to project disease course in patients of interest.The predictive power of this tool is limited by restrictions of the composition of patients and duration of observations in the current release of the database. The clinical data are restricted to data from the placebo groups of randomized clinical trials, which may not reflect disease outcomes in patients not involved in clinical trials and certainly do not reflect the impact of daily disease management of patients in non-research clinical settings. Additionally, the observation period of the included patients is limited to a maximum of 3 years (median follow-up 2.2 years) of observation, thus limiting the ability to accurately project longer term outcomes for patients with what is a life-long disease.A comparison of the tool with population based prevalence cohorts -7 is theIn addition, the utility of the OLAP tool as a predictor of disease course is limited by the patient characteristics in the parent dataset. For instance, there are only a small number of patients with a primary progressive course of MS in the SLCMSR dataset, and this subtype cannot be sufficiently analysed yet. The advantage of the OLAP tool (compared with a purely model based prediction), however, is that this limitation is transparent to the user figure .The \"individual risk profile\" project is based on a comprehensive database and the programming of an OLAP-tool. Our initial intention is to pilot the use of the database amongst neurologists and other researchers experienced in MS with an interest in clinical trials. This phase should provide informed feedback on the utility of the tool for clinical or research use. Updated versions are planned with expanded databases in particular inclusion of long-term natural history data and a broader spectrum of predictors.Most developmental steps of this project as well as principles of the creation of the underlying database are not disease-specific. It will be of interest to apply the methods and software developed at the SLCMSR for studying MS to other chronic diseases like heart failure, chronic obstructive pulmonary disease, or diabetes mellitus.Project name: OLAP Individual Risk ProfileProject home page: Operating systems: Web based applicationProgramming language: R, JavaOther requirements: CSS1/UTF-8 compliant browser is required License: Free, anyone may use the service for non-commercial purposes.Any restrictions to use by non-academics: No.The author(s) declare that they have no competing interest.Martin Daumer and Michael Scholz developed together the idea, Michael Scholz implemented the first version of the tool, and Christian Lederer planned and devised the refined method. Christian Lederer and Anneke Neuhaus programmed the current version of the OLAP-tool. Jerry Wolinsky is chair of the SLC's scientific advisory committee and has tested and evaluated several versions of the tool. All co-authors contributed in critically discussing the overall concept, testing the tool in various stages of its development in on site and during joint conference calls, writing and critical reviewing the manuscript. All coauthors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:IRPolap.R. The R source code underlying the IRP web application.Click here for file"}
{"text": "To determine the cause of the increased content of carbohydrate-bound phosphate in tumour lysosomal hydrolases, the activity and kinetics in human hepatocellular carcinoma of two enzymes involved in the formation of mannose-6-phosphate in lysosomal hydrolases UDP-GlcNAc: lysosomal enzyme GlcNAc alpha l-phosphotransferase (GlcNAc-phosphotransferase) and phosphodiester glycosidase were studied. The activity level of the phosphotransferase with artificial and natural substrates was elevated  in hepatoma compared to that in uninvolved tissue, while the phosphodiester glycosidase of hepatoma was at a level similar to that of the uninvolved tissue. To verify a previous observation that cathepsin D of human hepatoma contained increased GlcNAc-phosphomannose, the protease was examined for carbohydrate phosphorylation by the GlcNAc-phosphotransferase. The protease from normal human liver was much more phosphorylated than hepatoma protease, confirming the previous observation. The predominant phosphorylation of the protease occurred in one of two major heavy subunits, with some phosphorylation in one of two minor light subunits."}
{"text": "A cytogenetic follow-up study of patients treated with chemotherapy for gestational trophoblastic tumours was undertaken. In some cases, high levels of chromosome damage were found to persist in lymphocytes for several years after completion of therapy. These results are compared with those found in similar studies of non-malignant and other malignant diseases. The relevance of these findings to the risk of subsequent chemotherapy-induced malignancy is discussed."}
{"text": "This is a short comment on the editorial on Electromagnetic Interference in Implantable Rhythm Devices - The Indian Scenario in the July-September issue of the journal . Regardi"}
{"text": "An analysis of cytology reporting within Victorian Cytology Service demonstrates that the proportion of Papanicolaou smears which were reported as including an endocervical component increased from approximately one half during 1987-89 to more than three quarters during 1990-91. The improvement coincided with the routine provision of special sampling instruments to all practitioners supplemented by an education program. Despite the increase in endocervical sampling, no increase in the rate of reporting of high-grade intraepithelial lesions of the cervix has occurred. An increase between the two time periods in the cytological reporting of adenocarcinoma, adenocarcinoma in situ and endocervical dyskaryosis has occurred, but does not reach statistical significance."}
{"text": "To evaluate the natural history of a disease and the effects of therapeutic interventions, it is important to determine which are the causes of treatment failure and to assess the extent to which each cause contributes to the total failure rate. The paper presents a new biostatistical technique to decompose the total event-free survival of a diseased population into cause-specific failure rates. The technique was based on a competing risk approach thereby avoiding biases related to assumptions of independence between different types of event. Such assumptions are inherent in the conventional Kaplan-Meier or actuarial methods. The competing risk method was used to analyse the pattern of failure among 2,850 pre- and postmenopausal patients with early-stage breast cancer and the results were compared to those obtained using conventional methods. The following events were analysed: loco-regional recurrence, distant metastasis, contralateral breast cancer, other new primary malignancies, and intercurrent deaths. The rate of new primary malignancies was found to be significantly higher in post- than in premenopausal patients (6% vs 3% at 10 years). In low-risk, node-negative postmenopausal patients the incidence of recurrences from breast cancer were found to be no greater than other types of events. This observation highlights the significance of the effect of different adjuvant therapies not only on the disease itself but also on the risk of second primary malignancies and other intercurrent diseases. In general, it was found that the conventional statistical methods tended to overestimate the event-specific rates. In conclusion, the method based on competing risks permits an unbiased analysis of all types of events determining the total event-free survival. It is thus useful for the description of the natural history of breast cancer as well as other diseases."}
{"text": "The binding and biological activity of human TNF alpha on endothelial and tumour cells has been studied in the presence of monoclonal antibodies (MAbs). In particular, one monoclonal antibody to TNF alpha (MAb 32) has been identified which failed to inhibit binding and cytotoxicity of TNF alpha on WEHI-164 tumour cells but which was a potent inhibitor of TNF alpha-induced endothelial cell procoagulant activity on bovine aortic endothelial cells. The ability of MAb 32 to inhibit selectively the actions of TNF alpha on endothelial cells but not on tumour cells suggests a mechanism for enhancement of the anti-tumour action of TNF alpha in vivo when in complex with this antibody. Treatment of tumour bearing mice (WEHI-164 and Meth A fibrosarcoma) with TNF alpha-MAb 32 complex resulted in a 5- to 10-fold enhancement in the potency of the cytokine in comparison to free TNF alpha. Complexes between this cytokine and other MAbs generally resulted in either no effect or inhibition of TNF alpha activity in vivo and in vitro. Neither intact MAb 32 nor FAb' fragments of MAb 32 showed any tumour regressive activity in the absence of TNF alpha. The FAb' fragments were equipotent to the bivalent form of the antibody in enhancing TNF alpha activity. These data provide evidence that it is possible to segregate the individual biological activities of TNF alpha with concomitant enhancement of the tumour regressive activity of the cytokine in vivo."}
{"text": "Cytokinetic parameters of various types of lung cancer were determined in bronchoscopy specimens after in vivo labelling with the thymidine analogue bromodeoxyuridine (BrdU). The S-phase fraction and BrdU labelling index were measured flow cytometrically, allowing calculation of the S-phase transit time and potential tumour doubling time. The methodology used was found to be feasible for obtaining cytokinetic data from 76% of the bronchial biopsy samples. Despite the difference in clinical behaviour and growth pattern between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), no significant differences were observed between the mean values of the cytokinetic parameters of SCLC and NSCLC. The estimated cell loss factor was higher in NSCLC than in SCLC. It appears that the growth of a tumour, as clinically observed, is to a considerable extent influenced by cell loss. In accord with this assumption is the fact that we have observed non-BrdU labelled S-phase cells, both in tumour biopsies and in apparently normal tissue. The presence of these so-called unlabelled S-phase cells in relation to cell loss is discussed."}
{"text": "Burkitt's lymphoma, an Epstein-Barr virus (EBV)-associated non-Hodgkin's malignant lymphoma is endemic in an area of Africa known as the Lymphoma Belt. This zone is demarcated by climatic requirements of temperature and rainfall. EBV-activating plant factors are among several co-factors which have been proposed for the development of epidemic Burkitt's Lymphoma (eBL). The distribution of Euphorbia tirucalli, a plant which possesses EBV-activating substances and can induce the characteristic 8:14 translocation of eBL in EBV-infected lymphoblastic cell lines in vitro, conforms closely to the climatic requirements of the Lymphoma. This plant, other EBV-activating plants and plants of unknown EBV-activating status with medicinal uses, are found significantly more often at the homes of eBL patients in Malawi than in those of controls. The possible role of these plant factors in the pathogenesis of eBL and their routes of bodily access are discussed. It is postulated that the associations described in this paper provide support for the theory that EBV-activating plants are co-factors involved in the pathogenesis of some cases of eBL."}
{"text": "It has been suggested that the size of the nuclei of epithelial basal cells can be used in predicting the likelihood of malignant transformation of epithelium. This proposition was assessed in rat palatal epithelium after the carcinogen 4-nitroquinoline-1-oxide had been applied to the epithelium for varying periods of time. No consistent alterations in basal cell nuclear size, including area, perimeter, diameter and regularity of form were found with routine light microscopy as the epithelium passed through various stages of dysplasia to carcinoma. This finding casts doubt on the value of using a variation of basal cell nuclear size as a predictor of malignant transformation."}
{"text": "The mechanism of bowel obstruction in colorectal cancer is likely to involve interactions between tumour cells, host fibroblasts and the extracellular matrix. The role of fibroblast-mediated matrix reorganisation in malignant structures of the large bowel was examined in an in vitro collagen matrix model in which tumour cells and fibroblasts were cultured under serum-free conditions. Colon cancer cells secreted a factor(s) which enhanced the ability of colon fibroblasts to contrast a collagen matrix without an associated mitogenic response by the fibroblasts. Within uncontracted collagen gels marked elongation of fibroblast cell processes was observed in the presence of the tumour-derived factor(s). We propose that matrix reorganisation by host fibroblasts in the wall of the human colon is responsible, at least in part, for malignant large bowel obstruction."}
{"text": "To compare the relative heat sensitivities of human normal and neoplastic cells of the same tissue type, a study was carried out of the relative sensitivities to heat of granulocyte/macrophage progenitor cells (CFU-GM) derived from the peripheral blood and bone marrow of normal subjects and patients with chronic granulocytic leukaemia (CGL). Nucleated haemopoietic cells were incubated at temperatures in the range 41.5 degrees C to 44.0 degrees C for various periods before culture in agar. The results of these experiments showed that CFU-GM from normal blood were consistently less sensitive to damage by heat than normal marrow CFU-GM. There was no comparable difference in the relative heat sensitivities of CFU-GM from blood and marrow of patients with CGL and no significant difference between the heat sensitivities of CFU-GM derived from marrow from normal individuals and patients with CGL. The observed difference in heat sensitivity of CFU-GM from normal blood and marrow accords with other data suggesting that the two progenitor cell compartments are distinct: the blood CFU-GM may represent a more primitive population of committed progenitor cells. In CGL, CFU-GM in the blood may much more closely resemble those in the marrow. The data provide no support for the hypothesis that malignant cells differ intrinsically from their normal counterparts in respect of sensitivity to damage by hyperthermia."}
{"text": "Postmenopausal patients with primary breast cancer were treated with tamoxifen, ethynyloestradiol or prednisolone for up to 12 days before mastectomy and the effects of pretreatments with these drugs on the activities of phosphofructokinase (PFK), 6-phosphogluconate dehydrogenase (6PGDH) and alpha-glycerolphosphate dehydrogenase  in the carcinomas were compared with age, stage and menopausal status matched untreated controls. The administration of tamoxifen or prednisolone resulted in a significant increase in the activity of alpha-GPDH and the alpha-GPDH/6PGDH ratio, whereas ethynyl-oestradiol treatment produced a significant decrease in the activity of the enzyme and the ratio. When tamoxifen and ethynyl-oestradiol were administered together, it was found that tamoxifen failed to reverse the oestrogen-induced reduction in the activity of alpha-GPDH. Since increased activity of the enzyme or a higher alpha-GPDH/6PGDH ratio are associated with a lower risk of recurrence , it is postulated that the beneficial effects of tamoxifen or prednisolone in terms of prolongation of the relapse free interval might be mediated via alterations in the activity of alpha-GPDH in micrometastases. The activities of PFK and 6PGDH remained unaffected by these treatments."}
{"text": "The growth inhibitory effects of all-trans and 13-cis retinoic acid (RA) and of the synthetic retinoids TTNPB, TTNPB-ethylester and TTNN were studied on seven human epithelial ovarian cancer cell lines and one ovarian teratocarcinoma cell line. Six of seven ovarian adenocarcinoma cell lines were inhibited in their growth by RA and by synthetic retinoids in a dose dependent manner. No response to these substances was observed for the ovarian teratocarcinoma cell line. The knowledge that RA and retinoids exert their action on the cells via nuclear receptors led us to examine the expression of RAR-alpha, -beta and -gamma mRNA by these cell lines by polymerase chain reaction following reverse transcription. All cell lines expressed RAR-alpha and -gamma mRNA and six of the eight cell lines were found to express additionally RAR-beta mRNA, among them the ovarian teratocarcinoma cell line. Our data indicate that there was no direct association between the presence of RAR subtype transcripts and the response to retinoids in ovarian cancer cell lines."}
{"text": "Modern strategies for the diagnosis and treatment of cardiac arhythmias include besides non-invasive methods an increasing variety of invasive and curative therapeutic strategies. In order to define proper rhythmologic diagnosis and to develop an optimal treatment strategy for individual patients, a high degree of rhythmologic expertise is necessary. Adequate platforms for information exchange, where physicians can meet rhythmologic experts to allow proper handling of individual rhythmologic problems are desirable. Thus, the Heart Center Leipzig develops the Web- and Fax-based consultancy and information service \"EcgConsult\".The service utilizes the network capabilities of the Internet and of the common telecommunication network. This way information input can be achieved either by using a browser/email-client or by using a fax machine. All input from both networks is collected on a centralised mail-server (SSL-POP3 protocol). User interaction on the Web site is achieved with dynamic HTML and a moderated List-Server. The List-Server and an additional discussion area on the Web site are moderated by the Consultants at the Heart Center Leipzig, adequate processing of the site-content and technical management of the site have been outsourced to the university Internet workgroup Elchsoft/Medkonsult.A prototype of the site and the communication architecture for fax/email have been established and successfully beta-tested. Any consulting physician can easily send ECGs and additional material to the server with any fax-machine, where they are automatically TIFF-file converted. A password-protected site is already in use with selected clinicians (http://www.ecgconsult.de). For mobile site management, a web-based Control-Center has been designed. Outlines of contract models for members, guidelines for security purposes of the web-based communication, a business/cost plan and models for the logistic request management as well as for member/patient identification have been developed.The platform \"EcgConsult\" provides a network with fast and easy access to a specific target group and thus allows easy information exchange between the Heart Center Leipzig and rhythmologic experts and non-experts. This exchange may generate synergy effects by offering both groups a variety of data and information. Due to the use of web- and fax-based technology, the access to the service is easy and does not require PC-equipment or a scanner. The requests can be answered by the Heart Center consultants from any remote location world-wide. For the future open-ended architecture allows the participation of further consultants from clinics all over the world. The knowledge gathered from this project may help setting up guidelines for the development of other web-based medical competence centers / information services."}
{"text": "Spinal cord injury (SCI) causes the death of neurons and glial cells due to the initial mechanical forces  and through a cascade of secondary molecular events  that exacerbate cell death. The loss of neurons and glial cells that are not replaced after the injury is one of the main causes of disability after SCI. Evidence accumulated in last decades has shown that the activation of apoptotic mechanisms is one of the factors causing the death of intrinsic spinal cord (SC) cells following SCI. Although this is not as clear for brain descending neurons, some studies have also shown that apoptosis can be activated in the brain following SCI. There are two main apoptotic pathways, the extrinsic and the intrinsic pathways. Activation of caspase-8 is an important step in the initiation of the extrinsic pathway. Studies in rodents have shown that caspase-8 is activated in SC glial cells and neurons and that the Fas receptor plays a key role in its activation following a traumatic SCI. Recent work in the lamprey model of SCI has also shown the retrograde activation of caspase-8 in brain descending neurons following SCI. Here, we review our current knowledge on the role of caspase-8 and the Fas pathway in cell death following SCI. We also provide a perspective for future work on this process, like the importance of studying the possible contribution of Fas/caspase-8 signaling in the degeneration of brain neurons after SCI in mammals. Spinal cord injury (SCI) can cause permanent disability due to the dysfunction of motor, autonomic and sensory systems. There are also high economical costs associated with the care of SCI patients. In the USA, the lifetime cost of a SCI patient is between 1.1 and 4.6 million US dollars  barrier and trigger the release of cytokines and reactive oxygen species  increases neuronal survival, decreases retraction of corticospinal tract fibers and improves functional recovery after a transection SCI at T9 in mice (Sung et al., The studies in rodent models have important implications for human SCI, because the Fas pathway is also activated in primates, including humans, after SCI (Jia et al., As shown in the previous section, most studies focused on the role of caspase-8 and Fas in apoptosis of intrinsic SC cells. But, some of these studies also showed that the manipulation of FasL/Fas signaling leads to a significant increase in the regeneration/preservation of descending axons (Demjen et al., In contrast to mammals, lampreys show an amazing capacity for functional recovery following SCI. The regeneration of descending neurons is a key event in the recovery of swimming after SCI in lampreys (see Shifman et al., Glued (Carson et al., The work in lampreys suggests that activated caspase-8 could also play a role in the death of descending neurons of mammals after SCI. Interestingly, in olfactory neurons of mice, appearance of activated caspase-8 in the cell body after olfactory bulbectomy depends on microtubule-based retrograde transport of activated caspase-8 by its association with dynactin p150Several reports have confirmed that the activation of caspase-8 and the extrinsic apoptotic pathway is one of the mechanisms causing cell death after SCI and that the FasL/Fas signaling pathway plays a key role in this process. Surprisingly, no study has yet attempted to directly inhibit caspase-8 after SCI. This experimental approach could be of interest, especially because caspase-8 activation is not only caused by Fas receptor activation, which could lead to further improvements in recovery from SCI. Also, another aim for future work, and based on the lamprey results, should be to investigate the possible activation of caspase-8 in descending neurons of mammals after SCI and the implication of Fas signaling and microtubule retrograde transport in this process. Finally, translation of all this knowledge to pre-clinical studies or even clinical trials is of obvious and crucial importance.AB-I wrote the manuscript with help from DS-C. DS-C prepared the figure and the table. All the work was supervised by AB-I.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Current antidepressant pharmacotherapy remains unsatisfactory because of its limited adherence and partial therapeutic efficacy. Accordingly, there is a crucial need of validated animal models that fully reflect the nature of the disease and do not only separate facets of the disorder.We read with great interest the recent publication of As these data clearly contrast with those from previous published studies , an obviDaily variations in anxiety-like behavior are also observed in rodents. The importance of time-of-day (circadian) effects on the etiology of mood disorders and the timing of drug treatments (chronotherapy) as well as of the significant role of clock genes  has been"}
{"text": "A 23-year-old female patient with a family history of pulmonary tuberculosis and tuberculous spondylodiscitis was hospitalized for swelling of the left anterior-external surface of the left thigh, (A) with altered general status. Biology has shown a biological inflammatory syndrome. The ultrasound showed a collection opposite the great trochanter fusing towards the lodge of the gluteus muscle and forward towards the terminal part of the common chief ischio-psoas. MRI of the hips revealed an intra-muscular collection of the antero-lateral side of the thigh root, taking contrast in the periphery, involving the quadriceps muscle and tensor of facia lata, (B and C). The biopsy of the collection under ultrasound guidance brought back 30 cc of casein. The diagnosis of tuberculosis of the quadriceps muscle and tensor of the facia lata was based on the positivity of the tuberculin skin test, (D), the positivity of the PCR for Mycobacterium tuberculosis in the puncture fluid and histology showing multiple epithelioid granulomas centered by caseous necrosis. There were no other tuberculous sites. The patient was treated with antituberculosis drugs for 12 months with good progress. Muscular tuberculosis (MT) is a rare localization of the disease (0.01 to 2%). Its occurrence without associated bone involvement is exceptional. MT often simulates a muscular tumor. MRI contributes to the improvement of the sensitivity of the diagnosis of MT because it allows to specify the extent of the muscular lesions and to orient the site of the muscular biopsy. The diagnosis is essentially based on histology."}
{"text": "The type of bearing material that should be used in revision surgery after the failure of ceramic-on-ceramic total hip arthroplasty (THA) remains controversial. In the case of ceramic fracture, the residual ceramic particles can cause consequent metallosis when metal implants are used for revision THA. On the other hand, in the case of THA failure without ceramic fracture, revision THA with a metal femoral head provides satisfactory results. We report an unusual case of progressive osteolysis due to metallosis that developed after revision THA for ceramic liner dissociation without a liner fracture performed using a metal femoral head and polyethylene liner. The residual metal debris and abnormal pumping motion of the polyethylene liner due to the breakage of the locking system or the aspherical metal shell being abraded by the ceramic head seemed to be the cause of the progressive osteolysis. Alumina ceramic components have been used in total hip arthroplasty (THA) for over 30 years. These implants were introduced to reduce wear and to increase long-term survivorship. A modular layered acetabular component, consisting of an alumina ceramic liner housed in an ultra-high-molecular-weight polyethylene shell (ABS liner) that is held in a titanium alloy metal shell (AMS HA shell), was developed in Japan  for use in alumina ceramic-on-ceramic THA. The main limitations of this component are the risk of ceramic liner fracture and failure of the ceramic liner fixation system \u20133. MoreoA 64-year-old man underwent primary THA with alumina-on-alumina bearings on the right side for the treatment of secondary osteoarthritis due to developmental dysplasia of the hip by posterolateral approach . The impThe type of bearing that should be used after a fracture in ceramic-on-ceramic THA remains controversial, and there are no prospective studies since few patients suffer this complication. Revision THA with metal-on-polyethylene pairing is not feasible. Despite performing radical synovectomy and thorough washout of the hip joint, it may not be possible to remove all of the minute ceramic fragments following such ceramic fracture. While ceramic is a material with higher rigidity than metal, severe damage to the metal head and the polyethylene liner may occur due to wear from residual ceramic particles, resulting in early failure as metallosis , 9. On tIn the case of acetabular component failure without ceramic fracture, revision THA with a metal femoral head can be a reasonable treatment option because of the absence of residual ceramic particles in the joint . In the At the rerevision surgery, we considered that removal of the cup and radical debridement of the osteolytic lesion and pseudotumor were necessary. We performed rerevision THA using a reinforcement plate with bulk structural allograft. This technique is also useful for recovering bone stock and restoring the leg length and an adequate hip center .We have presented a unique case of progressive osteolysis after revision surgery comprising exchange of the femoral head and liner due to ceramic acetabular liner dissociation in THA with a modular layered acetabular component. It is important to consider the possibilities of damage to the metal shell as well as the polyethylene liner locking mechanism in the case of ceramic articulation failure treated by such exchange of the liner and femoral head. In such cases, the removal of the entire implant and complete debridement of the metal debris may be required for reconstruction surgery."}
{"text": "The Susan Britton Wills Unit at the Bristol General Hospital is a small and busy multidisciplinary psychiatric unit, providing a wide range of in-patient, out-patient and day-patient services for the residents of Bristol Health District."}
{"text": "Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance refers to a disruption of the sense of first-person perspective and self-presence that is associated with a variety of anomalous subjective experiences. Recent cross-sectional and prospective pilot studies provided preliminary support for the notion that SD may provide a means of further \u201cclosing in\u201d on individuals truly at high-risk for psychosis, particularly of schizophrenia spectrum disorders (SSD). The goal of this study was to replicate and extend these pilot findings by examining the long-term persistence of SD and the degree to which their level in adolescence predicts SSD seven years later in young adulthood.The 7-year stability of SD and their association with later in life SSD were explored in a sample of 40 young adults. SD was assessed with the Examination of Anomalous Self-Experience (EASE), prodromal symptoms and syndromes were assessed with the Structured Interview for Prodromal Syndromes (SIPS), present and lifetime diagnoses of schizophrenia-spectrum and other co-morbid disorders were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) in adolescence and the Operational Criteria (OPCRIT) checklist for psychotic and affective illness in young adulthood, level of distress with the Mood and Anxiety States Questionnaire (MASQ), and psychosocial functioning with the Strength and Difficulties Questionnaire (SDQ).Forty young adults  out of the 82 who had participated seven years earlier in a study on the association between SD and attenuated psychosis symptoms (APS) were available and agreed to participate in the 1-year follow-up . There were no significant differences between those who were available and those who lost for the follow-up assessment on any of the major socio-demographic or clinical variables at baseline. Eight (20%) of the 40 participants in the present study met diagnostic criteria for an SSD . The total EASE score was slightly higher in young adulthood compared to seven years earlier. However, this can reflect a difference in the administration method of the EASE between the two occasions. Consistent with our first hypothesis, the correlation between the total EASE score at baseline and 7-year follow-up was moderate and significant . Similarly, consistent with our second hypothesis, SD at baseline was a significant predictor of an SSD diagnosis in young adulthood.These results provide further support for the temporal stability of SD over time. Also, they provide further support for the notion that SD is a phenotypic indicator of risk for SSD."}
{"text": "Previous findings suggest that schizophrenia is associated with abnormalities in information integration. The recent Bayesian model of circular inference attempts to characterize the information integration style in schizophrenia . Nat Commun, 8:14218). The model suggests that during information integration of prior beliefs and sensory evidence, patients tend to put too much weight on the sensory evidence and to take it into account multiple times (over-count) compared to healthy individuals. An imbalance in excitatory/inhibitory regulation of hierarchical neural processing has been suggested to cause of this phenomenon . Here, we investigated whether circular inference could be extended to describe the integration of sensory information and socially acquired information and whether the specific information integration style could contribute to the characteristic symptomatology and the social impairments seen in the disorder.Thirty-five patients with schizophrenia or schizo-affective disorder and 40 matched healthy controls performed the task. Participants had to guess the color (red or green) of the next marble to be drawn from a hidden urn based on information from their own sample (eight marbles) and the choices and confidence (high or low) of four other people. We fitted and comparatively assessed four multilevel Bayesian models  describing how patients and controls integrated information. Positive and negative symptom severity and social functioning were also assessed.The circular inference model best described the information integration in both patients and controls (WAIC weight = 1). Patients tended to over-weigh  and over-count  sensory information and under-weigh  and under-count  social information compared to controls. Crucially, this varied with symptomatology: the higher the symptom severity, the more over-counting and the higher the weight on sensory information and the more under-counting and the less weight on social information. More weight on social information was associated with higher level of functioning in the patients .All participants integrated social and sensory information in a non-linear fashion. Patients displayed a distinctive tendency to rely more and less discriminatively on sensory than on social information. This information integration style may contribute to the characteristic symptoms and the social impairments in schizophrenia. Further exploration of this potential causal role is warranted."}
{"text": "Basic neuroscience research on brain plasticity, motor learning and recovery has stimulated new concepts in neurological rehabilitation. Combined with the development of set methodological standards in clinical outcome research, these findings have led to a double-paradigm shift in motor rehabilitation: (a) the move towards evidence-based procedures for the assessment of clinical outcome & the employment of disablement models to anchor outcome parameters, and (b) the introduction of practice-based concepts that are derived from testable models that specify treatment mechanisms. In this context, constraint-induced movement therapy (CIT) has played a catalytic role in taking motor rehabilitation forward into the scientific arena. As a theoretically founded and hypothesis-driven intervention, CIT research focuses on two main issues. The first issue is the assessment of long-term clinical benefits in an increasing range of patient groups, and the second issue is the investigation of neuronal and behavioural treatment mechanisms and their interactive contribution to treatment success. These studies are mainly conducted in the research environment and will eventually lead to increased treatment benefits for patients in standard health care. However, gradual but presumably more immediate benefits for patients may be achieved by introducing and testing derivates of the CIT concept that are more compatible with current clinical practice. Here, we summarize the theoretical and empirical issues related to the translation of research-based CIT work into the clinical context of standard health care."}
{"text": "This data article presents comparisons of energy generation costs from gas-fired turbine and diesel-powered systems of distributed generation type of electrical energy in Covenant University, Ota, Nigeria, a smart university campus driven by Information and Communication Technologies (ICT). Cumulative monthly data of the energy generation costs, for consumption in the institution, from the two modes electric power, which was produced at locations closed to the community consuming the energy, were recorded for the period spanning January to December 2017. By these, energy generation costs from the turbine system proceed from the gas-firing whereas the generation cost data from the diesel-powered generator also include data on maintenance cost for this mode of electrical power generation. These energy generation cost data that were presented in tables and graphs employ descriptive probability distribution and goodness-of-fit tests of statistical significance as the methods for the data detailing and comparisons. Information details from this data of energy generation costs are useful for furthering research developments and aiding energy stakeholders and decision-makers in the formulation of policies on energy generation modes, economic valuation in terms of costing and management for attaining energy-efficient/smart educational environment. Specifications TableValue of the data\u2022Accessibility to datasets of energy generation cost of a distributed generation system of electrical energy production using gas-fired and diesel engine generators that could be used for fostering systems of practical data-driven research in the understanding of energy cost modeling valuations and how this can be improved towards efficient integration of energy generation for a smart university campus \u2022Costs of energy generation data that could be employed for energy generation planning in the development of new energy generation plants as well as in the decision making of how to combine energy generation systems for electricity consumers in a smart university campus \u2022levelised cost of electric energy, society cost of electric energy, returns on investment on energy generating plants, projection of future energy costs for budget purposes, for energy stakeholders and decision-makers of energy production in a smart university campus Availability of energy generation costs that could be used for estimations of energy generation cost parameters and cost concepts, such as \u2022Applicability and/or developmental prospects of Smart Electrical Energy Network (SEEN) for a stronger, more sustainable controls of centralized distributed generation of electric energy system via systems of the electric energy generation costing for a smart university campus 1Although rising energy demand remains a global issue, it is still a well-known fact that a large and increasing portion of the populace in a developing country like Nigeria has no access to the national grid generated electric power Directly proceeding from 2As detailed, the electric energy generation cost data were monitored and cumulated for each month of the year 2017, at Covenant University, Ota, Nigeria, as a part of continuous data sourcing and management in the smart university campus. The generation of the distributed electric energy is required for the maintenance of conducive/comfortable education and working environments that promote the well-being of students and staffs in the fully residential university p-value, i.e. the probability value obtained from the Kolmogorov-Smirnov goodness-of-fit statistical analyses, are presented in The cumulative distribution function analyses of the energy generation cost data necessarily lead to the estimations of the descriptive statistics parameters to which was combined the testing of significance of the compatibility of the electric energy generation cost data to each of the statistical distributions"}
{"text": "This work deals with privacy implications and threats that can emerge with the large-scale use of electronic biometric documents, such the recently introduced electronic passport (e-Passport). A brief introduction to privacy and personal data protection is followed by a presentation of the technical characteristics of the e-Passport. The description includes the digital data structure, and the communication and reading mechanisms of the e-Passport, indicating the possible points and methods of attack."}
{"text": "Cerebellum and Ataxias a series of empirical and review articles provide a state of the art overview of non-invasive brain stimulation of the cerebellum.The feasibility to administer magnetic and electric fields in a non-invasive manner to influence brain areas has attracted scientists interested in studying the neural correlates of normal and pathological forms of behaviour. In particular, the possibility of non-invasive brain stimulation techniques to target the cerebellum has led to a notable rise of research dedicated to unravelling the functional contributions of the cerebellum to motor- and non-motor related behavior. In this issue of The study by Ben Taib and Manto  reports Results showed that, similar to the inhibitory effects of low-frequency repetitive transcranial magnetic stimulation, the LFSMC-related decrease in corticomotor excitability was counteracted by cDCS to the cerebellum. This study provides evidence that cerebellar cDCS may be a powerful tool to modify responsiveness of corticomotor excitability.If cDCS in animals has similar neurophysiological effects to those of cathodal tDCS in humans, and if the effects are not strictly mediated by changes in excitability at the level of the spinal cord, then this approach may have clinical implications in cerebellar patients. For instance, the administration of cathodal tDCS to the cerebellar hemisphere contralateral to the damaged motor cortex in patients might enhance excitability and potentially improve motor symptoms.In a sham-controlled study by John and colleagues  aimed atAlong this line, Ferrucci and colleagues  reviewedThe review by Tremblay and colleagues  exploredEven though tDCS to the cerebellum is still in its infancy, the currently available empirical evidence underlines the significant potential of this non-invasive brain stimulation technique in studying cerebellar functions. Further technical and methodological development will undoubtedly contribute to further refinement of tDCS, and the development of clinical applications."}
{"text": "In the Funding section, the last sentence is incorrectly included in the statement. The publisher apologizes for the error. The correct funding information is as follows: GlaxoSmithKline Biologicals SA funded this study/research and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and publication of this manuscript (GSK study number: GHO-09-3981)."}
{"text": "HIV drug resistance has been described in all antiretroviral drug classes and threatens the long-term success of HIV treatment. Here, we describe the first reported case of acquired resistance to the integrase strand transfer inhibitors in South Africa. This case illustrates the dilemma of treatment in the context of inadequate adherence and poor psychosocial support and highlights the potential risk of transmission of multidrug-resistant virus. The development of drug resistance is one of the biggest concerns in the long-term management of HIV-infected patients. An increasing number of confirmed cases of drug resistance to second-line antiretroviral treatment (ART) has prompted the South African national treatment programme to introduce third-line treatment. This is, to the best of our knowledge, the first report of drug resistance to third-line therapy in the South African public sector. The Research Ethics Committee of the Faculty of Health Sciences of the University of Pretoria approved the case study and granted a waiver of consent.The patient tested HIV-positive in 2006 at the age of 8 years. Her exposure to perinatal ART is unknown. She started her first ART regimen consisting of stavudine, lamivudine and efavirenz in the private sector in 2006 after completing a course of treatment for pulmonary tuberculosis. In 2007, she was transferred to the state sector. Here, she was changed to the standard second-line regimen in use at the time \u2013 zidovudine (AZT), didanosine and ritonavir-boosted lopinavir \u2013 because of virological treatment failure in October 2008. She initially responded well, but her viral load became detectable again in September 2009 and she was referred to an academic ART clinic in March 2010 because of virological failure. Her ART regimens, CD4 counts and HIV viral load results are shown in At the time of the referral, the patient was 12 years old and living in Pretoria with her aunt. Her mother lived in Limpopo and was also using ART. The patient was aware of her HIV status and it was known to all her close adult family members. She reported poor adherence with her ART treatment because it was unpalatable.She had three genotypic drug resistance tests (DRTs) over the next 2 years and the mutations evolved from low-level resistance to ritonavir-boosted lopinavir to extensive three-class resistance during this time . She movHowever, by 2013 the patient was not coping well and had developed urinary and faecal incontinence without a physiological cause. She had nearly been raped, had failed grade 9 and had become socially isolated. By December 2013, her viral load reflected the impact of the psychological problems on her adherence. Her mother passed away in 2015 and with that the patient lost her medical aid benefits and was referred back to the state sector. A fourth DRT  showed tCurrently, neither the patient nor the family seem to have grasped the seriousness of her condition. Despite multiple adherence counselling sessions and even contracting with the family that her pill-taking will be supervised, there is still inadequate supervision. She has poor coping skills, has not entirely accepted her illness and is ambivalent about taking her ART. She is now on a holding regimen consisting of FTC, TDF, AZT and abacavir (ABC). A tropism assay predicted that CCR5-antagonists are likely to be effective.This patient has come to the end of the line in terms of available ART. The virus displays intermediate to high-level resistance to all the available ARVs (either in the second or the third genotype) and even low-level resistance to the new INSTI, dolutegravir (DTG) and the new-generation protease inhibitor (PI), tipranavir. A potential new regimen should therefore preferably include an entry inhibitor (e.g. maraviroc) and tipranavir, together with TDF, FTC and DTG. The cost, however, is prohibitive and apart from TDF/FTC, none of the medications are available in the public sector at this time.2 This case also illustrates the complexity of the long-term management of HIV in the context of poor psychosocial support and suboptimal adherence. It raises concerns about the addition of drug classes in the face of ongoing non-adherence and highlights how management is complicated, and unnecessary costs incurred, when patients move between health sectors without an electronic patient record.This case raises the question about the positioning of DTG in the treatment guidelines once it becomes available in South Africa. A considerable minority of patients develop cross-resistance to DTG after exposure to RAL and elvitegravir, while resistance has only rarely been reported in patients exposed to DTG as the first integrase inhibitor.5 and clinicians have called for INSTI resistance testing for patients with an unexpectedly high number of pre-ART drug resistance mutations and for contacts of heavily treatment-experienced patients.6 This may become a reality in South Africa if efforts to prevent the emergence of resistance are not prioritised.This case also raises the issue of potential transmission of extensively drug-resistant virus in a teenager who is bound to become sexually active in the foreseeable future. Transmitted multiclass (including INSTI) resistance has been reported in the United States,This case of acquired multiclass resistance, including resistance to INSTIs, in a teenager in South Africa illustrates the complexity of the long-term management of HIV in contexts where inadequate adherence and poor psychosocial support abound and highlights the importance of the appropriate positioning of DTG in the national treatment programme."}
{"text": "A 48-year-old woman presented with right ankle pain that began while running two days prior. She noted that the ankle hurt with even light touch and the pain was unrelieved with ibuprofen. She denied a history of trauma. She was seen in the emergency department for this condition the day prior with a negative radiograph, but she returned because of increased ongoing pain. On examination, a five-centimeter (cm) area of erythema was found posterior to the medial malleolus and parallel to the posterior tibial tendon (PTT). The diameter, measured with point-of-care ultrasonography  of the long axis of the tendon in this region, was 4.9 millimeter (mm) The PTT is important for plantar flexion, inversion and supination of the ankle, as well as stabilizing the arch of the foot.6What do we already know about this clinical entity?Posterior tibial tendon tenosynovitis is an inflammatory condition affecting healthy young athletes and can be associated with posterior tibial nerve hyperesthesia.What is the major impact of the image?This image adds to the growing literature describing the use of ultrasound for evaluation of posterior tibial tendon and helps broaden the differential diagnosis related to ankle pain by emergency department providers.How might this improve emergency medicine practice?Ankle pain is a common presentation in EM practice. This image helps to highlight tenosynovitis of the posterior tibial tendon within the differential diagnosis and emphasizes the value of point-of-care ultrasound in establishing the diagnosis."}
{"text": "Schizophrenia is the most debilitating health problem that exists, and its cognitive impairments are the greatest predictor of disability. Since the earliest clinical descriptions of the illness, abnormalities of attention have been at the core of the cognitive symptoms of schizophrenia. Theories of attentional dysfunction in schizophrenia propose that the deficits arise from either an inability to maintain working memory representations that guide attention, or difficulty focusing lower-level visual attention mechanisms. However, these theoretical accounts neglect the role of long-term memory representations in controlling attention.To test competing accounts of the etiology of cognitive deficits in schizophrenia, we devised a cued visual search task that allowed us to examine the integrity of the memory mechanisms that control attention and the lower-level mechanisms for focusing attention on visual inputs in patients with schizophrenia and demographically matched controls. In this task, a target object was cued at the beginning of each trial. The task-relevant cue signaled the identity of the target that could appear in the search array presented a second later. Then the target remained the same for three to seven consecutive trials (length of run randomized) before it was changed to a different object. While patients and controls were repeatedly searching for the same target object, we used electrophysiological measurements of brain activity to directly measure how they were focusing attention on the search targets, as well as how they recruited working memory and long-term memory representations to control attention as they searched for the task-relevant targets. In a second experiment, we used a causal manipulation of brain activity to provide converging evidence for our hypotheses regarding the locus of the attentional deficits in schizophrenia and to determine whether it is possible to improve attention in patients. This experiment was a double-blind, sham-controlled, within-subjects design using transcranial direct-current stimulation (tDCS) and established electroencephalographic (EEG) signatures of working memory, long-term memory, and attention.Here, we show that the control of perceptual attention is impaired in people with schizophrenia, and that this impairment is driven by an inability to shift attentional control from working memory to long-term memory across practice. Contrary to predictions of the dominant models, this attentional impairment is observed in the face of exuberant neural activity indexing working memory and completely normal activity indexing the focusing of visual attention. Next, we provide converging evidence for the locus of attentional impairments in long-term memory by showing that noninvasive electrical stimulation of medial frontal cortex rectifies long-term memory related neural signatures and normalizes the ability of patients to find targets in complex visual scenes.The findings challenge existing views of the locus of dysfunction underlying attentional impairments in schizophrenia. Moreover, the results highlight the crucial importance of long-term memory systems in controlling attention and associated abnormalities in the hippocampus and other brain areas in schizophrenia."}
{"text": "Phenomenological research indicates that disturbance of the basic sense of self may be a core phenotypic marker of schizophrenia spectrum disorders. Basic self-disturbance (SD) refers to a disruption of the sense of first-person perspective and self-presence that is associated with a variety of anomalous subjective experiences. Recent studies including from our group provided first, preliminary support for the notion that SD is related to attenuated psychosis symptoms (APS) and depression among clinical  and non-clinical samples of non-psychotic adolescents. However, very few studies, if any at all, have looked at the ability of SD to predict change in APS and depression over time. The goal of this study was to address this lacuna in the literature by examining the unique and added contribution of SD to the prediction of change over time in APS and depression among community-dwelling adolescents.The 1-year longitudinal relationship between SD and change in APS and depression were explored in a sample of 100 non-help-seeking adolescents (age 13\u201315) from the community. SD was assessed with the Examination of Anomalous Self-Experience (EASE), prodromal symptoms and syndromes were assessed with the Structured Interview for Prodromal Syndromes (SIPS), present and lifetime diagnoses of schizophrenia-spectrum and depression disorders were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), level of distress with the Mood and Anxiety States Questionnaire (MASQ), and psychosocial functioning with the with the Strength and Difficulties Questionnaire (SDQ).Seventy-seven (77%) adolescents out of the 100 that had been assessed at baseline were available and agreed to participate in the 1-year follow-up . Except for a diagnosis of an affective disorder, which was slightly less prevalent among those who returned for the follow-up assessment, there were no significant differences between those who were available and those who lost for the follow-up assessment on any of the major socio-demographic or clinical variables at baseline. Consistent with our first hypothesis, SD at baseline predicted a significant amount of variance in APS change over time . However, inconsistent with our second hypothesis, SD at baseline did not have a significant added contribution to the prediction of APS change when APS at baseline was controlled for .These results provide preliminary support for a prospective association between SD and deterioration in prodromal symptoms among adolescents from the community. However, they fail to support an added value of SD over and above baseline APS for the prediction of APS deterioration. Because SD was assessed only at baseline, they leave unanswered the degree to which change in SD is associated with a change in APS and depression."}
{"text": "Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Recent evidence indicates involvement of the STING pathway in the induction of antitumor immune response. Therefore, STING agonists are now being extensively developed as a new class of cancer therapeutics. However, little is known about the consequences of activated STING-mediated signaling in cancer cells on the efficacy of the antitumor treatment. It has been shown that activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response. Understanding the function of STING pathway in cancer cells might provide important insights into the development of effective therapeutic strategies. This review focuses on the role of STING pathway in cancer cells, the largely unknown topic that has recently emerged to be important in the context of STING-mediated antitumor responses. Knockdown of either of following genes: On the other hand activation of STING can also have the immunosuppressive effects through the upregulation of programmed death-1 ligand (PD-L1). Interaction of PD-L1 with PD-1 leads to inhibition of the activation of T cells and therefore has a crucial role in tumor immune escape  was approved by the US Food and Drug Administration for the treatment of melanoma (Grigg et al. +IFN-\u03b3+ T cells. Combination treatment of STING agonist and anti-PD-1 antibody in CT26 and B16 murine tumor models induced regression of tumors that did not respond to the checkpoint inhibition alone (Fu et al. While oncolytic viruses are more effective in cancer cells without STING expression, PD-1 blockade treatment can turn out to be more effective in STING-positive tumors. Tumors from mice treated with a STING agonist show increased levels of PD-L1 and tumor-infiltrating CD8The rationale for combining STING agonists with DNA damaging agents needs to be further verified since it is not known if the increased resistance of cancer cells to genotoxic stress caused by the STING pathway activation (Gaston et al. Extensive studies are being carried out to evaluate the therapeutic potential of STING agonists in combination with the next-generation cancer immunotherapies. Basic studies that will elucidate the influence of such compounds on various cell subsets that are present in tumor microenvironment are of huge importance in this process. The majority of reports indicate that these are mostly tumor stromal cells of the immune system, such as dendritic cells, that are responsible for the majority of STING agonists-mediated antitumor effects. However, it cannot be excluded that also other cells, including cancer cells, are being actively targeted by these compounds and that activation or rather inhibition of the STING pathway in those cells may play a role in achieving their full therapeutics potential. Still the role of STING-mediated signaling in cancer cells remains largely unknown and there are many questions that remain unanswered. It is not known if the downregulation of STING expression and impaired signaling in cancer cells creates survival advantage or if it is just a non-important by-product of carcinogenesis. Little is also known about the functional consequences of STING activation in cancer cells. It needs to be verified if the induction of STING-mediated signaling in cancer cells could lead directly to cancer cell death or as suggested by Gaston et al.  to cytop"}
{"text": "The aim of this study is to evaluate the association between rs6280 and rs905568 genetic polymorphism of DRD3 gene and the treatment response of amisulpride.After six weeks treatment of amisulpride, 125 schizophrenia patients were interviewed based on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity (CGI-S). The genotyping for rs6280 and rs905568 was performed using TaqMan single nucleotide polymorphism (SNP) genotyping assay.There was no significant difference in the frequency of genotype and allele of rs6280 between the responders and non-responders based on the total, positive, and general score of PANSS and CGI-S score. However, there was a significant association between this SNP and treatment response in the negative score of PANSS . There was no significant association between rs905568 and the response in positive, negative, general, and total PANSS score and CGI-S score.This is the first positive association study between DRD3 gene and the treatment response of negative symptoms to amisulpride in Korean schizophrenia patients. A larger scale research on more SNP of the DRD3 gene will make a progress in the study of pharmacogenetics on the treatment response of the amisulpride."}
{"text": "In order to ensure a GMP quality product for cellular therapy, in vitro expansion of ASCs has been undertaken using xeno-free (XF), chemically-defined, and human blood-derived alternatives. These investigations usually include the criteria proposed by the International Society of Cellular Therapy (ISCT) and International Fat Applied Technology Society (IFATS). The majority of studies use these criteria to compare plastic-adherence, morphology, the immunophenotype and the trilineage differentiation of ASCs under the different medium supplemented conditions. Based on these studies, all of the alternatives to FBS seem to be suitable replacements; however, each has its own advantages and drawbacks. Very few studies have investigated the effects of the supplements on the immunomodulation of ASCs; the transcriptome, proteome and secretome; and the ultimate effects in appropriate animal models. The selection of medium supplementation will depend on the downstream application of the ASCs and their efficacy and safety in preclinical studies.Adipose-derived stromal cells (ASCs) are being used extensively in clinical trials. These trials require that ASCs are prepared using good manufacturing practices (GMPs) and are safe for use in humans. The majority of clinical trials in which ASCs are expanded make use of fetal bovine serum (FBS). While FBS is used traditionally in the research setting for  The The unknown and undefined composition of FBS is a major drawback. A preferable alternative would be a chemically-defined medium with a known composition such as commercially available serum-free (SF) or XF media . Platelet poor plasma (PPP), fresh frozen plasma (FFP), and platelet rich plasma  contains platelet GFs which are obtained by lysing platelets concentrated in a small volume of plasma  the MRC's Flagships Awards Project SAMRC-RFA-UFSP-01-2013/STEM CELLS as well as (b) the Extramural Unit for Stem Cell Research and Therapy. The National Research Foundation of South Africa also provided funding.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "In this study, silver chloride nanoparticles (AgCl NPs) were prepared using chitosan oligomer (CHI) and chitosan oligomer derivatives (CHI-FITC). The CHI and CHI-FITC were used as markers to confirm the formation of AgCl NPs using their fluorescence properties as well as stabilizers. The fluorescence properties of CHI and CHI-FITC were monitored by a luminescence spectrophotometer, and the morphology of the AgCl NPs was further confirmed by transmission electron microscopy (TEM) and X-ray diffraction (XRD). The fluorescence of CHI and CHI-FITC was quenched by the formation of AgCl NPs, and the Stern\u2013Volmer equation was used to compare the two types of stabilizer. The CHI and CHI-FITC stabilizer were linear and nonlinear, respectively, with respect to the Stern\u2013Volmer equation, and considered to be usable as fluorescence indicators to confirm the formation behavior of AgCl NPs through fluorescence quenching. The CHI and CHI-FITC served as stabilizers and as indicators of the formation of NPs. For the CHI/AgCl NPs, a linear static quenching behavior was observed when the decrease in fluorescence intensity according to the formation of AgCl NPs was substituted into the Stern\u2013Volmer equation. On the contrary, nonlinear quenching was observed for CHI-FITC/AgCl NPs. In addition, the quenching occurred more rapidly in the CHI-FITC stabilizer than in the CHI stabilizer because the formation of AgCl NPs was structurally affected by the fluorescence properties of FITC. The AgCl NPs obtained by environmentally friendly CHI and CHI-FITC as stabilizers have a considerable potential for use in fluorescence sensors and bio-imaging probes."}
{"text": "The application of opto-electronics in video-endoscopes improves the accuracy in diagnosis, through image processing and digital technology. Narrow Band Imaging (NBI), consists of using interference filters for the illumination of the target in narrowed blue and green bands of the spectrum. NBI is combined with magnifying endoscopy using an objective macro or an optical zoom. The NBI technique developed by Olympus Medical Systems is now available in the most recent models of video-endoscopes that use the non-sequential system of illumination (Lucera Spectrum) or the sequential R/G/B system of illumination (Exera II). The major contribution of the technique is in the characterization  of the flat and superficial neoplastic areas of the digestive mucosa, with a specific application to the identification of intestinal metaplasia and early neoplastic changes in the Barrett's esophagus. The technique also proves helpful for the assessment of the vascular pattern in chronic inflammatory disorders of the digestive mucosa."}
{"text": "I read the article \u201cAuer Rod-Like Inclusions in Reactive Plasma Cells in a Case of Acute Myeloid Leukemia\u201d by Pradhan when it was first published online . The manuscript is well written with the description of a rare presence of Auer rod-like inclusions in reactive plasma cells in a case of acute myeloid leukemia (AML). However, it is not the first case of Auer rod-like inclusions in reactive plasma cells in a case of AML in the literature as was claimed by the author in the article. Sharma et al. had already described a case of the presence of this type of plasma cell inclusion in a case of therapy-related AML. Needle-like or Auer rod-like intracytoplasmic inclusions in plasma cells were first described by Steinmann in 1940. A few cases of multiple myeloma with intracytoplasmic plasma cell inclusions are described in the literature . Some poConflict of Interest: The author of this paper has no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included."}
{"text": "Most of these findings have confirmed the validity of the original structures. This short article briefly reviews the most important advances on the structure and function of VDAC superfamily members collected during the last decade and summarizes how they enhanced our understanding of the channel.Mitochondria are evolutionarily related to Gram-negative bacteria and both comprise two membrane systems with strongly differing protein composition. The major protein in the outer membrane of mitochondria is the voltage-dependent anion channel (VDAC), which mediates signal transmission across the outer membrane but also the exchange of metabolites, most importantly ADP and ATP. More than 30 years after its discovery three identical high-resolution structures were determined in 2008. These structures show a 19-stranded anti-parallel beta-barrel with an N-terminal helix located inside. An odd number of beta-strands is also shared by Tom40, another member of the VDAC superfamily. This indicates that this superfamily is evolutionarily relatively young and that it has emerged in the context of mitochondrial evolution. New structural information obtained during the last decade on Tom40 can be used to cross-validate the structure of VDAC and vice versa. Interpretation of biochemical and biophysical studies on both protein channels now rests on a solid basis of structural data. Over the past 10 years, complementary structural and functional information on proteins of the VDAC superfamily has been collected from  Gram-negative bacteria, mitochondria, and chloroplasts are enveloped by two lipid bilayers, termed the inner and outer membrane. While all inner membrane proteins are alpha-helical, proteins in the outer membrane display beta-barrel structures with a wide variation in the number and tilt of beta-strands as well as the way the strands are interconnected by loops and turns . Early studies by electron microscopy (EM), performed in the laboratories of Frank and Mannella in the 1980s, yielded structural information on semi-crystalline arrays of a pore-forming channel isolated from the MOM  simulations based on the mVDAC1 (PDB-entry: 4C69) structure combined with a Markov state model showed the capacity to pass millions of ATP molecules per second via hundreds of different permeation pathways along a network of basic residues  and drug complexes Structure of VDAC3Structures of VDAC-ANT complexesStructures of VDAC in complex with pro-apoptotic proteins such as tBid, Bax, or Bak.KZ and UZ contributed to conception and design of the manuscript and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Corneal foreign bodies are reported to be the second most common type of ocular injury. Anterior segment optical coherence tomography (AS-OCT) is a valuable tool for the early diagnosis and monitoring the progress of treatment in cases of ocular trauma. Herein we aimed to report on a patient with an intra-corneal foreign body and the role of AS-OCT in management.A 34-year-old male presented with foreign body sensation in his left eye. Slit-lamp biomicroscopic examination revealed a peripherally located intrastromally embedded foreign body with a free anterior edge extending outwards from the cornea. It was not possible to visualize the foreign body\u2019s entire route through the cornea because of localized corneal edema. AS-OCT showed shadowing of the corneal layers corresponding to the location of the corneal foreign body. A hyper-reflective lesion was observed close to the inside edge of the foreign body in the cornea, indicating that the foreign body had not completely penetrated the cornea. The foreign body was removed via the external route, as it had not completely penetrated the cornea. During the postoperative period the patient was asymptomatic, although the left eye\u2019s cornea healed with scar tissue.AS-OCT facilitates non-invasive rapid imaging of ocular tissue at va rious depths, thereby providing accurate assessment of foreign body characteristics.The location of an intracorneal foreign body and the status of the surrounding ocular structure dictate the optimal surgical technique to be employed.AS-OCT in the present case facilitated localization and determination of the size of a corneal foreign body. In addition, AS-OCT findings assisted in selection of the appropriate surgical intervention. Ocular injury is the most common cause for emergency interventions in ophthalmology departments throughout the world, and is the second most common cause of visual loss  is a valuable tool for the early diagnosis and monitoring the progress of treatment in cases of ocular trauma . Recent advances in ocular imaging include high-resolution techniques for visualizing cornea. Intrastromal corneal foreign bodies can be accurately viewed using the Cirrus SD-OCT. The advantages of SD-OCT are that it is a non-contact imaging system associated with minimal discomfort in trauma patients and that it can be used to obtain high-resolution cross sectional images of the anterior segment, including the cornea.AS-OCT facilitates non-invasive rapid imaging of ocular tissue at various depths, thereby providing accurate assessment of foreign body characteristics. Reflectivity varies according to the type of foreign body. Foreign bodies of glass are well delineated on AS-OCT, with no internal reflectivity, whereas those of wood exhibit moderate internal reflectivity and those of metal exhibit high anterior reflectivity with shadowing (Jancevski and Foster Corneal foreign body imaging provides information regarding foreign body location, size and depth. In cases of ocular trauma AS-OCT can also identify unexpected lesions that are invisible or difficult to see via routine slit-lamp biomicroscopic examination (Wylegala et al. The high resolution of AS-OCT is ideal for evaluating the depth of corneal injury due to a foreign body. The location of an intracorneal foreign body and the status of the surrounding ocular structure dictate the optimal surgical technique to be employed (Hersh et al. AS-OCT provides vital details about Descemet\u2019s membrane integrity and the point of entry of a foreign body, which can be utilized to plan surgical removal. When Descemet\u2019s membrane was intact and the scar at the point of foreign body entry was known the foreign body was removed via the anterior route, whereas when Descemet\u2019s membrane was breached and the foreign body point of entry was healed the foreign body was removed via the anterior chamber using an air tamponade. No sutures were required when removing a foreign body via the anterior chamber, which preventing any astigmatic effect. AS-OCT is a non-invasive method for rapid imaging of ocular tissue of various depths, which provides accurate localization of foreign bodies and the status of surrounding ocular structures, facilitating preoperative surgical planning. This can also prevent any intra or postoperative refractive surprises thus providing best possible outcomes (Al-Ghadeer and Al-Assiri In some cases corneal thinning might be suspected after removal of a corneal foreign body. AS-OCT is extremely useful in such cases, as it facilitates quantitative assessment of remnant corneal thickness and indicates the risk of impending perforation. The presented patient was lucky in that that foreign body did not completely penetrate the cornea and there was no loss of tissue. In cases of corneal tissue loss cyanoacrylate glue and a bandage contact lens can be used if the defect is <2\u00a0mm (Vote and Elder The use of AS-OCT allowed to verify and even clarify clinical impression of the intra-corneal foreign bodies. This technology also served as a check on verification of depth and localization of foreign bodies. AS-OCT findings can also be used to aid in the selection of the most appropriate surgical intervention and to monitor the effects of treatment. The presented case highlights the benefits of AS-OCT in the management of intra-corneal foreign bodies, including informing the choice of method of foreign body removal."}
{"text": "In D-DSC, network is partitioned into clusters, where the clusterheads communicate their uncompressed samples carrying the side information, and the cluster members send their compressed samples. Sink performs joint decoding of the compressed and uncompressed samples and then reconstructs the event signal using the decoded sensor readings. Based on the observed degree of the correlation among sensor samples, the sink dynamically updates and broadcasts the varying compression rates back to the sensor nodes. Simulation results for the performance evaluation reveal that D-DSC can achieve reliable and energy-efficient event communication and estimation for practical signal detection/estimation applications having massive number of sensors towards the realization of Internet of Sensing Things (IoST).Spatial correlation between densely deployed sensor nodes in a wireless sensor network (WSN) can be exploited to reduce the power consumption through a proper source coding mechanism such as distributed source coding (DSC). In this paper, we propose the Decoding Delay-based Distributed Source Coding (D-DSC) to improve the energy efficiency of the classical DSC by employing the  Internet of Things (IoT), which defines the seamless interconnection and autonomous coordination of massive number of sensing and computing elements and physical entities through the Internet infrastructure, is an emerging research direction towards the long-standing goal of enabling the connected Universe. WSNs have evolved into Internet of Sensing Things (IoST) as part of the Internet of Things (IoT) , and nowDistributed Source Coding (DSC) because it only requires the correlation between the sensors for the compression j are recn times yields n-level tree structure that contains 2n sub-codebooks. Samples of master nodes are encoded simply by finding the closest representation of the data from the 2nu values in the root-codebook . For encoding process of slave nodes, the encoder first finds the closest representation of the data from the 2nu values in the root-codebook and then determines the sub-codebook that samples of slave node belongs to at level-n, where n is the minimum number of bits for encoding slave node data. The path through the root-codebook to this sub-codebook specifies the bits that are transferred to the sink  and a heat source initially located at  is moved with constant velocity over on the x-axis. The maximum velocity of the source is selected as the 10% of the propagation speed of the event signal Click here for additional data file."}
{"text": "We report two cases of failed attempts at closed reduction of high-energy tibial fractures with an associated fibula fracture. The first case was a 39-year-old male involved in high-speed motorbike collision, while the second was a 14-year-old male who injured his leg following a fall of three metres. Emergency medical services at the scenes of the accidents reported a 90-degree valgus deformity of the injured limb and both limbs were realigned on scene and stabilized. Adequate alignment of the tibia could not be achieved by manipulation under sedation or anaesthesia. Open reduction and exposure of the fracture sites revealed that the distal fibula fragment was \u201ctransposed\u201d and entrapped in the medulla of the proximal tibial fragment. Reduction required simulation of the mechanism of injury in order to disengage the fragments and allow reduction. Tibiofibula transposition is a rare complication of high-energy lower limb fractures which has not previously been reported and may prevent adequate closed reduction. Impaction of the distal fibula within the tibial medulla occurs as the limb is realigned by paramedic staff before transfer to hospital. We recommend that when this complication is identified the patient is transferred to the operating room for open reduction and stabilization of the fracture. High-energy tibial shaft fractures are challenging injuries to treat. They are often open and comminuted and may be associated with other life-threatening injuries . InitialA 14-year-old healthy male was admitted having fallen from a height of three metres in a derelict building. Paramedics reported a 90-degree deformity of his right leg when they arrived at the scene of injury. The limb was realigned and placed into a \u201cbox-splint\u201d for transfer. There was no evidence of neurovascular injury. Plain radiographs revealed a distal tibial metaphyseal fracture with an associated fibula fracture Figures  and thisA 39-year-old healthy male was admitted with multiple injuries following a high-speed cross-country motorcycle (\u201cMotocross\u201d) accident. On-scene emergency medical services reported a severe 90-degree deformity of the injured limb. The limb was realigned and placed into \u201cbox-splint\u201d for transfer to the emergency room. Assessment in the resuscitation room indicated a mid-shaft Gustilo-Anderson  Grade IIFailure of adequate closed reduction in high-energy tibial fractures requires operative exposure of the fracture site to achieve anatomical fracture reduction. Where closed reduction is not possible it is likely that periosteum or soft tissue is entrapped within the fracture and this may need to be removed. Interposition of soft tissue is a rare complication but has been reported in the literature \u20134. GraceThe two cases reported here represent an unusual reason for failure of closed reduction. To our knowledge this has not previously been reported in the literature. In both cases there was a high-energy valgus deforming force applied to the leg. The limbs were realigned by paramedics at the scene of the accident and immobilised in a \u201cbox-splint.\u201d We believe that transposition of the distal fibula fragment into the proximal tibia occurred at the time of this realignment prior to transfer to hospital. Realignment of the limb as a first-aid measure remains the correct course of action in order to protect the neurovascular supply and allow safe transfer of the patient to the receiving unit . HoweverThe initial radiographs taken in the emergency room suggest that the distal fibula had been transposed into the tibial medulla. In the first case Figures  and 2 twTibiofibula transposition is a rare complication of high-energy lower limb fractures and may prevent adequate closed reduction. Impaction of the distal fibula within the tibial medulla occurs as the limb is realigned by paramedic staff before transfer to hospital. Two X-ray views of the fracture are required to identify that a transposition has occurred and we recommend that when this is identified the patient is transferred to the operating room for open reduction and stabilization of the fracture."}
{"text": "Although, the role of Botulinum Toxin-A in the treatment of the neurogenic and non-neurogenic neurogenic bladder is becoming more defined, this is the first review article to characterize the emerging role of Botulinum Toxin-A in the pediatric urologic population. Injection of Botulinum Toxin-A at the level of the bladder works by inhibiting uninhibited bladder contractions and, possibly, by blocking some of the sensory nerve fibers. In children with sphincter dyssynergy, injection at the level of the urethral sphincter works by inhibiting the involuntary guarding reflex and blocking dyssynergic voiding."}
{"text": "In April 2016, the World Health Organization (WHO)\u2019s Control of Neglected Tropical Diseases (NTD) department and Nutrition for Health and Development (NHD) department convened a Guidelines Development Group meeting to review the WHO\u2019s recommendations for the control of soil-transmitted helminths in high-risk groups. Subsequent to this meeting, the WHO will announce whether it will reaffirm its long-standing recommendation of mass drug administration (MDA) in areas with more than 20% prevalence of soil-transmitted helminths . We recently released a new meta-analysis [There is consensus that the relevant drugs are safe and effective. Indeed, they are the standard of care for those known to be infected. Since individual collection and testing of stool samples prior to treatment is prohibitively expensive and logistically impractical in many low-income contexts, the relevant question for policy is whether the expected benefits of MDA exceed its costs, taking into account uncertainty.p = 0.0038) but conclude that there is \u201csubstantial evidence\u201d of no impact of mass treatment on weight or other outcomes at community level. This has led some to suggest that the long-term impacts discussed above are logically impossible and that the WHO policy is mistaken [The literature on long-run educational and economic impacts of deworming of children in several high-prevalence settings suggests that this is the case . Howevermistaken .Cochrane Handbook for Systematic Reviews of Interventions [p values when the standard errors are not reported in the original article and contacting original study authors for clarification when necessary. The updated, full sample in [The new meta-analysis  working ventions , such asample in  includesample in , substanp value <0.001 using the full sample in [We find that the 2015 Cochrane Review analysis  is statiample in  in isolaample in ) also leIn the full sample in , includiThe implied average effect of MDA on infected children in the full sample in  (calculaWhile the WHO decision will be based on health benefits, we believe that it is also worth noting recent research that provides new evidence on the long-run educational and economic benefits of deworming. Baird et al.  estimateIn light of the mounting evidence on both the short-run impacts on child weight and long-run educational and economic effects of deworming, we believe that the expected benefits of deworming are likely to greatly exceed the cost, and that the long-standing support of WHO and other international donors and organizations for mass deworming remains scientifically justified."}
{"text": "To elucidate the mechanism through which internalized stigma reduces the quality of life (QoL) of people with mental illness by exploring the mediating roles of self-esteem and sense of coherence (SOC).A cross-sectional analysis of 229 patients diagnosed with schizophrenia or affective disorders was undertaken to test a sequential mediation model assuming that more severe internalized stigma is related to lower self-esteem, which is associated with weaker SOC, which in turn relates to worse QoL.The proposed model was supported by the data. A sequential indirect effect from internalized stigma to QoL via self-esteem and SOC turned out to be significant . Support was also found for simple mediation models with either self-esteem or SOC as single mediators between internalized stigma and QoL.Self-esteem and SOC are personal resources that should be considered as potential targets of interventions aiming to prevent the harmful consequences of internalized stigma for the QoL of people receiving psychiatric treatment. Also significant were simple mediation paths from internalized stigma to QoL via self-esteem  and from internalized stigma to QoL through SOC . Examination of the pairwise contrasts of the indirect effects . There was a significant sequential indirect effect of internalized stigma on QoL through self-esteem and SOC [path aIn this study, we found evidence for a theoretical model proposing that self-esteem and SOC sequentially mediate the relationship between internalized stigma and QoL among people with mental illness. Our findings are in keeping with previous research which has already convincingly demonstrated a robust association of self-stigma with diminished self-esteem , 4 and dIt should be emphasized that apart from the two-mediator path, two simple mediation paths with either self-esteem or SOC as single mediators between internalized stigma and QoL were also found to be significant and the three indirect effects did not differ in terms of magnitude. This further corroborates the importance of both of these self-related variables for the QoL and highlights the complexity of the ways in which self-stigma acts on people with mental illness.Contrary to self-esteem, SOC is a construct that has not been thus far extensively studied in the context of internalized mental health stigma and the harms it causes. This may be somewhat surprising given the well-described role of SOC in coping with stressors or enhancing health and QoL , 24, 25 Regarding implications for clinical practice, with replication this study may support the need for targeting self-esteem and SOC in therapeutic programs aiming to prevent the harmful impact of internalized stigma on people with mental illness. There is some empirical evidence indicating that these personal resources are modifiable by means of specific group interventions. An example of a method of improving self-esteem may be the \u201cself-esteem module\u201d designed by Lecomte et al. . This isSome limitations of the study are to be mentioned. Most importantly, the cross-sectional design does not allow us to draw any definite conclusions about causality. While there is considerable evidence for the detrimental effect of self-stigma on self-esteem , it has Despite these limitations, this research provides further evidence for the significance of internalized stigma as a barrier to recovery from mental illness and extends the understanding of the mechanism of its impact on service users by showing how it may compromise their QoL through undermining their personal resources (such as self-esteem and SOC)."}
{"text": "Annayev et al.  reported We thank Drs. Sookaromdee and Wiwanitkit for their interest and contribution to our article. There is a growing evidence of renal dysfunction in patients with thalassemia. Although the process is multifactorial , oxidative stress seems to be the main mechanism of renal damage. Several studies have shown the beneficial effects of antioxidants  in prevention of chemotherapy-induced nephrotoxicity by decreasing oxidative damage. Considering the significantly increased life expectancy of thalassemia patients with long-term complications, we think the role and effects of antioxidant treatments in routine follow-up of the thalassemia patients should be investigated in prospective studies."}
{"text": "Information is presented on the new scientific line in medicine and biology: bio-liquid morphology. The interdisciplinary character of the given research area is emphasized. The problems and prospects of bio-liquid morphological analysis development both in applied and fundamental aspects are discussed."}
{"text": "Clinical and TranslationalMedicine are issuing an editorial expression of concern to alertreaders that concerns have been raised regarding the ethics of this study [The Editors-in-Chief of is study . Appropr"}
{"text": "This study addresses the issue of the existence of whole-word phonological representations of disyllabic and multisyllabic words in the Chinese mental lexicon. A Cantonese brain-injured dyslexic individual with semantic deficits, YKM, was assessed on his abilities to read aloud and to comprehend disyllabic words containing homographic heterophonous characters, the pronunciation of which can only be disambiguated in word context. Superior performance on reading to comprehension was found. YKM could produce the target phonological forms without understanding the words. The dissociation is taken as evidence for whole-word representations for these words at the phonological level. The claim is consistent with previous account for discrepancy of the frequencies of tonal errors between reading aloud and object naming in Cantonese reported of another case study of similar deficits. Theoretical arguments for whole-word form representations for all multisyllabic Chinese words are also discussed."}
{"text": "The original scanned image file of the film contained six lanes, with the wild-type sample run in duplicate at either end of the gel. While the sixth lane was cropped out of the image of the film probed with anti-Dnmt3L antibody, it was accidentally included in the image of the film probed with anti-Ezh2 antibody.The corrected figure is below. The authors regret the error."}
{"text": "The Editors-in-Chief are retracting this article  because The online version of this article contains the full text of the retracted article as electronic supplementary material."}
{"text": "Scientific Reports7: Article number: 4003710.1038/srep40037; published online: 01042017; updated: 05222018The original version of this Article contained an error in Figure 7A, where the immunoblot of flotillin from HeLa was a duplicate of the immunoblot of flotillin from HeLa-LAI.This error has been corrected in the HTML and PDF versions of the Article and the figure has been appropriately delineated. The original images for the immunoblots shown in Figure 7 are now included in the accompanying Supplementary Information file."}
{"text": "Objectives: To assess the sensitivity of patients who suffered a severe closed-head injury to the manipulation of attentional resources and encoding instructions during the execution of prospective memory tasks.Material and Methods: A group of patients with chronic sequelae of severe closed-head injury and a group of matched normal controls were given an experimental procedure for the assessment of time-based and event-based prospective memory. Availability of attentional resources at the time of intention recall and encoding conditions at the time of giving instructions were varied across experimental sessions.Results: The simultaneous execution of a concurrent task was more detrimental to accuracy in the spontaneous recall of the prospective intention in the post-traumatic than in the normal control group. Moreover, the instruction to encode more extensively by rehearsing aloud and mentally imaging the actions to be performed at the time of the study improved recall accuracy more in the post-traumatic than in the normal control group.Conclusions: Based on these data, we suggest that a prospective memory deficit in post-traumatic patients is due, among other things, to reduced availability of attentional resources and to poor encoding of actions to be performed."}
{"text": "Every day we are faced with an overwhelming influx of visual information. Visual attention acts as the filtering mechanism that enables us to focus our limited neural resources, by selectively processing only the most relevant and/or salient aspects of our visual environment. The ability to shift attention to the most behaviorally relevant items enables us to successfully navigate and interact with our surroundings. The dorsal visual stream is important for the rapid and efficient visuospatial orienting of attention. Unfortunately, recent evidence suggests that the dorsal visual stream may be especially vulnerable to age-related decline, with significant deterioration becoming evident quite early in the aging process. Yet, despite the significant age-related declines to the dorsal visual stream, the visuospatial orienting of attention appears relatively well preserved in older adults, at least in the early stages of aging. The maintenance of visuospatial orienting of attention in older adults appears to be facilitated by the engagement of compensatory neural mechanisms. In particular, older adults demonstrate heightened activity in the frontal regions to compensate for the reduced activity in the posterior sensory regions. These findings suggest that older adults are more reliant on control processes mediated by the anterior regions of the frontoparietal attention network to compensate for less efficient sensory processing within the posterior sensory cortices. Everything from playing tennis to simply walking down the street require the successful orienting of attention from one location to the next. This process of shifting attention is referred to as the visuospatial orienting of attention. A process which relies on an interacting network of structures, which include regions of the lateral prefrontal cortex  from surrounding items (distractors). A process which has typically been studied using the visual search paradigm  recordings in order to examine the electrophysiological correlates of attention shifts. These event-related potential (ERP) studies have most commonly focused on the P1 (80\u2013130 ms) and the N1 (140\u2013200 ms) components in relation to processing of target stimuli (Mangun and Hillyard, More recently, researchers have begun to focus on the neural activity elicited during the cue-target interval; much of this work has focused upon examining the modulation of prestimulus alpha activity along the fronto-occipital axis during the cue-target interval (Foxe et al., Recent studies indicate that the level of alpha power lateralization during the cue-target interval is significantly reduced in older adults (Vaden et al., Additionally, while the majority of research into the patterns of age-related cerebral reorganization have centered on intra-hemispheric patterns of reorganization, there is also extensive evidence to support inter-hemispheric patterns of reorganization (Cabeza et al., In summary, these studies suggest that in spite of the early age-related declines of the dorsal visual stream the visuospatial orienting of attention remains relatively well preserved, at least in the earlier stages of aging. This maintenance appears to be facilitated by the engagement of compensatory neural mechanisms; which is consistent with both the compensation-related utilization of neural circuits hypothesis (CRUNCH; Reuter-Lorenz and Cappell, The mini review was written by ETS-L with assistance and feedback from AJL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Stimulated-echo acquisition mode (STEAM) is one of the key pulse sequences in CMR imaging, as it alleviates rapid magnetization decay with T2 relaxation. Fat suppression is frequently implemented in cardiac imaging to improve visualization and tissue characterization, albeit at the cost of reduced temporal resolution and signal-to-noise ratio (SNR), as well as possible increase of specific absorption rate (SAR). The purpose of this work is to develop an efficient fat suppression method ) for STEAM sequences to enable imaging at high temporal-resolution, with high SNR, and no increase in scan time.The developed method is based on saturating the fat magnetization prior to applying the STEAM modulation; therefore, only the water-content of the tissues is modulated by the sequence, resulting in fat-suppressed images without the need to run the fat suppression module during image acquisition Figure . The potThe results from the in vivo experiments showed superior performance of the proposed SPM method compared to the CHESS and SSSP techniques Figure . The SPMAn efficient technique has been presented for suppressing the fat signal in a number of STEAM-based cardiac imaging techniques. The proposed technique improves the temporal resolution of the acquired images without sacrificing SNR, SAR, or scan time, which could result in accurate parameter measurement and improved cardiac image analysis."}
{"text": "Social care-related quality of life is a key outcome indicator used in the evaluation of social care interventions and policy. It is not, however, always possible to collect quality of life data by self-report even with adaptations for people with cognitive or communication impairments.A new proxy-report version of the Adult Social Care Outcomes Toolkit (ASCOT) measure of social care-related quality of life was developed to address the issues of wider inclusion of people with cognitive or communication difficulties who may otherwise be systematically excluded. The development of the proxy-report ASCOT questionnaire was informed by literature review and earlier work that identified the key issues and challenges associated with proxy-reported outcomes.To evaluate the acceptability and content validity of the ASCOT-Proxy, qualitative cognitive interviews were conducted with unpaid carers or care workers of people with cognitive or communication impairments. The proxy respondents were invited to \u2018think aloud\u2019 while completing the questionnaire. Follow-up probes were asked to elicit further detail of the respondent\u2019s comprehension of the format, layout and content of each item and also how they weighed up the options to formulate a response.A total of 25 unpaid carers and care workers participated in three iterative rounds of cognitive interviews. The findings indicate that the items were well-understood and the concepts were consistent with the item definitions for the standard self-completion version of ASCOT with minor modifications to the draft ASCOT-Proxy. The ASCOT-Proxy allows respondents to rate the proxy-proxy and proxy-patient perspectives, which improved the acceptability of proxy report.A new proxy-report version of ASCOT was developed with evidence of its qualitative content validity and acceptability. The ASCOT-Proxy is ready for empirical testing of its suitability for data collection as a self-completion and/or interview questionnaire, and also evaluation of its psychometric properties. In the UK, social care refers to long-term care services that aim to maintain the quality of life of adults with long-term health conditions or ageing-related support needs . The increased demand for social care due to ageing populations in Europe combined, in some countries, with the trend to reduce public spending has contributed to an interest in the evaluation of the effectiveness and cost-effectiveness of social care based on the outcomes of people who use services . The shiTo evaluate the effectiveness of social care based on personal outcomes rather than outputs, it is important to define the objectives of social care and to develop an appropriate instrument that reflects these objectives. Social care may be broadly conceptualised as services that compensate for the effect of impairments on overall wellbeing or quality of life \u20137. ThereThe construct of social care-related quality of life (SCRQoL) has been proposed as the basis for developing instruments to measure social care outcomes . SCRQoL If individual quality of life is used evaluate the effectiveness of interventions and policy of social care in this way, a key challenge is how to collect quality of life data from people with cognitive or communication difficulties, who are unable to answer on their own behalf even with support, alternative formats or communication aids, so to avoid the issues of sampling bias and systematic exclusion from \u2018having a voice\u2019 \u201321. In tThe aim of the study was to develop a new social care-related quality of life measure based on the ASCOT-SCT4 that could be used in circumstances where the individual is unable to self-report and other methods of eliciting outcomes information are not feasible. This article outlines the second phase of work that sought to apply the findings identified in the first phase of the project  to develThis qualitative study aimed to develop a proxy-report version of the self-completion ASCOT-SCT4 with adequate content validity and acceptability to proxy respondents . ContentControl over daily life; Occupation ; Social participation and involvement; Personal safety; Personal cleanliness and comfort; Food and drink; Accommodation cleanliness and comfort; and Dignity. The instrument has four response options for each item to distinguish between the ideal state, no needs, some needs and high-level needs in relation to each quality of life attribute Based on analysis of the first round of interviews, the modifications outlined in Table Occupation, Social participation, Personal safety and Personal comfort and cleanliness were modified to correspond to the original ASCOT-SCT4 item wording to improve acceptability and comprehension  would improve acceptability of the measure to proxy respondents The first round of interviews explored whether the adaptation of the pondents . InteresPersonal safety and Personal comfort and cleanliness were adapted to correspond to the original ASCOT-SCT4, which refers to feeling rather than being safe or clean and presentable. In subsequent rounds of cognitive interviews, the respondents were able to understand and respond to these two modified items with no evidence of any issues with acceptability.Based on this finding, the Based on advice from the ASCOT development team, the researchers asked respondents in the second round of cognitive interviews to compare two versions of the questionnaire  conceptual framework of proxy response was used to develop proxy questionnaire items that asked: (1) respondents to rate their own view (proxy-proxy perspective); and (2) what they thought the care recipient would say (proxy-patient perspective). This dual response approach was found to be acceptable to care worker and family carer proxies. The format allowed the respondents to express differences between their opinion and their understanding of the care recipient\u2019s perspective. These differences were explained by reference to different personal preferences influenced, for example, by social or cultural norms or health condition-related factors:Food and drink) by ticking multiple boxes in each column or writing yes/no to indicate whether each statement applied or not. They were, however, able to correctly complete the remainder of the questionnaire once they had realised that the format required one tick per column. Based on these findings, the questionnaire for version 3.0 was re-formatted to include \u2018please tick one box\u2019 above the response boxes , two family carers were initially confused by the layout. The interviewers had been briefed to allow the respondent to continue the questionnaire without prompts to highlight the questionnaire instructions to tick one box per column. In one of the two cases ([SR_IC_05]), the respondent spontaneously realised that their initial response with multiple ticks had been incorrect and amended their response. There were no issues with the remaining questions. In the other case ([SR_IC_07]), the respondent directly asked the interviewer whether they needed to tick multiple boxes in each column. Once they had seen the instruction, with a prompt from the interviewer, the respondent understood that only one tick per column was required to indicate their rating:\u201cTick, \u2018Please tick one box for each,\u2019 oh, \u2018Tick one box for each column.\u2019 Oh I see, so [sigh], so it\u2019s just the top one then isn\u2019t it?\u201d [SR_IC_07]In the third round of interviews  and distinguish this from their view of the care recipient\u2019s own perspective (proxy-patient perspective). The findings of this study indicate that proxy respondents found it acceptable to adopt both proxy-proxy and proxy-patient perspectives and that they were able to understand and respond to the items based on both perspectives.The aim of this research was to develop a proxy-report measure of social care-related quality of life and establish its qualitative content validity through cognitive interviews . This qufeeling safe rather than more objective judgements, such as being safe [being rather than feeling safe) were less acceptable than items framed around the individual\u2019s subjective perspective when proxy respondents were given a questionnaire based on dual proxy-patient and proxy-proxy perspective report. However, some proxy respondents still had difficulty in projecting themselves into the individual\u2019s internal state when adopting the proxy-patient perspective, especially when the proxy respondent had to rely on ambiguous external cues and behaviours to formulate their response.While an earlier phase of work found that care workers were hesitant to provide proxy judgements of individual care recipient quality of life especially when questions related to subjective concepts such as ing safe , this quing safe . FurtherWhile the two proxy perspective methodology has improved the acceptability of proxy report of social care-related quality of life in the eight ASCOT-SCT4 domains , there rproxy-patient perspective) or the proxy\u2019s judgement based on their internal standards, preferences and attitudes (proxy-proxy perspective) [The two proxy perspectives may be conceptualised as two separate sources of information based on the proxy respondent\u2019s mental construct of the care recipient\u2019s likely internal state informed by their knowledge of the individual (pective) . Based opective) , 39. WheThe study has some limitations. First, the first phase of cognitive interviews included only care workers who supported adults with intellectual disabilities in a supported living context. In the subsequent two rounds of interviews, we purposively sampled a mixture of care workers and family carers because of evidence that different types of proxy respondent may respond differently to proxy-report questionnaires , 67. We In conclusion, it was found that the item wording, format and layout of the ASCOT-Proxy questionnaire was understandable and acceptable to care workers and family carers invited to act as proxy respondents. Respondents\u2019 comprehension of items corresponded to the construct definitions captured by the items in the self-report version of ASCOT-SCT4. This was improved by modifications to the ASCOT-Proxy to minimise differences in item wording between the ASCOT-Proxy and ASCOT-SCT4, whilst maintaining the acceptability of the instrument. The next step to evaluate the feasibility and psychometric properties of the new instrument in the context of self-completion surveys is justified."}
{"text": "Although there are many well-known theories of adolescent development in the West, there is a notable lack of theory with empirical support to understand the process and outcome of Chinese adolescent development. This paper attempts to advance a Chinese conception of adolescent development in a migration context. A qualitative study approach was used to explore the experiences and views of 19 Chinese-Canadian adolescents from Hong Kong and ten of their parents. The findings indicate that parents and adolescents co-construct the dominant theme of \u201ccovert parental control\u201d in the adolescent development process, and the concept of \u201cself in relational networks\u201d as the adolescent development outcome. Based on the developmental experiences of these Chinese-Canadian adolescents, a culturally sensitive model of Chinese adolescent development is proposed. This model incorporates culture and migration as two essential components of the framework for a theory regarding Chinese adolescent development. It acknowledges the experience of Chinese-Canadian immigrants, takes account of the participants' personal meanings, and incorporates the indigenous Chinese cultural concepts of bao (reciprocity), guan (guidance), and guanxi (relationship)."}
{"text": "Globally, approximately two billion people are infected with the Hepatitis B virus with attributable death estimated at about half a million people annually across the globe. Chronic hepatitis B infection is also an important public health problem in Ghana. The main mode of transmission in endemic regions is the perinatal route. Mother-to-child transmission can be reduced by antiviral therapy especially in the last trimester and adherence to the national immunization schedule. The World Health Organization recommends to add the birth dose vaccine to the current expanded program on immunization (EPI) in all countries but especially for endemic regions. The evidence for the efficacy of the birth dose HBV vaccine is overwhelming and there is an urgent need for its introduction into the current EPI schedule in Ghana. The discovery of hepatitis B virus (HBV) by the Nobel Prize winner Baruch S. Blumberg has contributed significantly to the development of viral diagnostics and vaccines . One of The estimated prevalence of hepatitis B infection is high  in sub-Saharan Africa . This puHepatocellular carcinoma (HCC) incidence is higher in Africa compared to the rest of the world because of the higher prevalence of chronic viral hepatitis. HCC is also an important cause of cancer related death in Africa and South East Asia . HCC incThere is the need to focus on prevention through education and a special vaccination program for all in Ghana.HBV infection can be transmitted from mother-to-child during the perinatal period. Pregnancy and early childhood are the periods where acquisition of HBV has a high risk of becoming a chronic disease . The natImmunization is globally utilized as a means of preventing infections especially among children. Universal infant immunization for HBV was recommended following the overwhelming success of this approach in Taiwan . The WorHaemophilus influenzae type B, and hepatitis B (DPT/HiB/HepB) 5 in 1 vaccine at 6, 10, and 14 weeks of age. Measles and yellow fever vaccines are given at nine months of age [The EPI schedule for Ghana recommends Bacille Calmette\u2013Guerin (BCG) at-birth; oral polio vaccine (OPV) at birth, 6, 10, and 14 weeks of age ; three doses of diphtheria, pertussis, tetanus, s of age .Examining the current schedule shows that there are already some vaccines given at birth and therefore introduction of the birth dose vaccine for HBV will not disrupt the EPI program in Ghana. The hepatitis B monovalent vaccine can be given together with OPV-0 and BCG. However, this needs to be given ideally within 24 h of the baby\u2019s delivery.This modification to the immunization schedule in terms of timing is not problematic as it only introduces another at-birth dose vaccine at an extra cost. The health sector should be pro-active in leading the government towards the introduction of the birth dose vaccine for HBV as it has been proven efficacious in the prevention of mother-to-child transmission in many other countries ,25,26. TThere is an urgent need for the introduction of the at-birth dose vaccine for HBV in our current EPI schedule to help fully fight the menace of HBV infection in Ghana. In parallel with at-birth vaccination, increased surveillance programs should be implemented to facilitate accurate monitoring of HBV sero-prevalence in different regions of Ghana."}
{"text": "Urinoma or para-renal pseudocyst generally occurs as a result of trauma to the pelvi-ureteric system. It consists of an encapsulated collection of extravasated urine and is usually located in the peri-renal space or more uncommonly in the peritoneal, pleural or mediastinal cavities. There is only one previously reported case of urinoma secondary to abdominal aortic aneurysm (AAA) surgery. We report a case of symptomatic urinoma after infra-renal AAA repair and discuss the etiology, diagnosis and treatment of this unusual condition."}
{"text": "Nanomaterials highlights innovative work from around the world focused on harnessing the physical, chemical and topological properties of nucleic acids. It contains a mixture of articles examining composite materials that combine nucleic acids with carbon nanotubes (CNTs) or metallic nanoparticles, as well as theoretical investigations, and studies directed towards applications in a variety of areas. The latter include nanophotonics, new methods of DNA sequencing, and the development of new antibacterial agents or drug delivery vehicles. Highlights of the publications appearing in this Special Issue are discussed in the following paragraphs.This Special Issue of Kazuo Umemura  has provThe development of a new method for preparing hydrogels composed of multi-walled carbon nanotubes (MWNTs) and two types of DNA is the topic of the study undertaken by Zinchenko and co-workers . A featuE. coli. As a demonstration of the potential application of their discovery, the researchers immobilized the Ag/DNA nanoparticles onto the surfaces of cotton fabrics, which had been previously modified using a cationic polymer in order to facilitate electrostatic binding of the nanoparticles. The resulting materials were shown to exhibit significant bacteriostatic and bactericidal properties in standardized tests.DNA obtained from salmon milt was also used in research led by Tomomi Takeshima . In thisOne of the most exciting areas of nanotechnology research centers on the development of carrier systems for facilitating the delivery of therapeutic agents selectively to specific cells or molecular targets. As part of their efforts in this area, Kocabey and co-workers  have desCervantes-Salguero and co-workers  report tTitration of solutions containing non-covalent DNA/MWNT complexes, with didodecyl-dimethylammonium bromide (DDAB), resulted initially in the formation of sticky precipitates, which re-dissolved when excess cationic surfactant was added. Tardani and La Mesa  have proThe ability to use DNA as a template for the controlled assembly of clusters of sliver atoms is the topic of a detailed review by Gwinn and co-workers . DrawingLi and co-workers  review tThe search for more rapid and reliable methods of DNA sequencing is an important objective as researchers seek to develop new biotechnological devices and products. One method of DNA sequencing that has attracted considerable interest in recent years involves the use of nanopores composed of the protein alpha-hemolysin. Manara and co-workers  describeThe above articles showcase the breadth of nanotechnological research currently being undertaken throughout the world that seeks to take advantage of the many unique features of DNA. We hope that you enjoy reading this Special Issue, and look forward to your contributions to this journal in this fascinating area in the years ahead."}
{"text": "A 57-year-old man was admitted to our hospital for evaluation and management of stroke in the setting of an atrial septal defect. Shortly after receiving gadobenate dimeglumine for magnetic resonance imaging of the pelvic vessels, he experienced cardiac arrest from which he was resuscitated. His course was complicated by profound distributive shock. The presumed cause was a severe anaphylactic or anaphylactoid reaction to the gadolinium-based compound that he received."}
{"text": "Testing for the existence of a threshold sub-section of the Methods.After publication of the original article , it cameTwo formulae originally published in this sub-section were incorrect; the correct expressions are the negatives of the expressions published. The formulae should have appeared as follows:and"}
{"text": "Their regioselective installation on polyols generally requires lengthy reactions and the use of high boiling solvents. In the first part of this paper we demonstrate that regioselective silylation of sugar polyols can be conducted in short times with the requisite silyl chloride and a very limited excess of pyridine . Under these conditions, that can be regarded as solvent-free conditions in view of the insolubility of the polyol substrates, the reactions are faster than in most examples reported in the literature, and can even be further accelerated with a catalytic amount of tetrabutylammonium bromide (TBAB). The strategy proved also useful for either the selective TBDMS protection of secondary alcohols or the fast per-O-trimethylsilylation of saccharide polyols. In the second part of the paper the scope of the silylation approach was significantly extended with the development of unprecedented \u201cone-pot\u201d and \u201csolvent-free\u201d sequences allowing the regioselective silylation/alkylation (or the reverse sequence) of saccharide polyols in short times. The developed methodologies represent a very useful and experimentally simple tool for the straightforward access to saccharide building-blocks useful in organic synthesis. Their bulkiness allows in many cases regioselective silyl protection of primary alcohols. Commonly, O-silylation is performed by exposing the alcohol to a suitably substituted silyl chloride in the presence of a base, a catalyst (often coinciding with the base) and an aprotic solvent [The application of an orthogonal set of protecting groups represents a typical issue in organic synthesis in the elaboration of highly functionalized molecules such as carbohydrates, and lengthy multistep procedures are often needed to this aim \u20132. Silyl solvent . The use solvent \u201313.A regioselective silylation of polar saccharide polyols is typically performed with the appropriate silyl chloride in the presence of a high boiling solvent such as DMF or pyridine, often in the presence of a nucleophilic catalyst (more frequently imidazole and DMAP) \u201321. The The regioselective silylation of secondary saccharide alcohols can also be achieved either taking advantage of the inherent difference of reactivity among the hydroxy functions \u201332 or exOver the last years, we have addressed our interest towards the development of solvent-free protocols aimed at regioselective protection of highly functionalized saccharide substrates. This effort led to a simple protocol for the selective benzylation of primary saccharide alcohols , the firIn this paper, we wish to report the extension of the scope of the solvent-free strategies to the silylation reaction, and the feasible incorporation of this step into unprecedented one-pot, fully solvent-free sequences yielding orthogonally protected saccharide building-blocks under simple experimental conditions and in short times.1) was selected as the model substrate and exposed to TBDMSCl in the presence of a slight or moderate excess of several bases  was silylated in a good yield (6) required the employment of a higher stoichiometric excess of both pyridine and TBDMSCl  and the allylic (O-3) position, to provide a mixture of products  is beneficial for the achievement of a higher yield while maintaining the use of a minimal excess of the silylating agent .As a matter of fact, upon doubling the stoichiometric amount of TBAB, pyridine and TBDMSCl, the regioselective synthesis of di-20 [22 (as an anomeric mixture) was 3-O-silylated in a good yield, and the anomeric composition of the products revealed the higher reactivity of the \u03b1-anomer .Double silylation at primary positions of the disaccharide lactoside 20  also pro\u03b1-anomer , entry 5ursor 24   in order to establish which order of steps  might be higher yielding. Initial experiments indicated that the silylation step was not apparently effective when performed after the tin-catalyzed 3-O-benzylation of mannoside  occurs in a comparable yield under tin catalysis [O-silylation/3-O-benzylation) was found to be less effective in terms of yields, apparently because of the partial loss of the TBDMS group in the second step where relatively forced thermal conditions are needed . The method can indeed be regarded as a solvent-free approach because of the limited stoichiometric amount of the base that is not sufficient to dissolve the highly polar saccharide substrates. Under these conditions, a catalytic role played by TBAB was also evidenced. Besides the limited amount of the used base, the proposed method is endowed with further practical advantages such as the experimental ease , and high reaction rates, often comparing favourably with literature examples, in spite of the poor solubility of the starting substrates in the reaction medium. The scope of the silylation approach was also extended to secondary alcohols and to the per-In the second part of the paper, we have explored the feasible combination of the silylation methodology here introduced with a previously developed tin-catalyzed methodology for regioselective alkyl protection of carbohydrates. The merging of both methods led to unprecedented one-pot and fully solvent-free synthetic sequences, providing a straightforward and experimentally simple access to saccharide building-blocks orthogonally protected with a silyl at the primary position and a benzyl  group at well defined and predicatable secondary positions.File 1Experimental and analytical data."}
{"text": "Out-of-body experience (OBE) is a rare phenomenon during which one has the feeling of being located outside of the physical boundaries of the body, along with the sensation of perceiving the world from an elevated perspective. OBE is of particular interest for studying self-consciousness, as it involves abnormal forms of self-location and visuo-spatial perspective.OBE has been the subject of extensive investigations in parapsychology, neurology and cognitive neuroscience . She never reported OBE before or after surgery.Bos et al.  report tawake craniotomy since seminal observations by the Canadian neurosurgeon Wilder Penfield  tractography to the study of OBE. DTI revealed that the stimulated brain region was close to fibers running from the posterior thalamus to the occipital lobe (Figure Another novel aspect of the case report by Bos and colleagues is that it is the only case of OBE evoked during electrical stimulation of e Figure . This fie Figure  and the e Figure . A PET se Figure . The exaInterestingly, OBEs are also a common feature of near-death experiences. Studies of disembodied experiences during near-death experiences focusing on changes in cortical anatomy and surface electroencephalography have proven controversial (Blanke and Dieguez, The present case is also the only description of OBE during stimulation of the left TPJ. The left TPJ has been involved in complex bodily illusions, such as the induction of an illusory shadow person (Arzy et al., In conclusion, cases of OBE evoked by intracranial stimulation and focal brain damage should be reported systematically in the literature for a better understanding of the neural bases of embodiment. Future studies combining DTI, resting-state functional connectivity and measures of cortical thickness in neurological patients and neurologically normal individual with OBE will foster significant advances in the neuroscience of OBE, similar to studies of xenomelia, schizophrenia and depersonalization (Simeon et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Collective capability of producing patterned collective behaviors is one important field of research in work psychology  and low  levels of organization have been of particular interest . It is also likely that the coupling linkages do not necessarily need to be reciprocal between the co-agents, so that one-sided co-ordination should provide benefits to the global efficiency and parsimony of the system. It is even more likely that co-agents can face the difficulty of regulating each local coupling by grasping the overall picture at some point in their activity , thus counter-balancing the local couplings hypothesis. Related questions should then be addressed: does structural congruence between members, as achieved through recurrent interactions in team training (Maturana and Varela, JB originated the questioning. JB, MF co-wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Chowdhury (July-August 2016). Image Statistics and theFine Lines of Material Perception. A change has been made to this article after its publication on July 14, 2016 issue ofi-Perception. These corrections will be included in all subsequent versions of the articleonline.Author Biographies section, the image for author Kairen Tan was omittedand the biography should read as follows:In the Kairen Tan is a graduate student with a Masters of Information Technology at theUniversity of New South Wales. His research uses image processing and analysis to understandthe perception of surfaces and materials in real-world scenes."}
{"text": "In vitro and in vivo models of experience-dependent plasticity have linked changes in the localization of glutamate receptors at the PSD with a molecular reorganization of the PSD and alterations in spine morphology. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence, and addiction. A potential mechanism supporting these adaptive changes that we recently identified is the homeostatic targeting of NR2B-containing NMDA receptors to the synapse. This increase is associated with and dependent on a corresponding increase in the localization of the scaffolding protein PSD-95 at the PSD, and with an actin-dependent increase in the size of dendritic spines. These observations led us to propose a molecular model for ethanol-induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the PSD provide an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation, and synaptic plasticity. This model is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a role in the aberrant plasticity of addiction.Dendritic spines are morphologically specialized structures that receive the vast majority of central excitatory synaptic inputs. Studies have implicated changes in the size, shape, and number of dendritic spines in activity-dependent plasticity, and have further demonstrated that spine morphology is highly dependent on the dynamic organizational and scaffolding properties of its postsynaptic density (PSD)."}
{"text": "The consultation is open until 28 November 2016.On 17 October, the European Centre for Disease Prevention and Control (ECDC) launched a public consultation on the The aim of the consultation is to harvest input for the ECDC expert opinion which should provide European Union/European Economic Area Member States with scientific opinion and expert opinion to support the decision-making process on the possible introduction and monitoring of routine vaccination against rotavirus-induced gastroenteritis in infants.here on how to submit contributions.Please read more"}
{"text": "This because the income distribution received and paid for by each institutional sector required for a financial SAM is not available, i.e. the INE does not break down the data by institutional destination and source. In this sense, our contribution rely on estimating a complete series of from-whom-to-whom matrices of Property Income for the Spanish economy between 1999 and 2016, in which we have devoted special attention to staying in line with the Data Gaps Initiative (DGI-2) recommendation released by the Financial Stability Board (FSB) and the International Monetary Fund (IMF), claiming that more focus is needed on data sets that support the monitoring of risks in the financial sector in response to regulatory and macro-financial emerging policy needs).A common problem in compiling and updating Social Accounting Matrices (SAM) or Input-Output tables is that of incomplete information. In the case of the submatrix \u2018Property Income of the Account Allocation of Primary Income\u2019, the information published by the National Bureau of Statistics of Spain (INE) is limited because it is not possible to build the set of  Specifications TableValue of the data\u2022from-whom-to-whom matrix scheme. This representation allows the question \u2018who\u2019 is financing \u2018whom\u2019 to be answered, which allows a more detailed and complex analysis of the financial flows between sectors and their role in the economy.The dataset provides accurate estimates of the allocation of primary income account \u2013 property income \u2013 in a \u2022from-whom-to-whom framework by financial instruments turns out to be very useful for analyzing the real-financial interconnectedness of the Spanish economy.The novel approach to provide the stocks of Asset and Liabilities Matrices in a \u2022The dataset provides the necessary elements to estimate the breakout of the total income return, resulting in an outstanding sources of information for investment analysis and impact analysis of public policies.\u2022The set of submatrices results in a consistent accounting framework useful for improving and extending Social Accounting Matrices, sectorial-financial linkage analysis, macroeconomic forecasting and improve and enrich the scope of real-financial computable general equilibrium (CGE) models.1from-whom-to-whom basis, and the compilation guides suggested by Tsujimura and Mizoshita The real side information concerning the allocation of primary income account \u2013 property income \u2013 was obtained from the statistics of the Integrated Economic Accounts (IEA) provided by the National Bureau of Statistics of Spain (INE). The financial side information was retrieved from the financial statistics of the Flow of Funds (FoF) provided by the Bank of Spain (BdE). Both INE and BdE data sets correspond to the yearly series 1999 to 2016 due to the constraints to using the more recent official data set available to build a Property Incomes matrix for Spain. Given that both the real statistics of the INE and the financial statistics of the BdE shape the entire System of National Accounts (SNA93) The statistical information from the INE is available in integrated structured tables separated by years, while the database from the BdE is expressed in quarterly time series. Since the data from the BdE are in quarterly series, different treatments among figures expressed in flows from those expressed in balances were required, adding the former to form flows for the year and considering the figures of the last quarter as the closing balances of the respective year.2In the wake of the 2008 financial and economic crisis, the Group of Twenty economies (G-20) asked the Financial Stability Board (FSB) and the International Monetary Fund (IMF) \u201cto explore gaps and provide appropriate proposals for strengthening data collection before the next meeting of the G-20 Finance Ministers and Central Bank Governors.\u201d In its Spring Meeting in April 2009, the FSB-IMF came up with 20 recommendations 2.1from-whom-to-whom (or debtor/creditor) framework, correspond to the matrix form representation that allow the analysis of the financial connections among institutional sectors in a national economy and abroad. As have been pointed out by Shrestha et al. from-whom-to-whom representation of statistical information allows answering questions like \u201cWho is financing whom, in what amount, and with which type of financial instrument?\u201d. As regards of property income, it also permits tracing who is paying/receiving income  to/from whom. The from-whom-to-whom compilation approach also enhances the quality and consistency of data by providing more cross-checking and balancing opportunities.The integrated system of sector accounts in a from-whom-to-whom matrices as three dimensional tables where the flows from one sector to another sector for each type of financial instruments are showed. In this regard, to estimate the matrix Property Income, we based our approach on the definition provided by the SNA2008 manual, which states:The System of National Accounts 2008 (SNA2008) \u201c7.107 Property income accrues when the owners of financial assets and natural resources put them at the disposal of other institutional units. The income payable for the use of financial assets is called investment income while that payable for the use of a natural resource is called rent. Property income is the sum of investment income and rent.7.108 Investment income is the income receivable by the owner of a financial asset in return for providing funds to another institutional unit\u2026\u201d.Hence, we can use the balances account of the financial account relating to financial assets and liabilities across the institutional sectors as estimators of the shares of income received and paid by each institutional sector. Intuition suggests that the property income received and/or paid for each institutional sector should be directly proportional to its levels of assets and/or liabilities. Thus, we used the balance account of the financial account relating to financial assets and liabilities across the institutional sectors as estimators of the shares of income received and paid by each of them.2.2from-whom-to-whom matrix show how the income is received by the owner of a financial asset in return for providing funds to another institutional sector. The income payable for the use of financial assets is called investment income while that payable for the use of a natural resource is called rent The property income led rent PImxmxp= to/from whom, in what amount, and with which type of transaction?\u201d. Also, as have been pointed out by Shrestha et al. In this sense, the integrated framework on a 2.3from-whom-to-whom representation of the net worth of this economy in terms of stocks:from-whom-to-whom matrices in expression Financial instruments include the full range of financial contracts made between institutional sectors. These contracts are the basis of creditor/debtor relationships through which asset owners acquire unconditional claims on economic resources of other institutional sectors 2.4Like Leung and Secrieru Under the GRAS algorithm Eq. In this sense, we are capable to derive the breakdown of the Property Income by types of financial transactions for the Spanish economy, in which we have devoted special attention to staying in line with DGI-2 recommendation II.8, referring to the compilation of sectorial account flows and balance sheet data, based on from-whom-to-whom matrices expressed in transactions and stocks to support balance sheet analysis, and recommendation II.9, which encourages the development and dissemination of distributional information on income allocation."}
{"text": "The development of artificial organelles is a new, fast-growing field in which a variety of techniques have been employed. This article gives a brief overview of the history of artificial organelles, and describes the development of an artificial endoplasmic reticulum and Golgi organelle on a digital microfluidic platform. This device should be useful in high-throughput combinatorial proteoglycan/glycoprotein synthesis, providing critical information about the control of biosynthetic pathways for these important signaling molecules."}
{"text": "Clinical and TranslationalMedicine are issuing an editorial expression of concern to alertreaders that concerns have been raised regarding the ethics of this study [The Editors-in-Chief of is study . Appropr"}
{"text": "Such a law is relevant for the global oncology community because few low- or middle-income countries have enacted similar legislation.2 It may pave the way for enactment of similar legal directives in other developing countries, thereby resulting in a greater impact around the globe.The Government of India recently published a draft version of the Medical Treatment of Terminally-Ill Patients Bill for comments and feedback from the public.The legislation provides clarity to several facets of end-of-life care. Competent patients can decline introduction of life-sustaining medical treatment, a decision with which their physicians will be bound to comply. The legislation seeks to protect both the patient and the physician from legal complications that may arise from such a decision. It also emphasizes the importance of appropriate documentation and record keeping.3 Families of terminally ill patients have also reported less stress and greater satisfaction with care after such discussions.4 If the principle of patient autonomy is to be respected, the proposed bill should consider upholding advance directives as an integral part of end-of-life care of terminally ill patients.Although the Government of India must be applauded for moving ahead with this legislation, we believe that the current version may be a misstep for two reasons. First, the proposed bill prohibits the use of advance medical directives\u2014living wills or medical powers of attorney\u2014in India. Therefore, any advance medical directive prepared by a patient with a terminal illness for his or her health care providers and family in the event he or she becomes unable to take a decision about life-sustaining treatment will not be legally binding. This will result in increased use of life-sustaining treatment and intensive care unit admissions among terminally ill patients for whom death is an inevitable event. We fear this violates the autonomy of the patient. End-of-life discussions can reduce the rates of intensive care unit admissions and life-sustaining treatment use, such as the use of a ventilator, at the end of life.Second, it is unreasonable to expect the court to take decisions on withholding or withdrawing life-sustaining care from terminally ill patients who are unable to make informed decisions. The Indian legal system is already burdened by backlogged cases, and such an expectation could potentially harm the care of terminally ill patients by causing unnecessary delays. Instead, the bill should consider providing guidance to the formation of hospital-based ethics committees comprising physicians from various specialties, including palliative care, nurses, and representatives from the community, who could decide on the ethical aspects of withholding or withdrawing life-sustaining medical care.In summary, we congratulate the Government of India on its noble intention of creating legislation defining appropriate end-of-life care. We hope to bring attention to the potential negative impact of the proposed bill on patient autonomy with regard to advance medical directives."}
{"text": "It must be included in the differential diagnosis of posterior mediastinal and retroperitoneal mass. We report a case of retroperitoneal ganglioneuroma involving the celiac axis and superior mesenteric arteries in a 40-year-old female.Ganglioneuroma is a rare neoplasm arising from the sympathoadrenal neuroendocrine system and has anatomic distribution paralleling the sympathetic chain ganglia and the adrenal medulla. In some cases, ganglioneuroma is the end stage maturation of less-differentiated neoplasms such as neuroblastoma or ganglioneuroblastoma, but based on age at diagnosis (over 10 years of age) and anatomic location, many of these tumors appear to arise"}
{"text": "The authors of the paper \u201cCharacteristics of Articles About Human Papillomavirus Vaccination in Japanese Newspapers: Time-Series Analysis Study\u201d :e97) omitted information in the caption of The corrected article will appear in the online version of the paper on the JMIR website on March 16, 2018, together with the publication of this correction notice. Because this was made after submission to PubMed or Pubmed Central and other full-text repositories, the corrected article also has been re-submitted to those repositories.Please see the figure with the corrected caption here."}
{"text": "Does letter-form constrain errors in peripheral dyslexia? In Hebrew, 5 of the 22 letters have two different letter forms, one is used only when the letter occurs in word-final position, the other form is used in initial and middle positions. Is the information on final-forms encoded in the letter identity information and used for word identification, or is it discarded? The current research explored this question through the effect of final vs. non final letter form on the error pattern in neglect dyslexia (neglexia) and letter position dyslexia (LPD). Left word-based neglexia results in errors of omission, substitution and addition of letters in the left side of words, which in Hebrew is the end of the word. We examined whether final letter form blocks the addition of letters to the end of the word and whether omissions of letters after letters in non-final form are avoided. The predominant error type in LPD is migration of letters within words. We tested whether migrations also occur when they cause form change of either final-form letters that move to middle position or middle-form letters that move to final position. These questions were assessed in both acquired and developmental neglexia and LPD. The results indicated a strong effect of final letter-form on acquired neglexia and on acquired and developmental LPD, which almost completely prevented form-changing errors. This effect was not found in developmental neglexia, where words that end in final-form letters were actually more impaired than other words, probably because final-form letters appear only on the neglected side of the word for Hebrew-reading children with left developmental neglexia. These data show that early visuo-orthographic analysis is sensitive to final letter form and that final letter form constrains errors in peripheral dyslexia."}
{"text": "The case of a 67-year-old right-handed Chinese man with Central Pontine Myelinolysis [CPM] is described to illustrate the resulting cognitive and emotional disturbances. A comparison of the data in this report with that in published studies suggests that ethnicity does not seem to have much effect on the symptoms of CPM. Possible underlying neural-pathological mechanisms are discussed. This case further substantiates the speculation that the brainstem plays a role in higher cognitive processes and emotional regulation."}
{"text": "The renin-angiotensin-aldosterone system is now considered to be far more complex than previously thought when the vasoconstrictor and other physiological effects of the octapeptide angiotensin II in the circulating blood were emphasized. The reasons for this altered viewpoint, involving angiotensins other than the octapeptide in the regulation of blood pressure, water and electrolyte homeostasis, are briefly advanced and discussed."}
{"text": "Editorial on the Research TopicRadiation and the Immune System: Current Knowledge and Future PerspectivesAt present, the opinions about the interaction between ionizing radiation and the immune system are largely controversial. For long, high-dose ionizing radiation was considered as net immune suppressing mainly due to the exquisite radiosensitivity of the lymphoid system. While this increased radiosensitivity cannot be contested, a rapidly growing number of scientific publications have demonstrated a very heterogeneous quantitative and functional response of the different components of the immune system to radiation \u20133. A majIt was additionally recognized that some of the radiation-induced late side effects are of immune and inflammatory nature. At present, one of the most studied fields of research in radiation biology is focused around the biological effects of low doses, where the observed pathophysiological endpoints are due to mechanisms other than radiation-induced direct cell killing. Such mechanisms are for example radiation-induced bystander effects or abscopal effects, which by sharing common mediators with various immunological signaling processes, are most probably immune-mediated.Schaue, who gives a comprehensive historical overview regarding the interaction between ionizing radiation in general and RT, in particular, and the immune system.The multitude of studies investigating the interactions between ionizing radiation and the immune system lead to the emergence of a new, highly interdisciplinary scientific field called radioimmunobiology, with the potential to induce a paradigm change in this area and to achieve direct clinical applications within a relatively short term. Scientific primary and overview papers collected in the present Research Topic aim to give an up-to-date state of the art of the complex interactions between the immune system and ionizing radiation while highlighting future perspectives as well. This paradigm change is nicely illustrated in the review by Wennerberg et al. summarize further immune suppressive properties of radiation on the cellular and molecular level besides the impact of radiation on expression of inhibitory immune checkpoint molecules such as PD-L1. The impact of RT and radiochemotherapy (RCT) on the latter on tumor cells of different tumor entities is the focus of the research article by Derer et al. They show that, in particular, RCT increases the expression of PD-L1 on melanoma and glioblastoma cells. This demands radioimmunotherapies (RIT) to counteract radiation-induced immune suppression. For the design of beneficial RIT, many additional parameters have to be taken into account. What is the best radiation dose and radiation quality? Ebner et al. review the unique biological and physical benefits of particle irradiation that may be superior in some aspects for the generation of systemic radiation-induced immune-mediated effects. Besides the radiation quality, the dose and the chronological sequence of immune cell infiltration into the tumor has to be kept in mind. Frey et al. present data on timely restricted immune cell infiltration following hypofractionated radiation. Cytotoxic T cells follow the antigen-presenting cells and are present for only 2\u2009days. Here, re-irradiation of the tumor should be revisited to spare the immune cells, and boosting of the immune system at this time point could be particularly effective. Since the inflamed microenvironment of tumors impacts on growth and progression, several articles deal with modulation of inflammation by radiation. R\u00f6del et al. review radiation-induced mechanisms contributing to a modulation of proliferative and inflammatory processes. They focus on summarizing innovative concepts of treating hyperproliferative diseases by low and moderate doses of ionizing radiation. Since inflammatory events and bone metabolism are interconnected, radiation also impacts on bone turnover. Cucu et al. demonstrate in serum samples of patients who were exposed to very low doses of alpha-irradiation in radon spa that collagen fragments (in particular CTX-I) are decreased after radiation exposure. This suggests a reduced bone resorption by osteoclasts. The interleukin IL-33 has been described as an intracellular alarmin being involved in many inflammatory processes. Kurow et al. revealed that the release of full length IL33 in the damaged tissue does exacerbate radiation-induced skin reactions.Although the cell autonomous effects of ionizing radiation are well established, there is nowadays growing evidence that intercellular communication plays a major role in the outcome of radiation exposure at the tissue level. This is especially true in cancer therapy. Radiation exposure aims at killing tumor cells, but efficient tumor control/eradication also requires the activation of the immune system. The tumor microenvironment indeed contains various subsets of immune cells, both myeloid cells and lymphocytes. Among the myeloid cells, myeloid-derived suppressor cells and tumor-associated macrophages provide a supportive environment for tumor growth, in part by suppressing the activity of cytotoxic T cells. Manning et al. monitored the expression of about 250 genes associated with the inflammation response over the course of the RT in blood of patients with endometrial or head and neck cancer. Some of these inflammation-related genes could be promising biomarkers of radiation exposure and susceptibility to radiation-induced toxicity. Radiation-induced inflammatory reactions are also heavily involved in the development of radiation-related side effects in various tissues. Several papers within this research topic specifically focus on this aspect. Wirsd\u00f6rfer and Jendrossek summarize radiation-dependent mechanism of acute and chronic environmental lung changes following thoracic irradiation. Acheva et al. present new data regarding the mechanism of RT-induced skin side effects focusing on the role of NF\u03baB and Cox-2 in the generation of pro-inflammatory signals. Morini et al. investigate the impact of ionizing radiation on the permeability of the intestinal barrier in the context of colorectal cancer and show that several of the involved mechanisms are immune- and inflammation-related. Lumniczky et al. review radiation-induced immune and inflammatory reactions in the brain, highlighting potential mechanisms how these interactions can lead to long-lasting functional alterations and the development of cognitive impairment. Amelioration of chronic inflammation, induction of acute damage , and counter-balancing the tumor- and radiation-derived immune suppression can in sum result not only in specific and long-lasting antitumor immunity but also in less frequent or less severe side effects and lead to an increased resistance toward radiation. This is highlighted in the paper by Singh et al. who show that the radioprotective effect of two well-characterized antioxidant compounds (podophyllin and rutin) is mainly immune-mediated.Thus, radiation acts and modulates immune reactions, including inflammation, at various levels and in all tissues. Immune cells and, in particular, lymphocytes are key players in the response against radiation-modified tumor cells. In order to highlight transcriptionally responsive genes, which play a role in the inflammation response, Therefore, one of the beneficial effects of RT is, in some instance, to shift the equilibrium toward immune activation. For this, additional immunotherapy is mostly needed.Wu et al., in addition to the direct effects of radiation on the different immune cell subsets, a key event in the (re)-activation of tumor-associated immune cells is the type of tumor cell death induced by radiation, as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe differ in their ability to reverse immunosuppression and elicit these tumor-specific immune responses. As the release of metabolites such as inosine by dying or dead tumor cells can on the opposite stimulate the outgrowth of rare spared tumor cells , the net outcome of radiation-therapy will depend on the competition between immunogenic and pro-tumorigenic events. Vaupel and Multhoff in particularly focus in their commentary on the role of adenosine as a consequence of hypoxia as metabolic immune checkpoint in the tumor microenvironment. Furthermore, the outcome of radiation exposure depends not only on the type of tumor and its microenvironment but also on the dose and quality of radiation and the irradiation scheme used. Even if more studies are required, especially on the effects of protons and carbon ions exposure , it is clear that these parameters can modulate the different aspects of the intercellular communication in the irradiated tumor microenvironment (reviewed by Diegeler and Hellweg). In addition to their direct effects on mature lymphocytes and T lymphocyte response to irradiation-induced bystander signals, ionizing radiation also affects T lymphocyte development. This aspect of the interactions between radiation and the immune system is addressed by Calvo-Asensio et al. in a research article where they analyze the response of thymic epithelial cells (TECs) to radiation exposure in vitro and ex vivo. TEC represent less than 1% of the cells found in the thymus, but these highly specialized cells are essential for the generation of mature, functional T lymphocytes. Although they are quite radio-resistant, the expression of many genes essential for proper T lymphocyte development is de-regulated after exposure. These effects probably contribute to the profound T cell deficiency observed in patient exposed to radiation in the frame of the conditioning regime before bone-marrow transplantation.As discussed in their review by Szatm\u00e1ri et al. demonstrate in an in vivo experimental setup that extracellular vesicles are responsible for mediating certain radiation-induced bystander effects in the bone marrow. Erbeldinger et al. present a new method by which the effect of ionizing radiation on endothelial cells can be investigated in vitro where hemodynamical parameters are much closer to physiological conditions than using conventional cell cultures. In this system, they show that both low energy and heavily charged particles induce altered adhesion of peripheral blood lymphocytes and activation of the NF\u03baB pathway. With the perspective of space travel and a Mars mission in a reasonably near future, the impact of cosmic radiation becomes a particularly important health problem, and the potential effects of charged heavy particles on the immune system and their long-lasting health consequences will need to be addressed. Since heavy particles are increasingly used in therapeutic radiation as well, their interaction with the immune system, in the view of a potential combination with immunotherapy should be carefully studied. These issues are dealt with in detail in the mini-review by Fernandez-Gonzalo et al.Last but not least, a special focus is placed on the investigation of low-dose radiation-induced immune mechanisms and inflammatory reactions. Thus, the editors of the Research Topic hope that this collection of articles is able to give a good overview of the complex and often contradictory nature of the interactions between ionizing radiation and the immune system. Our intention was also to draw the attention of the non-radiobiological scientific community on these complex interactions and to highlight the fact that ionizing radiation is by far more than purely an immune suppressing agent. The increasing penetrance of low-dose ionizing radiation both through medical diagnostic or environmental sources or during cosmic travel in the population is becoming a major epidemiological concern world-wide and the mechanisms how low-dose radiation act and the potential long-term health consequences need to be thoroughly investigated.All authors contributed in the editing of the Radiation and the Immune System Research Topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Self-awareness is believed to be limited in human and great apes  and genital-unrelated (UR) behaviors than na\u00efve monkeys when facing the mirror wall. Data collected supported the hypothesis: trained rhesus monkeys are capable to recognize themselves via mirror image.In the visual-somatosensory training, heat-induced high-power spots were projected to monkeys' face, which is controversial that after training, the mark touching response in monkey is a conditioned behavior not spontaneous MSR.The improved study perfected training devices to help monkeys precisely learn the association between the face mark position and the image by simply using a mirror. Then, the new study approved the transition from the mirror use to mirror-induced self-recognition performance in the trained monkey and demonstrated the ability to use a mirror and MSR are distinguishing cognitive abilities.Previous studies suggested that monkey species could not exhibit self-recognition behaviors and failed the MSR test (Roma et al., The underlying mechanism of MSR is unknown. Along with human, chimpanzees are inherent of MSR without training, but monkeys not, which possibly means enhance sensory integration to a certain degree that required for MSR. It's possible that mirror neurons, which are discovered in the monkeys and considered the neural mechanism of imitation behaviors, are the reason of generating self-consciousness in rhesus monkey (Chang et al., There are still some limitations in the present study. Tooling use is an evident indicator of high intelligence in human and high-rank primate and can be transferred within the group (Bayart and Anderson, XL and TL completed the first version of the paper and XH presented suggestions to revise the paper. The workload of the three authors was equal.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Proteolysis by the ubiquitin-proteasome pathway (UPP) is now widely recognized as a major molecular mechanism playing a role in numerous normal functions of the nervous system as well as in malfunctions of the brain in several neurodegenerative diseases. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multi-subunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. Protein degradation has key functions in the nervous system including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism Hegde, . In neurMany questions pertaining to the UPP in the nervous system remain unanswered. How is the UPP-mediated degradation regulated spatially and temporally in neurons? What is the role of local protein degradation? How does the interplay between proteolysis and protein synthesis affect synaptic plasticity and memory? Do perturbations in the UPP have a role in the pathology of neurodegenerative diseases?Frontiers in Molecular Neuroscience Research Topic-Special Issue on Ubiquitin and the Brain: Roles of Proteolysis in the Normal and Abnormal Nervous System cover a wide range of topics from development of methods and primary research studies to reviews. These articles from researchers working on yeast, neuronal and glial cell culture and mouse models, often validated in postmortem human brain tissue, cover a wide array of topics such as receptor endocytosis and synaptic plasticity in the normal nervous system to abnormalities of the nervous system such as AD and Huntington's disease.The papers in this Pinto et al. reports the results of studies on visualizing a specific type of ubiquitin linkage to substrate proteins in which ubiquitin molecules are linked to each other through a covalent linkage to Lysine-48 (K48) in the ubiquitin sequence. The K-48 linkage targets substrate proteins for degradation. Pinto et al. study adapted a technique to monitor K-48-liked ubiquitin molecules in cultured rat hippocampal neurons. In this technique, a yellow fluorescent protein called Venus is split into non-fluorescent N- and C- termini and fused to sequences containing ubiquitin-interacting-motifs (UIMs). These parts come together when they bind to closely spaced ubiquitin molecules in a polyubiquitin chain assembled through K-48 linkage. Using this technique, the authors show that proteins tagged with K-48-linked ubiquitin chains accumulate in presynaptic terminals when synapses newly form.The paper by Vaden et al.) builds on their previous work on the role of a deubiquitinating (DUB) enzyme called USP14 in the mammalian neuromuscular junction (NMJ). Their studies suggest that the role of USP14 in maintaining the free ubiquitin levels is critical for NMJ structure but the function of NMJ (such as muscle coordination) is likely to be regulated by USP14 through a separate pathway. Apart of USP14, many other DUBs play a role in the nervous system. Ristic et al. argue in their review that looking at the UPP from the point of view of DUBs can provide novel insights into the exquisite regulation of proteolysis in the nervous system and might be helpful in devising therapeutic approaches.The studies by Scott Wilson and colleagues  protein. Tagging of mHtt by ubiquitin plays a role in clearance by the proteasome as well as through autophagy. The authors present strategies to study local clearance and accumulation in neuronal sub-compartments.Jarome and Helmstetter review the evidence for the roles of protein degradation in long-term memory (LTM) storage. They discuss the interplay between protein degradation and protein synthesis in the hippocampus and amygdala and other cortical areas during formation and consolidation of LTM.Massaly et al. review the evidence for role of the UPP in mediating the effects of drug abuse on the nervous system. They details the role of the UPP in regulating molecules that mediate drug-abuse-related neuroplasticity. In addition, they present evidence from the literature regarding how drugs of abuse regulate amounts and function of the various components of the UPP. The review by Figueiredo et al. discusses the role in neuroinflammation of a specific class of prostaglandins called J2 which are the toxic products of cyclooxygenases. Among the pleiotropic effects of J2 prostaglandins is perturbation of UPP. The authors suggest that the targeting neuroinflammatory pathways stimulated by J2 prostaglandins might be beneficial in treating several neurodegenerative diseases such as AD, Parkinson's and amyotrophic lateral sclerosis. Gong et al. discuss the role of components of the UPP such as the deubiquitinating enzyme Uch-L1, F-Box protein Fbx2, and the proteasome in development of AD and spinal cord injury. They suggest pharmacological manipulations of these components could be developed as a therapeutic strategy. In addition, the role of UPP is highlighted in neurodegenerative diseases such as AD, Parkinson's disease and Huntington's disease .The coverage of the role of proteolysis by the UPP in abnormalities of the nervous system ranges from drug abuse to neuroinflammation and neurodegenerative diseases. Jansen et al. tackles this issue and discusses among other things the differences between neurons and glia in how the two cell types react to impaired proteolysis by the UPP.Until recently, the investigation with regard to the role of proteolysis in neurodegenerative diseases largely focused on neurons and role of the UPP in glia was largely ignored. This has been true also of other diseases with protein conformational abnormalities such as Amyotrophic Lateral Sclerosis and Parkinson's disease. The review by Brau), which can be subsequently validated using mammalian model systems. The group of Dantuma has developed many tools to detect proteasomal activity  in vitro as well as in vivo. The authors (Dantuma and Bott) discuss \u201cthe paradigm shift that has repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins\u201d (review by Dantuma and Bott). For example, downregulation misframed ubiquitin (UBB+1) that interacts in AD with \u03b3-secretase (Gentier and van Leeuwen, The studies on the role of the UPP in neurodegenerative diseases can be greatly benefited by work on simple model systems such as yeast. This model system provides an easy readout of perturbations in the UPP and allows quick analysis of action of numerous chemicals on the UPP (see review by The research articles and reviews in this research topic now collected as an e-book highlight the complex role of ubiquitin-proteasome-mediated proteolysis in the neuronal and glial physiology and pathology. In spite of the considerable progress made over the last two decades, many challenges remain. For example, with respect to normal roles of the UPP in the nervous system, the roles of the UPP in memory formation especially in relation to the role of protein synthesis need to be better understood. The exact contributions and the interplay of the UPP with other protein-clearance systems such as autophagy in various neurodegenerative diseases also need to be delineated. As many new technological developments such as CRISPR/Cas9, allow precise testing of hypotheses, we may expect to see many additional interesting discoveries on both these fronts.Both authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as \u03b1-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients. Age is a major risk factor for Parkinson\u2019s disease (PD), but the precise molecular mechanisms underlying the disease are not fully understood. Recent advances in genetics and pathophysiology of PD have increased our understanding about the fundamental processes contributing to disease pathogenesis but in the majority of cases the precise etiology is unknown. However, evidence suggests that protein aggregation, mitochondrial dysfunctions, ER stress, neuroinflammation and reduced growth factor levels contribute to neurodegeneration and play key roles in PD , so that novel protein targets for the kinase should be experimentally verified under actual physiological conditions.c-Abl ABL1) is the cellular homolog of the Abelson murine leukemia virus oncogene and belongs to the Abl family of tyrosine kinase present in the cytoplasm and nucleus of the cell. c-Abl is expressed in most cells and is part of an intricate network of protein interactions and phosphorylation events in the cell  neurotoxin model of PD  was the first c-Abl tyrosine kinase inhibitor identified and has been used in the treatment of CML now for several years  is a second-generation c-Abl tyrosine kinase inhibitor that is used in CML in a daily dose of 300 mg to over 1000 mg per patient  c-Abl in the cerebrospinal fluid of treated PD patients  FS-ZONE Investigators ). FutureAll authors contributed to the writing of the manuscript that was finalized by DL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The function of the reticulo-endothelial system in mice bearing Lewis lung carcinomas has been measured by(1) the rate of clearance of carbon particles from the circulation in vivo and calculation of the phagocytic index K; (2) chemotactic locomotion of macrophages in vitro in the presence or absence of serum or tumour supernate. The ability of the bone marrow to develop macrophage colonies in vitro in the presence or absence of sera from tumour-bearing mice has also been tested. A clear depression of macrophage locomotion and macrophage colony formation in vitro was found in the presence of sera or tumour supernates from tumour-bearing mice as early as 24 to 72 h after tumour inoculation. Similarly, tumour-bearing mice showed marked depression of carbon clearance in tests repeated throughout the first 72 h after tumour inoculation. This early depression of macrophage function may be an important step in allowing escape of tumour cells from host resistance."}
{"text": "A case-control study was performed to determine the role of rural factors including occupation and previous malaria exposure in the development of classic Kaposi's sarcoma (CKS) in a high incidence area of Europe. The occurrence of CKS association with other malignancies was also examined. The results showed that the risk of having CKS was significantly increased in subjects farming cereals, while a previous history of malaria did not influence the risk of developing CKS. A near-significant increase in associated tumours was found."}
{"text": "Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years  and at 5 years  in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group."}
{"text": "Prostate-specific membrane antigen (PSM) is a glycoprotein recognised by the prostate-specific monoclonal antibody 7E11-C5, which was raised against the human prostatic carcinoma cell line LNCaP. A cDNA clone for PSM has been described. PSM is of clinical importance for a number of reasons. Radiolabelled antibody is being evaluated both as an imaging agent and as an immunotherapeutic in prostate cancer. Use of the PSM promoter has been advocated for gene therapy applications to drive prostate-specific gene expression. Although PSM is expressed in normal prostate as well as in primary and secondary prostatic carcinoma, different splice variants in malignant tissue afford the prospect of developing reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic screens for the presence of prostatic carcinoma cells in the circulation. We have undertaken characterisation of the gene for PSM in view of the protein's interesting characteristics. Unexpectedly, we have found that there are other sequences apparently related to PSM in the human genome and that PSM genomic clones map to two separate and distinct loci on human chromosome 11. Investigation of the function of putative PSM-related genes will be necessary to enable us to define fully the role of PSM itself in the development of prostatic carcinoma and in the clinical management of this malignancy."}
{"text": "A study has been made of the relationship between socio-economic factors and the incidence of acute lymphoblastic leukaemia (ALL) of childhood. It was found that the incidence of childhood ALL in 12 areas of Queensland. Australia, correlated well with some indicators of above-average socio-economic status for these areas. A similar result was found when Brisbane City was studied separately. Social class was determined from the fathers' occupations at the time of diagnosis. There was found to be a higher than expected number of ALL cases in each of the upper 5 social classes and a lower than expected number in the remaining 2 lower classes. Factors associated with differences in lifestyle amongst the various social classes may increase or decrease the risk of development of ALL."}
{"text": "Dear Editor,et al.[We read with great interest the article titled \u201cPneumatic displacement and intravitreal bevacizumab: A new approach for management of submacular hemorrhage in choroidal neovascular membrane\u201d by Chawla S et al.We would like to share our experience of a 52-year-old male patient who presented with blurring of vision in the right eye for the last one month and a sudden drop of vision with a central black spot of two days duration. The best corrected visual acuity (BCVA) was counting fingers close to face in the right eye and counting fingers at 4 meters in the left eye. Intraocular pressure and slit-lamp examination were within normal limits. Fundus examination of the right eye showed submacular hemorrhage with breakthrough vitreous hemorrhage  and the Fundus examination of the right eye after one week showed displacement of the submacular hemorrhage inferiorly . FFA of At nine months follow-up the BCVA in the right eye was 20/120P, N36. Fundus examination showed old sub-retinal hemorrhage displaced to the lower macular area. FFA of the right eye showed a scarred CNVM with blocked fluorescence in the inferior macular area corresponding to the persistent old hemorrhage. Optical coherence tomography of the right eye showed a normal foveal contour and the scarred extrafoveal CNVM.et al.,[Management of the cases with submacular hemorrhage secondary to CNVM are often challenging. Various treatment options are available for the submacular hemorrhage such as pneumatic displacement with or without TPA or vitrectomy with evacuation of the blood. Chawla et al., in theirAs mentioned in the literature, the visual prognosis in cases with submacular hemorrhage depends on a number of factors such as location of the CNVM , duration of the submacular hemorrhage - longer the duration worse is the prognosis due to photoreceptor damage, level of the hemorrhage -sub-retinal or sub-retinal pigment epithelial (RPE), the size and the thickness of the hemorrhage and lastly the underlying disease process.The combination of gas tamponade with an anti-vascular endothelial growth factor (VEGF) such as bevacizumab without using TPA does provide an inexpensive treatment option to our patients, however, the visual recovery may not always be predictable."}
{"text": "The sensitivity to melphalan of clones derived from individual lung colonies produced by i.v. injection of cells of the MT murine mammary carcinoma (caMT) and its melphalan-resistant sub-line (MTME16) has been examined. A degree of clonal heterogeneity was observed which was greater than could be explained by experimental variation. The distribution of melphalan sensitivities in both wild-type caMT and MTME16 raises questions as to the validity of a two-compartment model of drug-resistance development in tumours. A more complex model, possibly involving a continuous spectrum of drug sensitivity, is required. Differences in the sensitivity of the clonal lines of wild-type caMT in various passages were observed and this would appear to be due to phenotypic instability in these lines. This suggests that to use survival data from clones which have been passaged many times for predicting the response of the parent tumour may be misleading."}
{"text": "A rare case of lymphoepithelial cyst formed in the piriform sinus of the hypopharynx is reported. Histopathological examination revealed a lymphoepithelial cyst. It was removed by laryngomicrosurgical technique using a side-opened direct laryngoscope. Because this cyst was wide-based on the antero-medial region in the right piriform sinus of the hypopharynx, the mucous membrane around the cyst was incised electrosurgically and then detached to facilitate removal. In this paper, we describe our surgical procedure for removing the cyst in this case and discuss the possible causes of the disease."}
{"text": "The pharmacological interest in lonidamine is related to its ability to enhance the cytotoxic effects of several DNA-damaging anti-tumour agents. This study was undertaken to better understand the in vivo interaction between lonidamine and cisplatin in the treatment of human tumour xenografts, including three carcinoma models characterized by a different responsiveness to cisplatin, in spite of the presence of a wild-type p53 gene in all tumours. The drug combination was more effective in tumour growth inhibition than cisplatin alone against MX-1 breast carcinoma and A2780 ovarian carcinoma, both highly responsive to cisplatin, whereas no influence of ionidamine was observed on anti-tumour activity of cisplatin in the treatment of the relatively resistant IGROV-1 ovarian carcinoma. As cisplatin activity is related to induction of apoptosis, the modulation of drug-induced apoptosis by lonidamine was investigated. Under conditions in which lonidamine itself had negligible effects on tumour growth and apoptosis, the modulating agent stimulated the apoptotic response induced by cisplatin in the responsive but not in the resistant tumours. Tumour response was dependent not only on the drug activation of apoptosis, but mainly on the persistence over time of the event. In the breast carcinoma MX-1, hypersensitive to cisplatin and to the lonidamine+cisplatin combination, the efficacy of drug treatment was associated with phosphorylation of bcl-2 followed by down-regulation of the protein. Lonidamine itself caused a delayed phosphorylation of bcl-2. These results are consistent with the interpretation that lonidamine is effective in modulating biochemical factors involved in regulation of apoptosis."}
{"text": "The reactivity of alpha-1-antitrypsin (AAT) with Lens culinaris agglutinin (LCA) was studied by crossed immuno-affinity electrophoresis of the sera of 246 subjects from 6 groups , carcinoma metastatic to the liver and normal controls). Two species of AAT (LCA-reactive and -nonreactive species) were detected on crossed immuno-affinity electrophoresis in a gel containing LCA. The percentages of LCA-reactive species of AAT in neoplastic diseases of the liver were significantly higher than those in benign liver diseases and normal controls. There was no correlation between the percentage of LCA-reactive species of AAT and serum AAT concentration in any group. Furthermore, in studying 15 pairs of serum samples before and after the subsequent development of HCC, the percentage of LCA-reactive species of AAT after HCC occurrence was significantly higher than that before, although there was no statistically significant difference between the serum AAT concentration before and after development of the disease. The latter 15 patients were all of the normal protease inhibitor phenotype (PiMM) and no change in phenotype was observed before and after the development of HCC. The results indicate that measurement of the reactivity of AAT with LCA can be a useful marker for the diagnosis of HCC and carcinoma metastatic to the liver, especially when serum concentrations of alpha-foetoprotein or other tumour markers are within the normal ranges."}
{"text": "Skeletal lesions in multiple myeloma are predominantly lytic and when non-union of pathological fractures occur it is typically atrophic. We report a lady of 61 years of age with myeloma who presented with a pathological fracture through an ulnar myeloma deposit. The fracture was immobilised initially then irradiated. Nine months later she re-presented with marked forearm pain particularly on rotation. Radiographs demonstrated a hypertrophic non-union of a pathological fracture with a typical elephant's hoof appearance. The fracture was immobilised using an ulnar nail. Whilst non-unions in metastatic malignancy are typically atrophic, just occasionally hypertrophic non-unions can occur. Management principles remain the same with stabilisation of the entire bone and early mobilisation being appropriate. Multiple myeloma (MM) is an incurable disease that is characterised by the accumulation of clonal plasmocytes in the bone marrow . It accoThe characteristic bone lesion seen in myeloma is a sharply defined small lytic area with no reactive bone formation arising in the medulla; the absence of bone sclerosis is due to an inhibition of osteoblastic activity . InvolveRadiotherapy often forms an important part of management and can lead to resolution of bone lesions . We repoA 61 year old lady with multiple myeloma, diagnosed nine years previously presented to our fracture service with pain in her right forearm. On examination it was painful over the mid-aspect of her forearm with no superficial erythema or swelling. She was neurovascularly intact. Radiographs revealed an undisplaced pathological fracture of the ulna  of her pain was 9 out of 10. Radiographs demonstrated that she had gone on to develop hypertrophic non-union  of her pathological ulna fracture Figure . The oriThe fracture was stabilised with a reamed Foresight ulnar nail  especially in the lower thoracic or lumbar vertebral bodies .Radiation therapy for the treatment of bone tumours and soft-tissue sarcomas may deliver damaging doses of radiation to skeletal bone . It is kFailure of bone healing or non-union results from an arrest of the healing process. A non-union that occurs despite the formation of a large volume of callus around the fracture site is commonly referred to as a hypertrophic non-union whilst in an atrophic non-union, little or no callus forms and bone resorption occurs at the fracture site . FracturWhilst non-unions in metastatic malignancy are typically atrophic, just occasionally hypertrophic non-unions can occur. This is a rare occurrence and the management principles remain the same with stabilisation of the entire bone and early mobilisation being appropriate.Written informed consent was obtained from the patient for publication of this case and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.TO assessed the patient, participated at surgery and was responsible for drafting the article and collating all relevant images; RUA conceived the idea for the case report, performed the surgery and was involved in review of the manuscript. All authors read and approved the final manuscript."}
{"text": "The carcinogenic effects of radium and X-rays on the rat uterus have been investigated. Malignant endometrial tumours, usually adenocarcinomas, were produced in a small proportion of treated rats. One rat treated with X-rays developed an adeno-sarcoma (possibly carcino-sarcoma) of the endometrium. Benign mixed polypoidal endometrial tumours occurred also in radium and X-ray treated rats and in non-radiated controls; radiation increased the incidence of these tumours and may have induced malignant transformation in some. The incidence of lymphosarcomas and mammary tumours in the strain of rat used appeared to be influenced by radiation treatment.Review of the literature of human cases of mixed uterine tumours showed that in women over 40 years, more than one-fifth of the reported cases had a history of previous pelvic radiation; with other kinds of uterine malignancy a history of prior radiation treatment was considerably less. The results of our experiments enhance the suspicion that radiations are one factor in the causation of uterine cancer, especially mixed tumours."}
{"text": "Sir,We would like to thank Gianluigi Ferreti and his colleagues for their interest in our systematic review.et al. interrogated on the prognostic role of Ras in NSCLC. They cited seven studies with apparent conflicting results. Some comments have to be made. First, we discussed in our articles the controversial results of the literature relative to biological prognostic factors, justifying the need for meta-analyses, as we reported with K-Ras (In their letter, Ferreti et al. Some of these articles were not included in our systematic review for the following reasons:no prognostic analysis (no survival prognostic analysis but assessment of the predictive role of K-Ras for response to chemotherapy (assessment of K-Ras mutation on resected tumours after induction chemotherapy (publication after the deadline for the selection of the studies to be included in the meta-analysis (Secondly, we have some concerns with the studies cited by Ferreti et al commented (The last two studies that Ferreti In conclusion, our systematic review showed that K-Ras is a potential prognostic factor for survival in lung cancer according to the literature published on this topic till end of 2003. The predictive role of K-Ras for response to chemotherapy and the impact of K-Ras mutation on survival in patients receiving induction chemotherapy before surgery were not the subjects of our meta-analysis and need further investigations."}
{"text": "Purpose.  Conservative treatment in the form of limited surgery and post-operative            radiotherapy is controversial in hand and foot sarcomas, both due to poor radiation            tolerance of the palm and sole, and due to technical difficulties in achieving adequate            margins.This paper describes the local control and survival of 41 patients with soft tissue            sarcoma of the hand or foot treated with conservative surgery and radiotherapy.            The acute and late toxicity of megavoltage radiotherapy to the hand and foot are described.            The technical issues and details of treatment delivery are discussed.            The factors influencing local control after radiotherapy are analysed.            Subjects .  Eighteen patients had sarcomas of the hand and 23 of the foot.            All patients received post-operative radiotherapy, the majority receiving a dose of 60            Gy in 2-Gy daily fractions using a two-phase treatment.            Results .  The acute and late toxicity of treatment were within acceptable limits.            The actuarial 5-year overall survival of the whole patient group was 67.6% and the            local relapse-free survival was 44%.The local control was similar in tumours of hand            and foot, and in patients treated at first presentation or relapse.            Discussion.  Post-operative radiotherapy to the hand or foot appears to be a well            tolerated treatment resulting in long-term local control in a significant proportion of patients.            The increased frequency of recurrence within the high-dose volume           suggests the need for the use of higher total doses of radiotherapy."}
{"text": "Intra-medullary nailing is a standard form of treatment for diaphyseal tibial fractures. Insertion of the nail requires threading of the nail over a smooth guide-wire. Inadvertent complications during this stage have been reported. We report a case of inadvertent penetration of the tibio-talar joint by the smooth guide wire caused by incarceration of a fracture fragment between the nail and the guide wire at the time of insertion. This was noted intra-operatively. The guide-wire and the nail were removed followed by insertion of a new nail and completion of the procedure. The patient did not have any symptoms attributable to this at the time of healing of her fracture. A 54 year old Sri Lankan woman was admitted for management of a grade 1 open fracture of both bones of her right leg. She also had a proximal humerus fracture on the left shoulder. After preliminary care in the emergency room, she was taken up for definitive surgical treatment of her fractures. The wound in her right leg was excised and primarily closed. This was followed by intra-medullary nailing of the tibia. A knobbed guide-wire was inserted through a patellar tendon-splitting approach through the tibial tubercle. This was followed by reaming of the medullary canal. The knobbed guide-wire was exchanged for a smooth guide wire followed by insertion of the nail. As the nail was hammered inside, a prominence was felt on the skin of the sole. Checking under image intensifier revealed that the guide-wire had penetrated the ankle and the sub-talar joint . The naiAt the time of the last follow up, the patient did not have any residual ankle problems attributable to the complication.Complications related to guide-wires have been reported during intra-medullary nailing . Guide-wet al.We have had a similar complication in our patient who underwent closed reamed intramedullary nailing of fracture of her tibia. However, our case was considerably different from the previous report. The penetration of the wire was detected intra-operatively when the assistant felt the guide wire in the sole of the patient\u2019s foot. This had happened at the time of insertion of the nail over a straight guide-wire without any ball-tip . The nai"}
{"text": "The development of monoclonal antibodies (mAb) reactive with the thymicmicroenvironment has identified distinct subpopulations within the stromal component,but the function of these subregions in intrathymic T-cell differentiation remainsessentially an enigma. In this study, we have used such a panel of mAb to examine thechicken thymus during ontogenic development to gain insight into the contributions ofthese thymic regions to the distinct phases of T-cell development and to furthercharacterize the development of this organ. Our reagents have demonstrated thecomplex differentiation of the primitive endodermal epithelium into more specializedstructures and the development of other thymic stromal components frommesectodermal cells. We also describe molecules localized to the subcapsular andperivascular regions, which have an ontogenic expression corresponding to the earlylocalization and stimulation of thymic precursors and another molecule on themedullary vasculature expressed corresponding to the exit of mature cells from thethymus. In addition, two markers of distinct medullary epithelial clusters are initiallyexpressed corresponding to the appearance of T-cell receptor-1 (TcR-1) and TcR-2positive cells in the medulla, respectively. These mAb potentially represent excellentreagents for further definition of the thymic modulation of T-cell differentiation."}
{"text": "A 17-year-old patient with a small paratesticular embryonic sarcoma presented with symptoms of renal failure, polyuria and widespread bone metastases. Investigation revealed hypercalcaemia and uraemia without any evidence of hyperparathyroidism. The hypercalcaemia responded over a period of weeks to administration of mithramycin with initial improvement in the symptoms and metabolic derangements. Control was lost with the necrosis of intra-abdominal tumour deposits and haemorrhagic polypoid deposits in the alimentary tract. The value and hazards of mithramycin are well demonstrated by these rare complications of this type of tumour."}
{"text": "There may be need to assess intelligent quotient (IQ) scores in sub-Saharan African children with intellectual disability, either for the purpose of educational needs assessment or research. However, modern intelligence scales developed in the western parts of the world suffer limitation of widespread use because of the influence of socio-cultural variations across the world. This study examined the agreement between IQ scores estimation among Nigerian children with intellectual disability using clinicians' judgment based on International Classification of Diseases, tenth Edition(ICD - 10) criteria for mental retardation and caregivers judgment based on 'ratio IQ' scores calculated from estimated mental age in the context of socio-cultural milieu of the children. It proposed a viable option of IQ score assessment among sub-Saharan African children with intellectual disability, using a ratio of culture-specific estimated mental age and chronological age of the child in the absence of standardized alternatives, borne out of great diversity in socio-cultural context of sub-Saharan Africa.Clinicians and care-givers independently assessed the children in relation to their socio-cultural background. Clinicians assessed the IQ scores of the children based on the ICD - 10 diagnostic criteria for mental retardation. 'Ratio IQ' scores were calculated from the ratio of estimated mental age and chronological age of each child. The IQ scores as assessed by the clinicians were then compared with the 'ratio IQ' scores using correlation statistics.A total of forty-four (44) children with intellectual disability were assessed. There was a significant correlation between clinicians' assessed IQ scores and the 'ratio IQ' scores employing zero order correlation without controlling for the chronological age of the children . First order correlation controlling for the chronological age of the children showed higher correlation score between clinicians' assessed IQ scores and 'ratio IQ' scores .Agreement between clinicians' assessed IQ scores and 'ratio IQ' scores was good. 'Ratio IQ' test would provide a viable option of assessing IQ scores in sub-Saharan African children with intellectual disability in the absence of culture-appropriate standardized intelligence scales, which is often the case because of great diversity in socio-cultural structures of sub-Saharan Africa. One of the earliest objectives of developing scales to assess intelligence among children was to determine those children that would require special attention and instructions in educational systems. Alfred Binet, the French psychologist published the first modern intelligence test called Binet-Simon intelligence scale in 1904 .William Stern, the German Psychologist coined the abbreviation, 'IQ (intelligence quotient)' in 1912, with a proposition that individual's intelligence level can be measured as a quotient of mental age and chronological age. This proposition was adapted into the revised Binet-Simon scale which became the Stanford-Binet scale which was published in 1916 by Lewis Terman from Stanford University. The Stanford-Binet intelligence scale led to a mental age score and IQ was calculated as a percentage of mental age and chronological age ratio .Subsequently over the years, standardized intelligence scales that based IQ scoring on normal distribution curve rather than age-based quotient had been developed . The newThe modern standardized intelligence scales like Wechsler Intelligence Scales for Children  had been known to be influenced by socio-cultural variations in different environments that impact on child rearing practices and cultural expectations of a child in a particular society -6.It is well established that both genes and environments have influence on cognitive abilities ,8. FactoThe great diverse multi-ethnic and multi-culture nature of sub-Saharan African regions are often impediments to developing comparable standardized IQ assessment scales among children that would cut across sub-cultures as obtained in the Western region of the world. Nigeria for example, which is a country in sub-Saharan Africa has well over three hundred major and minor ethnic tribes and sub-cultures ,16 that The attendant influence of socio-cultural variations across regions on cognitive ability and social competence of children, necessitated the provision of a general guide by Diagnostic Criteria for Research of International Classification of Diseases, tenth Edition (ICD - 10)  for asseThis study assessed the agreement between 'ratio IQ' scores calculated from ratio of mental age and chronological age of children with intellectual disability as assessed by nursing staff and teacher (care givers) and clinicians' assessed IQ scores, based on the categories specified in the Diagnostic Research Criteria of ICD - 10 for mental retardation .The location of the study was the Therapeutic Care Center (TCC), Abakpa, Enugu, Nigeria. This privately owned center provides special educational instructions, and behavioral modification to children with intellectual disabilities in south eastern Nigeria. The participants are children with intellectual disability admitted into the boarding facility of the TCC, Abakpa, Enugu, Nigeria. All children with suspected learning disability admitted into the center were studied. The children have associated co-morbid medical conditions ranging from Pervasive developmental disorders (PDD), Down syndrome and Cerebral palsy.Ethical approval for this study was obtained from the Institutional Review Board (IRB) of Federal Neuro-Psychiatric Hospital, New Haven, Enugu, Enugu State, Nigeria. Informed consent was obtained from the parents of the children studied and from the authority of Therapeutic Care Center (TCC), Abakpa, Enugu, Nigeria.This questionnaire was designed to obtain socio-demographic information of the children, which included their chronological or actual age and mental age as estimated by the consensus agreement of the nursing staff and teacher (care givers) who are of the same socio-cultural background with the children and responsible for the care of each child studied at the TCC, Abakpa, Enugu, Nigeria. From the information obtained about the estimated mental age and chronological age of the children, 'ratio IQ' score was calculated for each child using a ratio of culture-specific estimated mental age and chronological age multiply by a factor of 100.The diagnostic criteria stated that depending upon the cultural norms and expectations of the individuals being studied; research workers must make their own judgments as to how best to estimate intelligence quotient (IQ) or mental age according to the bands given in Table Two clinicians that are of the same socio-cultural background with the children independently assessed each child with the diagnostic criteria in Table The socio-demographic questionnaire was used to obtain information from which 'ratio IQ' score was calculated for each child. Each child was also assigned IQ scores based on the clinicians' assessment and placement of the child in specific diagnostic categories as spelt out in ICD - 10 diagnostic criteria  shown inTwo major specific areas were assessed to estimate the mental age of the children which are:i. Cognitive ability - This was assessed based on age appropriate;Verbal test.\u2022 Ability of the child to communicate, being able to pronounce words, phrases and sentences that are comprehensible and appropriate for age - Performance test.\u2022 Ability of the child to copy and draw shaped objects such as circles, squares and triangles - ii. Social competence - This was assessed based on the age appropriate;Adaptive self care.\u2022 Ability of the child to care for self, which includes cleaning up self and dressing for classes in the morning. This was rated in the range of, Need hundred percent help in caring for self; Need substantial help in caring for self and, Need minimal help in caring for self - Adaptive social skills.\u2022 Ability of the assessed children to relate with other pupils and teachers in the areas of expressing their needs and wants - The criteria followed by the clinicians in assigning the assessed children to specific diagnostic category of ICD-10 criteria for mental retardation were essentially the same as that followed by the teachers and nursing staffs in estimating the mental age, with the exemption that assessment of social competence by the clinicians were based on observation of the children's ability to relate with other pupils and the teachers to express their needs and wants.The clinicians involved in assessment of the children are psychiatrist trainees at Senior Registrar level of their training and had been working with children with learning disabilities for a minimum of six months period. All assessment by the clinicians, teachers and the nursing staffs were based on the same specific socio-cultural milieu with the children assessed.The major difference between the care givers' and clinicians' assessment is that the clinicians had access to categories of ICD-10 diagnostic criteria for mental retardation and based their assessment on this, but the care givers did not. The IQ of each child was assessed by the care givers from a ratio of estimated mental age and the chronological age of the child.Data were analyzed using the Statistical Package for Social Sciences (SPSS), version 15.The frequency and percentage distribution of the children in different diagnostic categories of mental retardation as specified by ICD - 10  based onA total of forty four (44) children with intellectual disability were independently assessed by the care-givers and the clinicians for estimation of mental age and classification under different categories of ICD - 10 diagnostic criteria for mental retardation . There wThe actual or chronological age range of the children was from 4 to 18 years. The mean chronological age of the children was 13.16 \u00b1 3.58 years. The mean mental age as assessed by the care-givers was 4.82 \u00b1 1.90 years. The mean mental age as assessed by the clinicians using ICD - 10  diagnostFour (9.1%), 27 (61.4%), 11 (25.0%) and 2 (4.5%) of the children with intellectual disability were classified under the ICD - 10 categories of F 70, F 71, F 72, and F 73 respectively as assessed by both the clinicians' IQ scores and calculated 'ratio IQ' scores.2 = 0.00, df = 3, p = 1.000).Table Correlations between mean IQ scores as assessed by the clinicians, using the median IQ scores in each diagnostic category and mean 'ratio IQ' scores as calculated from ratio of estimated mental age and chronological age of each child.When the chronological/actual ages of the children were not controlled for, the correlation between clinicians' assessed IQ scores and 'ratio IQ' scores was statistically significant . The zero order correlation co-efficient is shown in Table When the chronological/actual ages of the children are controlled for, the correlation between clinicians' assessed IQ scores and 'ratio IQ' scores showed a much higher level of statistical significance .Figure Both the clinicians' assessment of IQ scores and 'ratio IQ' scores calculation based on mental age as estimated by the care-givers showed agreement in classification of the children into different diagnostic categories of mental retardation as specified by ICD - 10 . The corThe observation that cultural background could influence neural activity that underlies both high and low level cognitive function  indicateSpecial educators providing educational instructions to children with intellectual disability may need a quick assessment of a child IQ score in sub-Saharan African sub-cultures, where there is wide variation in cultural practices and societal structures. Employing a ratio of culture-specific estimated mental age and chronological age of the child would provide a viable option in the absence of culture appropriate standardized 'deviance IQ' tests like Wechsler Intelligence Scales for Children  used widely among children in the western parts of the world.Both the clinicians' assessment of IQ scores and estimation of mental age of the children by the care-givers from which the 'ratio IQ' scores were derived were subjective. However, the effect of this subjectivity had been cushioned by allowing two independent assessors with the same socio-cultural background with the children in each case of the clinicians and care-givers to reach a consensus on a particular child following the criteria highlighted in the procedure section. The 'ratio IQ' scores produced for each child from the estimation of mental age would serve an approximate guide in educational needs assessment of these children and for purpose of research.Another limitation of mental age estimation in children as proposed by this study is that, lack of background knowledge of normal child development by the care-givers may constitute an impediment in estimation of mental age. It is therefore recommended that people in position of caregivers willing to estimate mental age of children with intellectual disability according to the procedure highlighted in this study have some background knowledge of normal child development.In view of the confounding cultural and environmental influence on human intelligence -14, therTherefore, for the purpose of educational needs assessment and research in sub-Saharan African children with intellectual disability, consensus estimation of mental age in relative to peculiar socio-cultural milieu of the child would provide a viable option of estimating IQ score through the ratio of estimated mental age and chronological age of the child, in the absence of culture appropriate standardized 'deviance IQ' tests.The authors declare that they have no competing interests.All authors contributed to the conception of the study. MOB was involved in writing the initial draft of the manuscript. MOB, VNU, INO, CMA and POE were involved in revising the manuscript. All authors read and approved the final draft of the manuscript."}
{"text": "Ten cell lines of human squamous carcinomas of the tongue and larynx have been established from surgical specimens removed from 36 unselected patients, in order to provide systems for investigating the invasive and tissue-destructive capacity of squamous carcinomas of the head and neck. The morphology, ultrastructure and growth characteristics of the 10 lines are described. Detailed cytogenetic analysis of the first 4 lines indicates that each is karyotypically unique, with no evidence of cross-contamination. Nine of the 10 cell lines secrete immunoreactive beta human chorionic gonadotrophin (beta-hCG) in the culture medium. No correlation was demonstrated between the ability of the cell lines to secrete plasminogen activator and their capacity to grow in soft agar or as xenografts in immune-deficient mice."}
{"text": "A total of 165 adult patients with Hodgkin's disease (HD) were questioned following treatment to examine their perceptions of actual and desired involvement and provision of information in the treatment decision-making process. Irrespective of the degree to which patients felt they had been involved in the decision-making process and of the outcome of their particular treatment, patients who felt satisfied with the adequacy of information given were significantly more likely to feel happy with their level of participation in the overall process of decision-making (P < 0.001). As part of a strategy investigating patient priorities, patients were asked to rank a series of possible acute and late treatment-related morbidities. Counter-intuitively, the majority of long-term survivors felt early short-term side-effects were more, or equally, as important as late morbidity with respect to influencing choice of therapy. Unpredictable importance was placed by patients on side-effects such as weight gain and fatigue in relation to other complications such as infertility and risk of relapse. Patients do not necessarily share doctors' priorities in decision-making or place the same emphasis on different types of morbidity. Experienced surrogates may assist us in understanding patients' perspectives and priorities."}
{"text": "Gorham's (vanishing bone) disease is an extremely rare condition of the bone. The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity. When the disease is established, an X-ray and magnetic resonance imaging show complete loss of affected bone. There are very few reports found in literature on bone scan appearance of the disease. A bone scan of a 24-year-old female patient with known Gorham's disease revealed absence of tracer uptake in the right iliac bone, right sacroiliac joint, and part of the right ischial pubic rami, which matched the radiographic abnormalities. Consequently this disease should be added to the gamut of cold defects seen on bone scan. Gorham's (vanishing bone) disease is an extremely rare condition of the bone. The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity. When the disease is established an X-ray and MRI show complete loss of affected bone. Very few reports are found in literature on bone scan appearance of the disease.A bone scan was performed on a 24-year-old female patient with known Gorham's disease. This was correlated with a pelvic radiograph and corresponding MRI.Images showed absence of tracer uptake in the right iliac bone, right sacroiliac joint, and part of the right ischial pubic rami, indicating absence of bone in the mentioned regions, which matched the absent bone tissue on the pelvic X-ray  and 2.Cold defects on bone scan have been reported in many disease conditions. Gorham's"}
{"text": "Aprotinin was bound and endocytosed by Landsch\u00fctz ascites carcinoma (LAC) cells in vitro. Addition of the antiprotease to cultures of these cells led to a dose-dependent growth-inhibitory and cytotoxic effect. In mice inoculated with LAC cells and treated with aprotinin there was a transient reduction in both the number and concentration of recovered ascites cells during the early phase of tumour growth. This was accompanied by a temporary increase in the proportion of peritoneal phagocytes (mononuclear phagocytes and polymorphonuclear leucocytes) relative to carcinoma cells. However, the number and concentration of ascites cells eventually achieved was comparable in saline and aprotinin-treated animals."}
{"text": "Bronchomalacia in adults is rare. A case is reported here of a 65-year-old man with severe cough and mucostasis, caused by a benign bronchomalacia of the ventral wall of the left main bronchus. Thiswas treated successfully with the insertion of a silicone Dumon stent as an alternative to surgicalbronchoplasty."}
{"text": "The effects of doxorubicin on the cellular biochemistry of the HeLa cell using 1H spin echo nuclear magnetic resonance spectroscopy (NMR) of the intact and viable cell in conjunction with dual wavelength HPLC of cell lysates is reported. Directly dose-related changes were observed in lactate and reduced glutathione concentration. Doxorubicin induces a time-dependent depletion of the cytosolic pool of glutathione and a change in the glycolytic pattern of the cell. The glutathione depletion could be partially reversed by controlled pre-treatment of the cells with N-acetylcysteine and cysteine, the protection being linked to the intracellular concentration of the thiol."}
{"text": "The formulae for calculation of carry-over and sample interactionare derived for the first time in this study. A scheme proposed by Thiers et al. (two samples of low concentration followed by a high concentration sample and low concentration sample) is verified and recommended for the determination of the carry-over coeffcient.The derivation demonstrates that both widely used schemes of a high concentration sample followed by two low concentration samples, and a low concentration sample followed by two high concentration samples actually measure the sum of the carry-overcoeffcient and sample interaction coefficient. A scheme of three low concentration samples followed by a high concentration sample is proposed and verified for determination of the sample interaction coeffcient. Experimental results indicate that carry-over is a strongfunction of cycle time and a weak function of ratio of sample time to wash time. Sample dispersion is found to be a function of sample time. Fitted equations can be used to predict the carry-over, absorbance and dispersion given sample times, and wash timesfor an analytical system. Results clearly show the important role of intersample air segmentation in reducing carry-over, sample interaction and dispersion."}
{"text": "Data on self-reported cancer by a sample of 3349 elderly persons in the south-west of France were validated against registry data in the same region: only 21% of the persons on the cancer registry reported occurrence of cancer. Breast cancer was found to be most frequently accurately reported."}
{"text": "Anorectal malformation, one of the most common congenital defects, may present with a wide spectrum of defects. Almost all male patients present within first few days of life.A five-month-old baby boy of Indian origin and nationality presented with anal atresia and associated rectourethral prostatic fistula. The anatomy of the malformation and our patient's good condition permitted a primary definitive repair of the anomaly. A brief review of the relevant literature is included.Delayed presentation of a patient with high anorectal malformation is rare. The appropriate treatment can be rewarding. Anorectal malformation (ARM) is one of the most common congenital defects having an incidence of between one per 1500 and one per 5000 live births . This anARM may present with a wide spectrum of defects, ranging from relatively low malformations to very complex high defects . ARMs arA five-month-old baby boy of Indian origin and nationality presented to the department of Pediatric Surgery at the Institute of Medical Sciences, Banaras Hindu University with absent anal opening, along with passage of flatus and feces through the urethra since birth without any problem Figures  and 2. OOur patient was planned for the primary posterosagittal anorectoplasty (PSARP). Intra-operatively, a large rectourethral prostatic fistula was found and closed. The post-operative period was uneventful Figure  and the The bad financial conditions of the family led to the delayed presentation of the child to a specialist.The most unusual fact of this case is the age of presentation. As mentioned previously, male patients with ARM usually present within the first four or five days of life. This is due to the presence of a narrow fistulous communication between the rectum and the urinary tract, which does not allow the bowel to decompress.Although the diagnosis of ARM is made at birth , the sitA (long-term) study noticed  that allThis case has a few peculiarities. First, it is probably the oldest ever reported case of high ARM presenting at five months of age; the previous case presented at 45 days of life . Second,This is an extremely uncommon case of a patient with high ARM in respect of the anatomy of malformation and the time of presentation. A primary repair without colostomy is unusual in such patients, but proved to be appropriate and successful in this child having a large fistula and a non-distended rectum.The authors declare that they have no competing interests.ANG, SPS and AP operated upon the patient. AP, ANG and VK carried out the literature review. All authors read and approved the final manuscript.Written informed consent was obtained from the parents of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the journal's Editor-in-Chief."}
{"text": "It has been shown that thin metal-based films can at certain frequencies act as planar near-field lenses for certain polarization components. A desirable property of such \u201clenses\u201d is that they can also enhance and focus some large transverse spatial frequency components which contain sub-diffraction limit details. Over the last decade there has been much work in optimizing designs to reduce effects  that are detrimental to image reconstruction. One design that can reduce some of these undesirable effects, and which has received a fair amount of attention recently, is the stacked metal-dielectric superlens. Here we theoretically explore the imaging ability of such a design for the specific purpose of imaging a fluorescent dye (the common bio-marker GFP) in the vicinity of the superlens surface. Our calculations take into consideration the interaction (damping) of an oscillating electric dipole with the metallic layers in the superlens. We also assume a Gaussian frequency distribution spectrum for the dipole. We treat the metallic-alloy and dielectric-alloy layers separately using an appropriate effective medium theory. The transmission properties are evaluated via Transfer matrix ( In conventional far-field fluorescence microscopy the spatial resolution is severely restricted by the diffraction-limit The use of superlenses for fluorescent imaging purposes is additionally complicated by the interactions between the fluorescent dyes and the metal film(s), which will distort the local field The electric field of GFP can as a first approximation be taken as that of an oscillating electric dipole with a finite frequency spectrum, and described by a Gaussian with its peak at The superlens we consider consists of a stack of The interactions of electric dipoles with metallic surfaces and tips has been studied theoretically Changes in the emission spectra and lifetime of a dipole due to near-field interactions with very thin  and propagation matrices (P). For a stacked superlens with M is:We write the electric fields with the position dependent modified frequency on the sample side of the superlens as P for a layer T for the interface between layers The indexes The Optical Transfer Function (OTF) is determined by the ratio of the total emerging and incident field. For a range of superlens-source distances we find the largest OTF is obtained when Reconstructed images of oscillating electric-dipoles with their axis perpendicular and parallel to the superlens surface are studied as a function of distance from the superlens. We find that the transmitted intensity increases by a factor of not adjusted but fixed at We find that, for negligible absorption in both the source medium (water) and dielectric layer, the superlens is characterized by very high transmission in and around the The results of a similar self consistent calculation for the change in a In this manuscript we have theoretically studied a double-layer planar superlens for fluorescence imaging applications. We have found that when the parameters  are tuned the superlens is characterized by a high transmission at desirable wavelengths. Whilst the maximum theoretical resolution of the proposed superlens may be very high see e.g.  & Fig. 3A fluorophores brightness will depend in detail on numerous factors, such as the fluorophore's local environment In the far-field the maximum resolution is often estimated using the Rayleigh Criterion. In the near-field however a definition of resolution is somewhat more arbitrary, and will depend a greater deal on the photon statistics irection , we findIn One interesting question is whether the change in the fluorescence decay-rate with fluorophore-superlens distance can be used for obtaining 1) The complicated interactions of the sample with the dynamic SNOM probe 2) The superlens-SNOM approach would allow for the study of processes in viscous or inhomogenious media and at (cell) surfaces in which direct SNOM scanning is either very complicated or not possible. In the SNOM-superlens setup the superlens may be fabricated on an ultra-thin silicon based membrane, which could in itself be part of the superlens structure - e.g. the middle dielectric layer (see A promising method of image acquisition would be to fabricate a sub-wavelength grating on the image side of the superlens. It is then possible to reconstruct the sub-diffraction limit details by measuring the scattered propagating negative diffraction orders in the far-field ayer see .In conclusion we have presented calculations that suggest the feasibility of imaging a GFP-like fluorescent source through a stacked superlens. We have proposed a design based on a double layer metal-alloy/dielectric stack that operates slightly off resonance. Experimental realization of the introduced superlens will rely on overcoming the undesirable effects of surface roughness and the challenges associated with image acquisition discussed above. However, recent advances in nanofabrication technologies give a bright outlook for the use of stacked superlenses, such as the one discussed in this manuscript, in fluorescence imaging applications."}
{"text": "Docetaxel is a new taxoid with clinical activity in breast and lung cancer. Using docetaxel-sensitive and -refractory mammary and pancreatic murine tumours, as well as human-derived neoplasms, we investigated if a determinant of docetaxel sensitivity could be found at the level of its mechanism of action. Because microtubules represent the cellular targets of the drug, we studied their heterogeneity in the tumour models to try to explain the differences in drug sensitivity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones. It was also found that Tau protein levels differed markedly among the tumours. In the human-derived sensitive neoplasm, beta-tubulins and some Tau isoforms were found to be more abundant than in the resistant one. Western blot analysis of MAP2 revealed the presence of several immunoreactive species. Some of these polypeptides were also found in higher amounts in the docetaxel-sensitive tumours. The possible meaning of these correlations is discussed in connection with the regulation of microtubule dynamics."}
{"text": "Hip screw migration of peritrochanteric fracture fixation devices is a described complication in English literature. Medial migration occupies the majority of these cases whereas lateral migration is rare. We report the case of an 85-year-old woman whose intramedullary osteosynthesis of a trochanteric fracture was complicated by hip screw lateral migration. Mobilization was not influenced and no cut-out or non-union was detected. The migrated hip screw was easily removed and the discomfort vanished. The need for adequate surgical technique and radiographic examination after re-injuries even if the patient remains ambulatory is emphasised. Fractures of the trochanteric region of the femur are very common in the elderly. Many fixation devices have been developed for these fractures; the most widely used being the numerous versions of intramedullary nails which tend to replace the sliding nail plate systems. Intra-operative blood loss and operating time is much minimised, immediate load-bearing is ensured, and postoperative morbidity remains low . DespiteOne of the most common complications of intramedullary systems is lag screw migration combined with hardware cut-out or non-union ,5. HereiAn 85-year-old woman presented with a hip fracture after a fall. The radiographic control revealed a type 31-A.2.2, secondary to the AO classification, intertrochanteric fracture Figure  of the rPeritrochanteric fractures represent a significant risk in every age group. Moreover in the elderly they may represent a risk to life. Intramedullary nailing is widely used for fixation of such fractures ensuring less operating time, minimized wounds, immediate weight bearing, faster mobilization and thus less morbidity . NeverthThe most common and well-documented mechanical complication of these devices are: a) cut-out of the hip screw through the femoral head with varus collapse of the fracture ; b) fracLateral migration is more rare than medial. Up to our knowledge there are not any published cases of lateral migration, in a single use of a hip screw, without a new fracture or a cut-out accompanying the migration. Studies concerning the use of perhaps the most studied nail (Gamma nail - Howmedica) conclude that there have been no instances of implant failure without non-union or re-fracture .Hip screw migration is considered to be an evolutionary complication and the ability of the implant to resist migration under dynamic loading is of critical importance. Walking subjects the implant-bone interface to combined axial and torsional loading and may play a role in lag screw migration. In our case slight, painless lateral migration (of approximately 10 mm) was noticed 2.5 months post surgery and full lateral migration was noticed two weeks later after the occurrence of a new fall. The new injury caused great nail protrusion and haematoma of the hip accompanied with tenderness which gave away after the lag screw removal. We could not reach any profound explanation for the migration mechanism. The fact that the way of the lag screw into the femoral head was reamed and that the diameter of the non-threaded part of the lag screw was the same with that of the thread could provide some explanation for the behaviour of the screw and more particularly for the convenience of total migration once it was slightly detached from its original position. Moreover the osteoporotic bone of the patient did not offer an adequate grip to stabilize the sliding screw and prevent its loosening. Osteoporosis on the other hand did not seem to create any delay to bone union.One could suppose that this is the case of a semi-completed Z-effect since the lag screw migrated laterally as if the optional anti-rotational screw (which we did not use) was there to play the role of the medially migrated half. It should be reminded here that Werner-Tutschku et al  were the25 mm should rarely fail by cut-out [The age of the patient, the quality of the bone, the pattern of the fracture, the stability of the reduction, the angle of the implant, and the position of the lag screw within the femoral head have all been related to this mechanism of failure, but there has been no clear consensus as to the interrelationships or relative importance of each factor. Previous clinical studies suggest that lag screws placed with a tip-apex distance (TAD) of less than  cut-out ,15. In oIntramedullary nailing tends to become the treatment of choice for proximal femoral fractures and has a low implant failure rate. Although closed reduction and minimally invasive exposure minimise delayed union and non-union they are not enough for the avoidance of such complications. Caution is needed in the placement of the lag screw in manner that respects the limitations of Tip Apex Distance. A well centred lag screw contributes to better transmission of axial forces and inducts the earlier callus formation. Thus complications such the one described in this paper do not result in re-fractures, non-union or mal-union.AP: Anteroposterior; PFN: Proximal Femoral Nail; TAD: Tip Apex Distance; TFN: Trochanteric Fixation Nail; CCD: Caput Collumn Diaphysis.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.NL collected the data and drafted the manuscript. GM involved in revising the manuscript for important intellectual content. IG was the consultant surgeon responsible for the patient. All authors read and approved the final manuscript."}
{"text": "Tumours of the vulva and vagina are rare and there are relatively few studies of circulating markers in these conditions. The urinary measurement of the core fragment of the beta-subunit of hCG has been proposed as a useful tumour marker in non-trophoblastic gynaecological malignancies. This study describe the measurement of urinary beta-core in 50 patients with vulvovaginal malignancy. In contrast to other studies corrections were made for both the effect of urine concentration and the age of the patient. Each patient was followed up for at least 24 months, and at this time their status was correlated with their initial level of urinary beta-core. The sensitivity of beta-core was only 38%, but of those patients with elevated levels 90% had died within 24 months, while only 32% of those with normal levels had died. For both patients at initial presentation and those with recurrent disease, there was a highly significant difference in the survival curve between those with elevated beta-core levels and those with normal levels. This is similar to findings in cervical carcinoma, and suggests that for lower genital tract cancer the measurement of urinary beta-core may be valuable as a prognostic indicator, allowing a more informed approach to treatment and follow-up."}
{"text": "Serum vitamin A concentration were measured in 26 newly diagnosed lung-cancer patients and found to be significantly lower than those of patients of similar age with either non-malignant lung or non-lung diseases. The levels of vitamin A in the lung-cancer patients, but not in the controls, were significantly correlated with serum concentrations of retinol-binding protein (RBP) and zinc. It is suggested that low levels of zinc might reduce the synthesis of RBP and thus reduce the mobilization of vitamin A from the liver."}
{"text": "As indicated in the sample size paragraph, study power was considered in terms of both the whole year group and the high-risk sub-group. The incorrect emphasis in the published study protocol paper on the high risk sub-group analysis was a legacy of the funding proposal protocol, in which the sub-group sample size calculations critically determined the number of schools required for the trial.In preparing the main results paper from this trial, we have noticed an important error in the study protocol paper. In the Some other changes to the paragraph are also required to contextualise the corrected status of the outcomes. The corrected version of the paragraph should read:The trial's primary outcome measure is smoking prevalence measured (i) among the high-risk group and (ii) among the entire year group. The high-risk group is defined as those students who, at baseline, had experimented with cigarettes, were ex-smokers, or were occasional (less than weekly) smokers. These students are a primary target group because they are at greatest risk of becoming regular smokers, and the feasibility study showed an effect amongst this group [18]. Smoking prevalence is defined as students smoking a cigarette in the previous seven days. These outcome measures are being validated by measurement of salivary cotinine (a metabolite of nicotine), as studies have found cotinine to be the most accurate biomarker of smoke exposure in the previous two to three days . Secondary outcome measures include perceptions of norms regarding adolescent smoking, and intention to quit.We apologise for any inconvenience caused in our oversight with regard to this important detail.The pre-publication history for this paper can be accessed here:"}
{"text": "This paper describes a simple flow-injection (FI) manifold for the determination of a variety of species in industrial water. The chemical systems involved in the determination of ammonia (formation of Indophenol Blue), sulfate (precipitation with Ba(II)), and iron  were selected so that a common manifold could be used for the sequential determination of batches of each analyte. A microcolumn of a suitable ion exchange material was used for on-line preconcentration of each analyte prior to injection; linear ranges for the determination of the analytes at the ng/ml levels were obtained with good reproducibility. The manifold and methods are ready for full automation."}
{"text": "In 1996, investigation of a hantavirus pulmonary syndrome (HPS) outbreak in southern Argentina found evidence of person-to-person transmission of a hantavirus. The infection control ramifications of this finding led to this review of hantavirus epidemiology in the United States; the review suggests that Sin Nombre virus infection is rarely, if ever, transmitted from person to person and that existing guidelines for prevention of HPS remain appropriate for North America."}
{"text": "Multidrug-resistant strains of Mycobacterium tuberculosis seriously threaten tuberculosis (TB) control and prevention efforts. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance in M. tuberculosis. Drug resistance in M. tuberculosis is attributed primarily to the accumulation of mutations in the drug target genes; these mutations lead either to an altered target  or to a change in titration of the drug . Development of specific mechanism-based inhibitors and techniques to rapidly detect multidrug resistance will require further studies addressing the drug and drug-target interaction."}
{"text": "The 'deleted in colon carcinoma' (DCC) gene has been considered a candidate tumour-suppressor gene that encodes for a transmembrane protein with strong structural similarity to members of the superfamily of neural cell adhesion molecules. It has been mapped to the chromosomal region 18q21.1 and it is implicated in cellular differentiation and developmental processes. In human osteosarcoma allelic loss frequently occurs on the long arm of chromosome 18, suggesting a possible involvement of the DCC gene in the pathogenesis of this tumour entity. In the present study the mRNA and protein expression and rearrangements at the DNA level of the DCC gene were addressed in 25 osteosarcomas and several tumour cell lines, including osteosarcoma- and colon carcinoma-derived cell lines. Using an reverse transcriptase polymerase chain reach in (RT-PCR)-based approach DCC expression was found to be lost or substantially reduced in 14 of 19 high-grade osteosarcomas, in three of six lower grade osteosarcomas and most of the tumour cell lines, in contrast to normally differentiated osteoblasts. Immunohistochemical studies on DCC protein expression of 14 selected tumours correlated well with the RT-PCR-based results. In view of the putative tumour-suppressor characteristics of the DCC gene its loss or reduction of expression could be a specific event in the development or progression of many high-grade osteosarcomas."}
{"text": "Ligand-bound CRP activates            complement and the protein reportedly binds various Fc receptors. Coincident            with a now decade-long resurgence in clinical interest in associations of CRP with            disease, our laboratory has been investigating the biology of CRP in vivo using            human CRP transgenic mice (CRPtg). At that time we confirmed that CRP affects            a host defense function mediated at least in part through the elimination of            pathogens. Less appreciated and not as well understood as CRP's ability to bind            antigen and aid in the elimination of microbes, is its known ability to bind            autoantigens and presumed capacity to promote clearance of apoptotic cells. These            latter properties of CRP have long been suspected to contribute to homeostasis and            to autoimmune disease. In this article we review and update the evidence            generated in CRPtg by our group and in vitro by others' that indicates CRP is more            than just an antimicrobial molecule and convenient marker of inflammation - rather,            it protects against autoimmunity. A mechanistic            hypothesis is presented to account for this cause-and-effect relationship.C-reactive protein (CRP) is a blood component comprised of five identical            subunits with a combined molecular mass of 110 kDa; in the presence of Ca"}
{"text": "Dear Editor,I read the article 'Effectiveness of using teachers to screen eyes of school-going children in Satna district of Madhya Pradesh, India' with dueThe children not attending school can be covered comprehensively by promoting regular eye camps with the aid of the local Government and encouraging the people to attend the same by proper use of media. The high false-positive rate in the study, adding t"}
{"text": "BMC Biology that the mechanisms responsible for maintaining the imprinted state in Drosophila may be evolutionarily conserved and that CTCF may also play a critical role in this process.The nuclear factor CTCF has been shown to be necessary for the maintenance of genetic imprinting at the mammalian H19/Igf2 locus. MacDonald and colleagues now report in http://www.biomedcentral.com/1741-7007/8/105See research article  Igf2) and the RNA gene H19. However, understanding of the mechanisms controlling imprinting in non-mammalian species has lagged behind and it is unclear whether imprinting in insects and mammals is a conserved biological process with the same underlying molecular mechanisms. In this issue of BMC Biology, Lloyd, Meller and colleagues [Drosophila CCCTC binding factor (dCTCF) protein in the maintenance of maternal imprinting and propose that dCTCF has an evolutionarily conserved role in the maintenance of the imprinted state.Genetic imprinting is an epigenetic phenomenon that results in the expression of certain genes in a parent-of-origin chromosome-specific manner. Although imprinting was originally discovered in insects  and has lleagues  examine Drosophila is associated with position-effect variegation, in which chromosomal rearrangements place genes with visible phenotypes close to heterochromatin. MacDonald et al. [Drosophila mini-chromosome in which most of the X chromosome is deleted and the garnet gene is placed next to the centromeric heterochromatin; the garnet protein resembles clathrin and nonclathrin adaptin proteins and is similar to the delta subunit of the mammalian AP-3 adaptin complex. The rearrangement causes a variegated expression of garnet, such that the eyes of the adult flies show sectors of expressing and non-expressing cells characteristic of heterochromatin-induced silencing. Interestingly, this variegated expression is imprinted and it is observed in individuals carrying the paternal mini-X-chromosome, whereas the maternally transmitted copy shows normal expression of the garnet gene [All but one case of imprinting described in d et al.  use a Drnet gene . This obgarnet gene expression in the maternal versus paternal chromosomes, the authors [garnet gene from the maternal mini-X-chromosome, leading to a variegated eye color similar to that seen from the paternally inherited chromosome. This observation suggests that dCTCF is required for the non-variegated expression of the garnet gene when it is maternally inherited.To study whether dCTCF is involved in the differential regulation of  authors  examinedgarnet phenotype: the transcription of the gene under the control of regulatory sequences and the spreading of heterochromatin silencing - these two components may not be easy to separate mechanistically. In the mammalian H19/Igf2 locus, direct transcriptional activation can be distinguished from indirect effects from the surrounding chromatin thanks to information obtained from the analysis of the function of CTCF in the spatial organization of the maternal locus. This organization functions to maintain the imprinted expression of H19 and the silencing of Igf2 on the maternal chromosome. If CTCF binding in the imprinting control region (ICR) is abolished, both Igf2 and H19 can be transcribed from the maternal allele because of the disruption in the CTCF-mediated maternal allele chromatin organization; this organization prevents the interaction between enhancers and the promoter of Igf2. These observations suggest that the role of CTCF in the maintenance of imprinting involves its ability to mediate interactions that result in a specific three-dimensional architecture of the locus. In fact, CTCF is not directly involved in the transcription activation of the mouse H19 and Igf2 genes [Two different processes affect the visually observed f2 genes -10.Drosophila, the primary effect of the maternal imprint is to inhibit the spread of heterochromatin-induced silencing . The finding that the garnet gene is poorly expressed from the paternally transmitted mini-X-chromosome and is not affected by reduced dCTCF expression [garnet gene in the maternally derived mini-X-chromosome could then be accomplished by the establishment of a distinct barrier to the spread of heterochromatin (Figure garnet transcription that indirectly antagonizes heterochromatin spreading (Figure garnet in the maternal germline would be the imprint that inhibits heterochromatin spreading in the somatic cells of the progeny.In pression  suggestsn Figure  or by a g Figure . In the et al. [H19/Igf2 locus. Given the functional conservation of CTCF as an insulator protein between flies and mammals, it is interesting to ask whether this is also the case in Drosophila. MacDonald et al. [garnet gene is not subject to heterochromatin-induced silencing in a mini-X-chromosome inherited from females heterozygous for mutations in the dCTCF gene. This observation suggests that dCTCF is not required for the establishment of the maternal imprint. However, the question remains as to whether further reduction in the levels of dCTCF in the maternal germline may actually show an effect on this process. For example, it is possible that dCTCF expression during oogenesis is much higher than in somatic cells, and that the small reduction in dCTCF levels in heterozygous mutant females is not sufficient to affect the establishment of the imprint. Alternatively, there may be other mechanisms that can prevent the spreading of heterochromatin during gametogenesis independent of dCTCF. Such a mechanism could use other insulator proteins or alternative processes to prevent heterochromatin spreading.After showing a role for dCTCF in the maintenance of the maternal imprint, MacDonald et al.  exploredd et al.  found thDrosophila, it is possible that the role of dCTCF in maintaining the imprinted state is related to the ability of this protein to mediate interactions that create a chromatin domain insulated from heterochromatin silencing (Figure et al. [Drosophila will shed new light not only on the understanding of the mechanisms controlling this process, but also on the understanding of the evolutionary conservation of CTCF function.CTCF has multiple roles in chromatin organization and gene regulation that derive from its ability to mediate intra- and inter-chromosome interactions . Given tg Figure . The fine et al.  agree wi"}
{"text": "Contemporary theory of spiking neuronal networks is based on the linear response of the integrate-and-fire neuron model derived in the diffusion limit. We find that for non-zero synaptic weights, the response to transient inputs differs qualitatively from this approximation. The response is instantaneous rather than exhibiting low-pass characteristics, non-linearly dependent on the input amplitude, asymmetric for excitation and inhibition, and is promoted by a characteristic level of synaptic background noise. We show that at threshold the probability density of the potential drops to zero within the range of one synaptic weight and explain how this shapes the response. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled networks of threshold units. Our work demonstrates a fast-firing response of nerve cells that remained unconsidered in network analysis, because it is inaccessible by the otherwise successful linear response theory. For the sake of analytic tractability, this theory assumes infinitesimally weak synaptic coupling. However, realistic synaptic impulses cause a measurable deflection of the membrane potential. Here we quantify the effect of this pulse-coupling on the firing rate and the membrane-potential distribution. We demonstrate how the postsynaptic potentials give rise to a fast, non-linear rate transient present for excitatory, but not for inhibitory, inputs. It is particularly pronounced in the presence of a characteristic level of synaptic background noise. We show that feed-forward inhibition enhances the fast response on the network level. This enables a mode of information processing based on short-lived activity transients. Moreover, the non-linear neural response appears on a time scale that critically interacts with spike-timing dependent synaptic plasticity rules. Our results are derived for biologically realistic synaptic amplitudes, but also extend earlier work based on Gaussian white noise. The novel theoretical framework is generically applicable to any threshold unit governed by a stochastic differential equation driven by finite jumps. Therefore, our results are relevant for a wide range of biological, physical, and technical systems. Understanding the dynamics of single neurons, recurrent networks of neurons, and spike-timing dependent synaptic plasticity requires the quantification of how a single neuron transfers synaptic input into outgoing spiking activity. If the incoming activity has a slowly varying or constant rate, the membrane potential distribution of the neuron is quasi stationary and its steady state properties characterize how the input is mapped to the output rate. For fast transients in the input, time-dependent neural dynamics gains importance. The integrate-and-fire neuron model The analytical treatment of the threshold process is hampered by the pulsed nature of the input. A frequently applied approximation treats synaptic inputs in the diffusion limit, in which postsynaptic potentials are vanishingly small while their rate of arrival is high. In this limit, the summed input can be replaced by a Gaussian white noise current, which enables the application of Fokker-Planck theory The spike threshold renders the model an extremely non-linear unit. However, if the synaptic input signal under consideration is small compared to the total synaptic barrage, a linear approximation captures the main characteristics of the evoked response. In this scenario all remaining inputs to the neuron are treated as background noise see . CalculaLinear response theory enables the characterization of the recurrent dynamics in random networks by a phase diagram In simulations of neuron models with realistic amplitudes for the postsynaptic potentials, we observed a systematic deviation of the output spike rate and the membrane potential distribution from the predictions by the Fokker-Planck theory modeling synaptic currents by Gaussian white noise. We excluded any artifacts of the numerics by employing a dedicated high accuracy integration algorithm Our theory applied to the integrate-and-fire model with small but finite synaptic amplitudes Consider a leaky integrate-and-fire model The membrane potential of the model neuron follows a first order stochastic differential equation. Therefore, in this section we consider a general first order stochastic differential equation driven by point events. In order to distinguish the dimensionless quantities in this section from their counterparts in the leaky integrate-and-fire model, we denote the rates of the two incoming Poisson processes by In the presence of an absorbing boundary at First we consider the diffusion limit, in which the rate of incoming events diverges, while the amplitude of jumps goes to zero, such that mean Now we return to the problem of finite jumps. We proceed along the same lines as in the diffusion limit, seeking the stationary solution of the Fokker-Planck equation (2). We keep the boundary conditions at If The general solution of the stationary Fokker-Planck equation (3) is a sum of a homogeneous solution The normalization condition determines the as yet unknown constant probability flux We now apply the theory developed in the previous section to the leaky integrate-and-fire neuron with finite postsynaptic potentials. Due to synaptic impulses, the membrane potential drifts towards t region  the apprt region  our analts , see , the dene noise  . The insWe now proceed to obtain the response of the firing rate plitudes .The instantaneous response of the firing rate to an impulse-like perturbation can be quantified without further approximation. The perturbation shifts the probability density by response  which foThe increasing and convex dependence of the response probability on the amplitude of the perturbation is a generic feature of neurons with subthreshold mean input that also persists in the case of finite synaptic rise time. In this regime, the membrane potential distribution has a mono-modal shape centered around the mean input, which is inherited from the underlying superposition of a large number of small synaptic impulses. The decay of the density towards the threshold is further enhanced by the probability flux over the threshold: a positive synaptic fluctuation easily leads to the emission of a spike and therefore to the absorption of the state at the threshold, depleting the density there. Consequently, the response probability The integral response (15) as well as the instantaneous response (5) both exhibit stochastic resonance; an optimal level of synaptic background noise Due to the convex nature of the instantaneous response  its relaAn example network in which the linear non-instantaneous response cancels completely and the instantaneous response becomes dominant is shown in hoot at  . Figure shown in . The pooIn this work we investigate the effect of small, but non-zero synaptic impulses on the steady state and response properties of the integrate-and-fire neuron model. We obtain a more accurate description of the firing rate and the membrane potential distribution in the steady state than provided by the classical approximation of Gaussian white noise input currents The instantaneous non-linear response is potentially a relevant mechanism for processing of transient signals by neurons. In auditory cortex, the irregular firing of neurons has been shown to be driven by simultaneous coactivation of several of their synaptic afferents Our finding of an immediate non-linear response has an implication on the intensely debated question how common input affects the correlation of the spiking activity of pairs of neurons Synapses with spike timing dependent plasticity (STDP) Postsynaptic potentials exhibit a finite rise time, whereas the membrane potential of the integrate-and-fire neuron model jumps at each incoming synaptic event. Although this is a simplification, the model reproduces experimental spike trains surprisingly well Previous work has shown that the spike generation mechanism influences the transient properties of neurons The hybrid approach combining a diffusion approximation with an explicit treatment of finite jumps near the boundary allowed us to uncover hitherto unknown properties of the integrate-and-fire model by analytical means. The diffusion approximation, however, still limits our approach: for synaptic amplitudes"}
{"text": "Advance health care directives and informed consent remain the cornerstones of patients' right to self-determination regarding medical care and preferences at the end-of-life. However, the effectiveness and clinical applicability of advance health care directives to decision-making on the use of life support systems at the end-of-life is questionable. The Uniform Anatomical Gift Act (UAGA) has been revised in 2006 to permit the use of life support systems at or near death for the purpose of maximizing procurement opportunities of organs medically suitable for transplantation. Some states have enacted the Revised UAGA (2006) and a few of those have included amendments while attempting to preserve the uniformity of the revised Act. Other states have introduced the Revised UAGA (2006) for legislation and remaining states are likely to follow soon.presumption of donation intent and the use of life support systems to ensure medical suitability of organs for transplantation. The default choice trumps the expressed intent in an individual's advance health care directive to withhold and/or withdraw life support systems at the end-of-life. The Revised UAGA (2006) overrides advance directives on utilitarian grounds, which is a serious ethical challenge to society. The subtle progression of the Revised UAGA (2006) towards the presumption about how to dispose of one's organs at death can pave the way for an affirmative \"duty to donate\". There are at least two steps required to resolve these challenges. First, physicians and hospitals must fulfill their responsibilities to educate patients on the new legislations and document their preferences about the use of life support systems for organ donation at the end-of-life. Second, a broad based societal discussion must be initiated to decide if the Revised UAGA (2006) infringes on the PSDA and the individual's right of autonomy. The discussion should also address other ethical concerns raised by the Revised UAGA (2006), including the moral stance on 1) the interpretation of the refusal of life support systems as not applicable to organ donation and 2) the disregarding of the diversity of cultural beliefs about end-of-life in a pluralistic society.The Revised UAGA (2006) poses challenges to the Patient Self Determination Act (PSDA) embodied in advance health care directives and individual expression about the use of life support systems at the end-of-life. The challenges are predicated on the UAGA revising the default choice to  In 1990, the U.S. Congress passed the Patient Self-Determination Act (PSDA) reinforcing individuals' rights to determine their final health care. The PSDA became effective in 1991 so that patients can make decisions about their medical care and specify whether they want to accept or refuse specific medical care [The PSDA requires Medicare and Medicaid providers, including hospitals, to give adult individuals, at the time of inpatient admission, certain information about their rights under state laws governing advance health care directives, including: (1) the right to participate in and direct their own health care decisions; 2) the right to accept or refuse medical or surgical treatment; (3) the right to prepare advance health care directives and (4) information on the provider's policies governing the utilization of these rights [ the righAlmost 16 years later, advance health care directives and power-of-attorney for health care still play a limited, yet important, role in assisting with health care decisions about the use of life support systems and medical technologies at the end-of-life . About 2Criticisms have been rightfully expressed concerning the current deficiencies of construction, documentation, accessibility and applicability of advance health care directives . The maiConsidering the above shortfalls, this commentary highlights additional and unique challenges posed by the Revised Uniform Anatomical Gift Act (UAGA) 2006 on advance health care planning and directives about the use of life support systems at the end-of-life . Some stIn 2006, the publication of two influential reports from the Institute of Medicine and National Conference on Donation After Cardiac Death opened a new era for deceased organ donation ,10. TradThe National Conference of Commissioners on Uniform State Laws (NCCUSL) promulgated the Revised UAGA (2006) with the substantial and active participation of the major stakeholders representing donors, recipients, physicians, procurement organizations, regulatory agencies and the US Department of Health & Human Services. The stakeholders represented a broad spectrum of organizations with special interest or advocacy for the practice of organ transplantation. The primary intent of revising the UAGA in 2006 was to solve the critical organ shortage by maximizing the likelihood of organ donation. To accomplish this objective, the Revised UAGA (2006) increases opportunities of organ procurement after cardiac death for transplantation . The anaThe Revised UAGA (2006) reaffirms that if a donor has a document of gift, there is no reason to seek consent from the donor's family as they have no right to give it legally . If an iThe Revised UAGA (2006) section 14 was drafted in accordance with the controlling federal law requiring hospitals to notify an organ procurement organization (OPO) of any individual whose death is imminent or who has died in-hospital to increase opportunities of organ procurement for transplantation . In casenot to have life prolonged by the administration of life support systems should not be construed as an expression of a contrary intent for the use of life support systems for donation purpose [is a prospective donor.The Revised UAGA (2006), section 14, emphasizes the general direction in an advance health care directive or power-of-attorney for health care that the patient's wish  purpose . In effecontrary intent to prevent the use of life support systems for organ donation purposes in either a declaration or advance health care directives.If determined to be a prospective donor, the Revised UAGA (2006), section 21, creates a default rule requiring that measures necessary to ensure the medical suitability of an organ for transplantation may not be withheld or withdrawn. The initiation and/or continuation of life support systems is the default rule and overrides a prospective donor's expression in an advance health care directive not to have life prolonged by life support systems. To resolve the tension between the presumed intent to donate organs and the expressed intent not to have life support systems administered merely to prolong life, section 21 presumes that for a prospective donor the desire to save lives by making an anatomical gift trumps the desire to have life support systems withheld or withdrawn. The Revised UAGA (2006) requires a prospective donor to expressly provide In 2007, an amendment was introduced to the Revised UAGA (2006), section 21, to recognize the conflict between initiation and/or continuation of life support systems based on becoming a prospective donor and the expressed wishes of appropriate end-of-life care in advance health care directives. Section 21(b) (2007) requires the attending physician to resolve the conflict with the prospective donor or surrogate decision maker for clarification of intent and any contraindications for appropriate end-of-life care.With the new UAGA legislation, advance health care planning should include education on the new requirement of the Revised UAGA (2006) about the use of life support systems for organ donation at the end-of-life. These changes are predicated on the UAGA revising the default choice to presumption of donation intent and, therefore, the requirement for life support systems to ensure medical suitability of organs for transplantation. Figure Patients with documents of gift are considered donors irrespective of advance health care directives and they are required to comply with organ procurement protocols figure . In the The laxity of criteria of medical suitability for donation is most disturbing to patients who become prospective donors without documents of gift and who have unequivocal advance health care directives expressing intent for withholding and/or withdrawal of life support systems at the end-of-life figure . Under sIn the endeavor to solve the critical organ shortage, the Revised UAGA 2006) has transformed the traditional 'altruistic' to a disturbing 'utilitarian' approach towards organ procurement for transplantation. National palliative and hospice care organizations ,17 promo06 has trThe Revised UAGA (2006) has not adopted presumed consent for organ procurement. Nevertheless, the most disturbing consequence of the Act is that patients will be forced to have life support systems initiated or continued while awaiting the assessment of their organs for donation. In an epidemiologic study of the use of intensive care at the end-of-life in the US, one in five Americans die using intensive care services . It is lThe application of life support systems for the purpose of organ donation without explicit consent is contraindicated at end-of-life and inconsistent with recommended practice guidelines for quality palliative care ,22. LifeThe Revised UAGA (2006) requirement of life support systems for patients with clearly contrary end-of-life wishes represents a radical departure from the PSDA (1991) and original intent of advance health care directives. In fact, it can be argued that the Revised UAGA (2006) intrudes into patients' autonomy and infringes on their rights to self-determination of medical care at the end-of-life.Some states have already enacted the Revised UAGA 2006) and a few of those have included amendments while attempting to preserve the uniformity of the revised Act (Figure 006 and aPSDA = Patient Self Determination ActOPO = Organ procurement organizationUAGA = Uniform Anatomical Gift ActUS = United StatesSee table There are no affiliations or financial involvement with any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript. The authors declare that they have no competing interests.The JLV, MYR and JLM attest they have made substantial contributions in drafting the manuscript and revising it critically for important intellectual content; that they have given final approval of the version to be published; and that they have participated sufficiently in the work to take public responsibility for appropriate portions of the content. JLV, MYR and JLM read and approved the final manuscript"}
{"text": "Two types of mouse tumour have been used to study the radiomodifying actions of Misonidazole (MISO) and WR-2721 when used alone and in combination with each other. Single dose studies were performed in both of the tumours and fractionated studies were performed on the anaplastic carcinoma, CA MT. Radioprotection with WR-2721 was seen in both tumours, being most marked at low X-ray doses. The protection was more obvious and the sensitization by MISO less in the fractionated experiment. The combination of MISO and WR-2721 gave an intermediate response compared with either drug used alone, resulting in some sensitization with single doses and an overall protection with repeated small doses. An interactive toxicity of the 2 drugs was also observed, suggesting an additive effect when assessed in terms of lethality. These studies indicate that the effects of both MISO and WR-2721 are dependent upon the oxygen status of the cells in the tumour, and that MISO can act in an oxygen-mimetic manner to modify the radioprotection observed with WR-2721."}
{"text": "An animal model was used to study the effects of oral treatment with a small molecular selective inhibitor of cysteine proteinases, Z-Phe-Arg-fluoromethylketone (Z-Phe-Arg-FMK) on primary tumour development. Poorly differentiated rapidly growing and moderately differentiated slowly growing human pancreatic tumours were implanted in the neck of nude mice that were orally treated or not with the inhibitor. Growth rates of the tumours were determined during 38 days after implantation. The poorly differentiated tumours were not affected by treatment with the inhibitor. Development of the moderately differentiated tumours was inhibited significantly by Z-Phe-Arg-FMK treatment. Moreover, the amount of stroma was increased and the volume of cancer cells was reduced in the moderately differentiated tumours that had grown in the treated animals. Reduction in size of the tumours was not achieved by reduction in growth rate but in a delay of the onset of growth. It is concluded that cysteine proteinases play a transient role at the start of tumour development only when cancer cells are surrounded by stroma as was the case in the moderately differentiated but not in the poorly differentiated pancreatic tumours. However, this role of cysteine proteinases can easily be taken over by other proteinases. \u00a9 2000 Cancer Research Campaign"}
{"text": "There was a spelling error in the name of a member of the UNAIDS/WHO/SACEMA Expert Group on Modelling the Impact and Cost of Male Circumcision for HIV Prevention. The correct name is Laith Abu-Raddad."}
{"text": "When assessing the value of a particular treatment, it is important to consider the impact it may have on the quality of life of those being treated. This is particularly so for cancer patients, whose life expectancy may be short. Patients with advanced colorectal cancer who participated in two international comparative studies of raltitrexed ('Tomudex') vs standard 5-fluorouracil (5-FU) plus leucovorin (LV) completed previously validated quality-of-life questionnaires  at various times during the studies. Early statistically significant advantages of raltitrexed vs 5-FU plus LV on quality of life were observed at week 2 in five of eight of the EuroQol and three of four of the Rotterdam Symptom Check List dimensions. Such advantages were not observed using the EORTC questionnaire, which was not completed until week 12. The necessary dose delays and different dose schedules made it difficult in these studies to compare the impact on quality of life of the two treatments. It may be that performance status, effect on disease-related symptoms and the incidence of toxicity are the most important indications of a patient's quality of life."}
{"text": "Our studies of the metastatic behaviour of FSA1231 and FSA1233 show that the role of selection processes of metastatic variants at the secondary sites is minimal in the spontaneous metastasis of these systems. In contrast, tumour-cell release efficiency (number of blood-borne clonogenic tumour-cells) correlates well with the difference in spontaneous lung metastasis efficiencies of the cell clones FSA1231 and FSA1233. Also, the different tumour-cell release efficiencies could explain the discrepancy between artificial and spontaneous metastasis of these cell clones."}
{"text": "The experimental results of the study show that inorganic tin and methyltin substancesinduce slight inhibition of the catalytic activity of horse liver alcohol dehydrogenase (HLADH), unable to beimproved during pre-incubation with the enzyme. The conditions for carrying out the kinetic investigation ofthe mentioned phenomenon were optimized and as it turned out the mechanism of methyltin trichlorideaction, as the most effective methyltin inhibitor, is more complex than the proposed interaction of the metalatom with SH-groups of the enzyme protein. It was demonstrated that the tin compounds act in the samemanner as methylmercury compounds and might serve as oxidative agents towards the co-enzyme NADH.Kinetic data on MeSnCl3 were calculated. Data acquired on NAD-dependent ADH from horse liver and thoseregarding NAD-dependent LDH from sturgeon liver were compared.The study of inorganic tin (SnCl"}
{"text": "The treatment of breast cancer patients has changed rapidly in the past decade, but empirical data at local and national level are scarce. Predicting the consequences of screening for primary treatment is consequently difficult. The aim of this analysis of records on admissions to hospital of women with breast cancer and/or for breast surgery (1975-90) together with a survey of all Dutch radiotherapy departments (1986-88) is to show the change in breast-conserving therapy and other primary treatment before the start of breast cancer screening in The Netherlands. There was a modest increase in breast-conserving therapy after 1981, coinciding with the first publication on its trial, followed by a sharp increase between 1985 and 1990, after the second publication. At the end of that 5 year period, 36% of all women with newly diagnosed invasive breast cancer underwent this type of surgery. Breast-conserving surgery is always followed by radiotherapy, but there has been a clear reduction in post-operative radiation after mastectomy. The percentage of breast-conserving therapy is at present higher in The Netherlands than in the USA. Implementing the Dutch screening programme will result in a maximum increase in breast-conserving therapy at national level of 34%, which stabilises at +21%, or a 50% maximum increase at local level. The number of women treated by mastectomy will ultimately decrease by 9%. Given the rapidity of change towards the use of breast-conserving surgery, which is enhanced by screening, recent information will be needed in predicting capacity and assessing whether screen-detected women are treated adequately."}
{"text": "The level of expression of keratinocyte growth factor (KGF) mRNA has been measured in human breast cell lines, purified populations of epithelial cells, myoepithelial cells and fibroblasts from reduction mammoplasty tissue and a panel of 42 breast cancers and 30 non-malignant human breast tissues using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) procedure. We found similar levels of KGF mRNA in malignant and non-malignant breast tissues. The study of the amount of KGF mRNA in breast cell lines and purified populations of cells revealed that fibroblasts are the predominant source of KGF with malignant and non-malignant epithelial cells containing very low levels of KGF mRNA. We have examined the distribution of fibroblast growth factor receptor (FGFR)-2-IIIb, which is a high-affinity receptor for KGF and find that it is present on malignant and non-malignant epithelial cells. The level of FGFR-2-IIIb present on breast cancer cell lines was sufficient for KGF stimulation of breast cancer cell proliferation. Other members of the fibroblast growth factor family have been either not expressed in the human breast  or have been found at much reduced levels in breast cancer  and this is the first member of the family to potentially influence the progression of breast cancer through stimulation of cell division."}
{"text": "A case-control study of occupational and recreational sun exposure, Mediterranean and other sun-exposed holidays, tanning history and history of isolated episodes of severe sunburn has been carried out on 113 patients with cutaneous malignant melanoma and 113 age- and sex-matched controls. Social class and skin type were also considered in the analysis of the data which involved the use of conditional multiple logistic regression. A highly significant increase in the history of severe sunburn was recorded in melanoma patients of both sexes in the 5-year period preceding presentation with their tumour. Higher social class and negative history of recreational sun exposure were also significantly increased in patients by comparison with controls. In the male group severe sunburn, lack of occupational sun exposure and higher social class were significant factors while in the female group only severe sunburn was significantly increased in the melanoma patients. This study thus provides evidence to suggest that short intense episodes of UV exposure resulting in burning may be one of the aetiological factors involved in subsequent development of melanoma."}
{"text": "Cancer of the oesophagus was a rare disease in the South African black population until the last few decades. Increases in incidence have occurred and at present it is the commonest cancer in black men in many parts of South Africa. A case-control study of 200 oesophageal cancer patients and 391 hospital controls has been carried out in order to determine the risk factors in the urban black population of Soweto. The results indicate that the cancer patients were long-term urban residents from a very low socio-economic group. The association between smoking pipe tobacco and oesophageal cancer previously noted in South Africa is confirmed. In addition, consumption of traditional beer was found to be a major risk factor."}
{"text": "Many existing tools have poor user interfacesand limited real-time performance when applied to realistically large datasets; muchof the user's cognitive capacity is therefore focused on controlling the tool ratherthan on performing the research. The UTOPIA project is addressing some of theseissues by building reusable software components that can be combined to makeuseful applications in the field of bioinformatics. Expertise in the fields of humancomputer interaction, high-performance rendering, and distributed systems is beingguided by bioinformaticians and end-user biologists to create a toolkit that is botharchitecturally sound from a computing point of view, and directly addresses end-userand application-developer requirements.Bioinformaticians routinely analyse vast amounts of information held both in largeremote databases and in flat data files hosted on local machines. The contemporarytoolkit available for this purpose consists of an"}
{"text": "Results are presented which show that mesothelial cells (MC) from ovarian cancer patients can both stimulate and inhibit the clonogenic growth of ovarian tumour cells (TC) in a dose-dependent fashion. TC lines from both non-ovarian and ovarian tumours were variable in their response to MC. Colony formation was rarely induced when the TC population was non-clonogenic and a bladder cell line showed inhibition of colony formation in the presence of MC. Primary tumour cultures from ovarian cancer patients also showed a variable response to MC. Fibroblasts from malignant, benign and non-neoplastic sources were significantly less effective in stimulating the clonogenic growth of responsive cell lines. Conditioned medium was a poor substitute for the presence of intact viable cells, and distance between feeder cell and TC was an important factor in determining the magnitude of response. A significant relationship between the feeder effect of MC and their proliferation in soft agar was observed when epidermal growth factor was used in the medium. The relevance of the findings in the context of the pattern of spread of ovarian cancer is discussed."}
{"text": "The effects of X-radiation on the Nembutal-induced redistribution of the cardiac output in two types of transplanted mouse tumours and some normal mouse tissues have been investigated, using rubidium-86 and 125I-human serum albumin. Irradiation causes an increase in 86Rb uptake (relative blood perfusion) by the tumours of anaesthetized mice, but has little or no effect in non-anaesthetized mice. The increase is dose- and time-dependent. Tumour plasma space is not significantly affected by radiation and Nembutal. Muscle blood perfusion is severely decreased in anaesthetized mice and is not affected by radiation, at least within the time limits of the experiments. This means that radiation-induced functional vascular changes in normal and neoplastic tissues follow different time courses. On the basis of the present results, and of the results of other authors, it is argued that irradiation damages the vasculature of tumours in such a way that it becomes more sensitive to changes in systemic blood pressure."}
{"text": "The new trends in immunochemistry related to the replacement ofradioisotopic labels with non-radioactive labels are presented. Immunoenzymatic, fluorescent and chemiluminescent techniques are described in terms of their basic principles and their most common applications. The advantages of computer-controlled calibration are also discussed."}
{"text": "Recently, eight allelic variants of the pertactin gene (prn1-8) have been characterized in Bordetella pertussis strains isolated in Europe and the United States. It has been suggested that the divergence of the pertactin types of clinical isolates from those of the B. pertussis vaccine strains is a result of vaccine-driven evolution. Sequencing of the prn, which is relatively time-consuming, has so far been the only method for the differentiation of prn types. We have developed a rapid real-time polymerase chain reaction assay suitable for large-scale screening of the prn type of the circulating strains. This method correctly identified the prn type of all tested 41 clinical isolates and two Finnish vaccine strains. The method is simple and reliable and provides an alternative for sequencing in pertussis research."}
{"text": "Saccharomyces cerevisiae and the nematode Caenorhabditis elegans.The availability of complete genome sequences necessitates the development of standardized functional assays to analyse the tens of thousands of predicted gene products in high-throughput experimental settings. Such approaches are collectively referred to as \u2018functional genomics\u2019. One approach to investigate the properties of a proteome of interest is by systematic analysis of protein\u2013protein interactions. So far, the yeast two-hybrid system is the most commonly used method for large-scale, high-throughput identification of potential protein\u2013protein interactions. Here, we discuss several technical features of variants of the two-hybrid systems in light of data recently obtained from different protein interaction mapping projects for the budding yeast"}
{"text": "A study of Burkitt's lymphoma (BL) in Papua New Guinea for the years 1958-87 revealed four instances of familial BL. Incident cases occurred within 1 year of each other in the four families. Personal follow-up was possible for three of these families whose pedigrees showed that two or more siblings were affected. There was no significant variation of the incidence of BL by year of diagnosis or month of onset. There was significant variation in annual average incidence of BL between the three provinces studied, with the highest incidence in the Nuku and Lumi census districts (of the West Sepik Province). This is the first report of familial BL outside Africa."}
{"text": "The anti-tumour action of methylene dimethane sulphonate (MDMS) has been further investigated in relation to its immunosuppressive properties. Following a dose of 10 mg/kg, the proportion of permanent regressions of Yoshida lymphosarcoma transplants is lower in animals treated during the first 5 days of tumour growth. Re-implants on day 28 to those animals in which regression of the tumour had occurred indicated that the immune response to the tumour increases during the first 7 days of tumour growth.Studies of the effect of MDMS on the primary antibody-forming cell response of mice to sheep red cell antigens showed this drug to be an immunosuppressant comparable in strength to x-radiation. MDMS given to rats prior to tumour transplantation also acted as an immunosuppressant in this system resulting in an increased rate of tumour growth. For both responses the maximum immunosuppressive effect was obtained when the interval between drug administration and antigenic challenge was minimal."}
{"text": "A mortality study of French Polynesia in the period 1984-92, although limited by the small population living close to the test sites and the high proportion of deaths attributed to ill-defined causes, found no excess of cancer that could confidently be attributed to the 41 atmospheric test explosions in 1966-74. A study of cancer incidence is planned."}
{"text": "Objective: To test whether special training of general practitioners alters the care of dementia patients through their systematic recommendation of caregiver counseling and support groups.More than 90% of dementia patients are cared for by their general practitioners, who are decisively involved in the diagnosis, therapy and recommendation of support services. 129 general practitioners enrolled 390 dementia patients and their informal caregivers in a prospective, three-arm cluster-randomized 2-year study. Arm A constituted usual care, in Arm B and C support groups and caregiver counseling  were recommended by the general practitioners. The general practitioners received arm-specific training. Diagnostic and therapeutic behavior of physicians was recorded at baseline. Informal caregivers were questioned in follow-up after 2 years about the utilization of support services.The diagnostic behavior of the general practitioners conforms to relevant guidelines. The procedure in newly-diagnosed patients does not differ from previously diagnosed patients with the exception of the rate of referral to a specialist. About one-third of the newly-diagnosed dementia patients are given an anti-dementia drug. The utilization of support groups and counseling increased five- and fourfold, respectively. Utilization of other support services remained low (< 10%), with the exception of home nursing and institutional short-term nursing.Trained general practitioners usually act in conformity with guidelines with respect to diagnosing dementia, and partly in conformity with the guidelines with respect to recommended drug therapy. Recommendations of support services for informal caregivers by the general practitioner are successful. They result in a marked increase in the utilization rate for the recommended services compared to offers which are not recommended by the general practitioner.ISRCTN68329593 Medical care of elderly people in Germany is given by general practitioners in the majority of cases. This applies also to dementia patients: more than 90% are diagnosed and cared for by the general practitioner . He is rVarious studies have thus far investigated the diagnostic behavior of general practitioners toward dementia patients ,7-9. StoIn the literature, a guideline-supported care rate of patients with Alzheimer's disease (AD) with evidence-based anti-dementia drugs of 26% ,16 or evFor diagnostics, the International Guideline of the National Institutes for Health and Clinical Excellence (NICE) recommend thorough exploration, including the medical history, a physical-clinical examination, and performance of a cognitive screening. Moreover, a laboratory series  should be part of the basic screening. Other procedures  should only be performed after careful consideration. Imaging procedures are recommended for diagnostics of dementia subtypes . The diaFor the treatment of AD patients, the German \"Dementia\" Guideline for general practitioners recommends drug therapy  and non-drug therapy , whereby the use of anti-dementia drugs is subject to critical discussion . The criIn addition to treating dementia patients, the aim is to support informal caregivers with appropriate support and respite services which have been found to be effective -28, suchInitiative Demenzversorgung in der Allgemeinmedizin: Dementia Care Initiative in Primary Practice) presented here, the care of dementia patients living at home and their informal caregivers was to be optimized with respect to diagnostics, therapy and support services. This took place on the basis of training of general practitioners and systematic recommendation of support groups in the form of peer groups and actively approaching caregiver counseling of informal caregivers.In the German IDA-Study  be increased by recommendation of the general prac-titioner?What effect does the utilization of family caregiver counseling have on the utilization of other available support services?This was a three-armed cluster-randomized controlled longitudinal study of patients with dementia living at home with at least one care-giving informal caregiver. Patients in the study region of Middle Franconia, Bavaria, Germany, were included if they had mild or moderate dementia (MMSE 10-24) according to the diagnosis criteria of DSM-IV  respectiGeneral practitioners in all study groups participated in a training course on dementia diagnosis. In the two intervention groups B and C, they additionally received training on evidence based dementia treatment. They also recommended support groups and actively approaching family counselling to caregivers beginning either at baseline (study Arm C) or after the 1-year follow-up (study Arm B).http://www.controlled-trials.com/. A detailed description of the study design has already been published elsewhere , par, par29]]General practitioners behave largely in conformity with guidelines in their diagnostic procedures in dementia patients. The therapeutic behavior with respect to prescription of anti-dementia drugs was in the majority less in accordance with guideline recommendations. However, there are some hints that behavior in conformity with guidelines could be promoted by means of training. Utilization of support services by informal caregivers remains low, as long as the informal caregivers are not intensively motivated to use such services. The role of the general practitioners as a motivator for informal caregivers is very significant, since the mediation of support services through the general practitioner led to a clear increase in utilization. For research, it is important to investigate the efficacy of further concepts in overcoming barriers to utilization among the informal caregivers of dementia patients.The sponsors have commissioned two academic research institutions with the scientific evaluation of the IDA project by giving unconditional research funds. A contract between the sponsors and academic researchers ensures that the latter have the full scientific responsibility and have the right to publish the results. Members of the sponsoring organizations closely cooperate in design and conduct of the project, but only the academic researchers have full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. CD, EG, MGS, RH and PMe are independent scientists who have received funding for this study as described above. CD received an honorarium for presentation of the IDA-study results at a public symposium from Eisai GmbH. Sponsoring organizations: SW is employee of the AOK Bavaria - Health insurer, JL is employee of the Federal Association of the AOK, HM is employee of Eisai GmbH, PMa is Head of Market Access of Pfizer Germany and SR is a former employee of Pfizer Germany. The IDA project was initiated and financed by the four partners with equal rights in conception, development and implementation: the AOK Bavaria - Health insurer and the Federal Association of the AOK - one of the largest statutory health insurances in Germany - and the research-based pharmaceutical companies Eisai and Pfizer. The aim of this public-private-partnership is to improve the care of dementia patients and the support of their informal care-givers.CD carried out the statistical procedures, interpretation of the data and wrote the manuscript. RH is principal statistical investigator, participated in the design of the study and gave advice concerning data analysis. EG is principal clinical investigator, participated in the design of the study and helped to draft the manuscript. PMe contributed to the data analysis by calculating cluster-effect adjusted measures. MGS carried out the data management and quality assurance of the data. JL planned and supervised the project and gave advice concerning structuring the manuscript. HM, PMa, SR planned and accompanied the research project and revised the manuscript. SW was the head of the local project team and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/314/prepub"}
{"text": "Rheumatoid arthritis (RA) is a chronic and disabling polyarthritic disease, which affects mainly women in middle and old age.            Proteus mirabilis microbes and RA. We propose that sub-clinical Proteus urinary tract infections are the main triggering factors and that the presence of molecular mimicry and cross-reactivity between these bacteria and RA-targeted tissue antigens assists in the perpetuation of the disease process through production of cytopathic auto-antibodies.Extensive evidence based on the results of various microbial, immunological and molecular studies from different parts of the world, shows that a strong link exists between             Proteus anti-bacterial measures involving the use of antibiotics, vegetarian diets and high intake of water and fruit juices such as cranberry juice in addition to the currently employed treatments.Patients with RA especially during the early stages of the disease could benefit from"}
{"text": "In this report from the 1st European Conference of the European Science Foundation Programme on Functional Genomics, we provide coverage of the high-profile plenarytalks and a cross-section of the many presentations in the disease analysis symposiaand functional genomics technologies workshops."}
{"text": "Successful anterior cruciate ligament reconstruction with a tendon graft necessitates solid healing of the tendon graft in the bone tunnel. Improvement of graft healing to bone is crucial for facilitating an early and aggressive rehabilitation and ensuring rapid return to pre-injury levels activity. Tendon graft healing in a bone tunnel requires bone ingrowth into the tendon. Indirect Sharpey fiber formation and direct fibrocartilage fixation confer different anchorage strength and interface properties at the tendon-bone interface. For enhancing tendon graft-to-bone healing, we introduce a strategy that includes the use of periosteum, hydrogel supplemented with periosteal progenitor cells and bone morphogenetic protein-2, and a periosteal progenitor cell sheet. Future studies include the use of cytokines, gene therapy, stem cells, platelet-rich plasma, and mechanical stress for tendon-to-bone healing. These strategies are currently under investigation, and will be applied in the clinical setting in the near future. One of the most challenging and important problems physicians are facing is the failure of anterior cruciate ligament (ACL) reconstruction after injury and primary surgical repair -4. It isACL reconstruction using semitendinosus and gracilis tendons has become popular in recent years. Tendon-to-bone incorporation of the tendon graft within a bone tunnel is a main concern when using a tendon graft for ligament reconstruction. Successful ACL reconstruction with a tendon graft requires solid healing of the tendon graft in the bone tunnel as soon as possible after surgery. Enhancing the healing of the tendon graft to the bone is crucial to facilitate an early and aggressive rehabilitation and a rapid return to full activity. The basic biology of the tendon graft-bone tunnel healing remains incompletely understood. Distinct variability occurred in the morphological characteristics of the healing at the site of attachment of the tendon and the bone. The tendon-to-bone healing in a bone tunnel occurs by bone ingrowth into the fibrovascular interface tissue that initially forms between the tendon and the bone. First, progressive mineralization of the interface tissue occurs. Subsequently, the bone grows into the outer tendon and the tendon graft becomes incorporated into the surrounding bone. Progressive re-establishment of the continuity of collagen fibers between the tendon and the bone results in restoration of a tendon-bone junction -16.The primary site of weakness during the early postoperative period is the tendon-bone interface, particularly while the tendon attaches to the bone within the intraarticular environment. The osteointegration of the tendon grafts used for the replacement of an ACL may still be unsatisfactory and may be associated with postoperative anterior-posterior laxity. The firm attachment of the tendon graft to the bone allows earlier and more aggressive rehabilitation and a quicker return to full activity.To improve the healing of the ACL graft, new strategies to promote the intra-articular and intraosseous healing are evolving. Although these strategies are currently under investigation, they are expected to be clinically applied in the near future. The strategies to improve the tendon-to-bone tunnel healing focus on providing appropriate molecular signaling thereby allowing cell differentiation which result in an effective healing response between the tendon and the bone. A sufficient population of stem cells is required for optimal tissue regeneration. The mesenchymal stem cell-treated grafts have cartilage at the tendon-bone interface -20. BoneThese various methods demonstrate the challenge of achieving a secure biologic fixation of the tendon graft in a bone tunnel with the current ACL reconstruction techniques.Our strategy to enhance the tendon-to-bone healing is to use the periosteum, hydrogel with periosteal progenitor cells (PPCs) and BMP-2 and PPC sheets.The periosteum consists of multipotent mesodermal cells. In addition, it contains chondroprogenitor and osteoprogenitor cells, which can form both cartilage and bone under appropriate conditions -37. The In the bone tunnel model, cross sections of the bone tunnel showed that the periosteal tissue formed a fibrovascular interface between the tendon and the bone. Due to the new bone formation, the cancellous bone in the bone tunnel interdigitated with the fibrous interface tissue four weeks after operation. There was progressive mineralization and maturation of the new bone that grew into the interface fibrous layer. There appeared to be excellent integration between the fibrous interface layer and the bone and between the tendon and the interface layer at eight weeks after operation. Progressive collagen fiber-bone anchoring, maturation and organization between the tendon and the bone lining cells occurred. In addition, fibrocartilage formed between the tendon and the bone .In the ACL reconstruction model, radiographs showed bone resorption as well as the formation of new bone around the femoral and tibial bone tunnel in the periosteum-treated tendon graft. There was further matrix deposition at the tendon-to-bone interface. Eight weeks after operation, the periosteum-enveloping specimens demonstrated cartilage and bone formation around the tendon graft in the femoral and tibial tunnel. There was extensive formation of new bone trabeculae and cartilage at the tendon-to-bone interface with new bone direct apposition to the tendon .The periosteum-treated tendon graft was used for ACL reconstruction to enhance the healing of the tendon graft in the bone tunnel. The graft was composed of double loops of semitendinosus and gracilis tendons. A periosteal flap was harvested from the anterior tibial cortex and divided into two flaps. The periosteum was wrapped with the cambium layer, placed outside to face the tunnel wall and then sutured on the tendon at both sides where the tendon graft approaches the tunnel opening Fig. 1)..1). In tPPCs have the potential to differentiate into osteogenitor and chondrogenitor cells in an adequate microenvironment. PPCs are used to enhance the tendon-to-bone healing process by forming a fibrocartilage interface. A novel injectable hydrogel supplemented with PPCs and BMP-2 was developed for an easier delivery into the bone tunnel.Photopolymerization allows for an impressive degree of spatial and temporal control with implications for diverse, minimally invasive applications for tissue regeneration. -50 PPCs Hyaluronic acid (HA) is applied for biomaterial fabrication and application to transduce intrinsic signals within a structure and to enhance tissue formation. In addition, it plays a crucial role in promoting cell differentiation and cell growth ,57. In oIn the bone tunnel model, we tested the feasibility of HA tethered to BMP-2 to stimulate PPCs to direct the fibrocartilagenous attachment and new bone formation in an extra-articular tendon-to-bone healing model. The PPC-BMP-2 hydrogel was injected and photogelated in the bone tunnel after placing the tendon graft into the bone tunnel. The histological analysis showed that interface fibrocartilage and new bone formed within six weeks. The healing of the tendon-to-bone interface underwent a gradual remodeling process. The biomechanical testing revealed a higher maximum pull-out strength and stiffness with a statistically significant difference. It appears that photoencapsulation of BMP-2 and PPCs has a powerful inductive ability for the healing between tendon and bone .In the ACL reconstruction model, the PPC-BMP-2 hydrogel was injected and photogelated in the femoral and tibial tunnel after ACL reconstruction with a flexor digitorum longus tendon in rabbits. Histological analysis of the tendon-to-bone interface in the femoral and tibial tunnel showed that an interface layer was formed by the hydrogel. After eight weeks, there was further matrix deposition with fibrocartilage formation at the tendon-to-bone junction. After 12 weeks, large areas of fibrocartilage at the tendon-to-bone junction formed an interface. The use of the PEGDA-based hydrogel provided an adequate matrix for the encapsulation of cells and signal factors. In addition, it was an effective local delivery method to reach the bone tunnel through injection. After the hydrogel is injected, it can be solidified via a photoinitiated polymerization process which ensures encapsulation of the stem cells and growth factors  Fig. 3)3).A scaffold-free method using polymerized fibrin-coated dishes to generate functional PPC sheets that can be used as periosteum-like tissue transplants was developed. Polymerized fibrin-coated polyethylene dishes were fabricated with fibrinogen monomers which were mixed with thrombin. PPCs derived from the periosteum of the tibia of rabbits were cultivated on a fibrin-coated surface. The laminated cell sheets were detached from the polymerized fibrin layer by proteases secreted from the cells. The PPC sheets were seeded onto the small intestinal submucosa (SIS) layer. The PPC sheets could be harvested non-invasively as intact, transplantable sheets by using an intrinsic protease. The PPC sheets were wrapped around the tendon grafts which were then used for ACL reconstruction in rabbits. There was further matrix deposition with formation of fibrocartilage at the tendon-to-bone junction after eight weeks. The bioengineered PPC sheets and SIS co-layer cell sheet act as artificial periosteum which offers a novel therapeutic strategy to augment the healing at the tendon-to-bone junction Fig. .Current techniques of ACL graft reconstruction require healing of a tendon graft in a bone tunnel. The attachment site of the graft to the bone differs from the human anatomy where ligaments attach to the surface of bone. There are no sites in the body where a tendon is surrounded by bone such as in a bone tunnel. A common cause for an unsatisfactory ACL reconstruction is a failure of the graft-to-bone healing. Three fundamental factors may be responsible for the lack of cell signaling and differentiation resulting in an ineffective healing response between the tendon and the bone. These factors include the presence of inflammation in the postnatal organism, tendon-to-bone interface motion and an insufficient number of undifferentiated cells at the healing tendon-to-bone interface.The successful ACL reconstruction with a tendon graft necessitates effective healing of the tendon graft in the femoral and tibial bone tunnel. The tendon-to-bone healing progresses via an interzone of vascular, highly cellular fibrous tissue, which undergoes a maturation process that lasts until its matrix consists of oriented collagen fibers and the fibrous interface becomes indistinctable. ,60 The tWhen a bone-patellar tendon-bone (BPTB) graft is used for ACL reconstruction, the fixation of the graft depends on the bone-to-bone healing. However, the length of the patella tendon portion of most BPTB grafts is greater than the intra-articular length of the ACL, resulting in tendon-to-bone healing  rather than bone-to-bone healing. It is believed that the graft fixation strength is lower and the healing is poorer in the tendon graft compared with the bone plug healing in the tunnel. In the tendon graft, the weakest site was the graft-wall interface at three weeks and the intraosseous tendon graft at six weeks .Spatial and temporal differences in the tendon-to-bone healing exist in the different regions of the bone tunnel. The healing of the tendon-to-bone interface tissue shows a wide chondroid matrix at the intra-articular aperture, in contrast to a narrow, fibrous matrix at the intra-osseous portion. The collagen continuity between the tendon graft and the bone tunnel increased over time, with a more parallel orientation and increased collagen fiber continuity between the tendon and the bone. Significant differences in the healing between the tendon graft and the bone exist throughout the length of bone tunnel. The etiology of these differences includes a variable biological and biomechanical environment at different sites of the tunnel.  AdequateOn the basis of a normal ACL structure and the known function of the insertion site, the ideal tendon graft would attach broadly to the surface of the bone at the site of the femur and tibia by an intermediate zone of fibrocartilage.The periosteum contains multipotent mesodermal cells. It has been shown that the environment has an influence on the differentiation of cells in free periosteal grafts . The perThe cambium layer serves as a fibrous layer between tendon and bone when the periosteum is sutured on the surface of the tendon and transplanted into a bone tunnel. The bone ingrowth into the cambium layer as well as the interdigitation between the periosteal tissue and tendon can be observed after four weeks. The interface of the fibrous layer, which originates from the wrapped periosteum, becomes progressively incorporated. The organization of the interface develops over time. There is an extensive formation of fibrocartilage at the tendon-bone interface. The periosteum has the powerful inductive ability to enhance the healing between the tendon and the bone tunnel. The periosteum can induce the differentiation of mononuclear cells into chondroblastic and osteoblastic cells. Subsequently, it directs the production of fibrocartilage or osteoid followed by mineralization and progressive remodeling which occurs during the healing process . The perThe expansion of the tunnel is significantly greater following ACL reconstruction using hamstring tendon autografts. This is because of the greater distance between the normal insertion site and the biomechanical point of action of the ACL. The greater distance creates a potentially larger force moment during graft cycling which may lead to the greater expansion of the bone tunnel . AdequatIn order to enhance the tendon-to-bone tunnel healing, our laboratory intended to develop an injectable hydrogel to fill the tendon-bone tunnel interface in a tissue-engineering approach. Tissue-engineering therapies for biomimetic material rely on the stimulation of signaling growth factors to induce cellular chemotaxis, proliferation, differentiation and a notable formation of new tissue at the required site. Recent studies have shown that various growth factors play important roles in tissue repair both in vivo and in vitro ,61,67-72Based on the finding that the tendon-to-bone healing progresses by bone ingrowth into the fibrous tissue interzone, exogenous osteoinductive agents should be used to augment this process. We demonstrated improved healing by applying injectable photopolymerizable hydrogel at the tendon-to-bone interface ,74. Our Cell therapy for tissue regeneration together with tissue engineering technology develops rapidly. Functional cell sheets for transplants are formed by cells. Biomaterials serve as cell carrier. The cell sheets can be easily detached and maintain the complete connective matrix in cells, cell phenotype, proliferation and differentiation. In our study, periosteum-like cell sheets were formed for orthopedic tissue regeneration. The PPCs and chondrocytes were used to produce periosteum-like cell sheets. The PPC carriers were prepared by polymerization of fibrinogen monomers mixed with thrombin. Natural acellular SIS was used as delivery vehicle for the cell sheets. The PPC sheets were placed onto a SIS layer thereby forming an artificial periosteal bilayer. The PPC sheets were wrapped around the tendon graft and placed into the bone tunnel. Histology showed higher matrix deposition with fibrocartilage formation at the tendon-bone junction after four weeks. Our results suggest that well-organized and functional PPC sheets maintain their differentiated capacity and keep their ex vivo osteochondral potential. The PPC sheets could act as periosteum to offer a novel approach to enhance the healing at the tendon-bone junction.Successful ACL reconstruction with a tendon graft requires solid healing of the tendon graft in the bone tunnel. Recent improvements in ACL reconstruction techniques have highlighted the importance of new biologic strategies to promote the intraarticular and intraosseous healing. Future techniques to improve the tendon-to-bone healing may include the use of cytokines, which will provide important signals for tissue formation and differentiation, gene therapy techniques, which will ensure the prolonged presence of molecules important for the healing process, stem cells, which will help produce a population of undifferentiated cells, and transcription factors, which will help direct nuclear gene expression. In addition, platelet-rich plasma or platelet gel from autologous blood facilitates delivery of serum-derived cytokines. Several techniques are being developed to inhibit the expression of molecules that might prohibit successful healing. Furthermore, modulation of the biomechanical environment may have profound effects on the cellular and molecular events at the healing tendon-bone interface . These bThe author declares that they have no competing interests.CHC prepared all the manuscript."}
{"text": "The optimal radical non-surgical management of carcinoma of the oesophagus has yet to be determined. The combination of high-dose radiotherapy with chemotherapy is being explored, particularly in North America. The MRC Upper GI Working Party has debated the areas where there is scientific uncertainty and which clinical trials may be appropriate to undertake in the UK."}
{"text": "We have studied the radiomodifying action in mouse skin of WR-2721 and misonidazole (MISO) when used alone or in combination. The radioprotection with WR-2721 was drug-dose dependent and highly influenced by the O2 concentration at the time of irradiation. Significant sensitizaton was observed with MISO, especially in air-breathing mice. The combination of WR-2721 and MISO produced a radiation response intermediate between the resistant and sensitive responses to either drug alone. The precise degree of sensitivity was dependent on the relative doses of protector and sensitizer. We have also studied the interaction of both drugs in terms of drug-induced lethality, which showed a clear toxic interaction. The WR-2721 LD50 was reduced by a factor of 1.4 with only 200 mg/kg of MISO. We conclude that the combination of WR-2721 and MISO shows an interaction in terms of drug toxicity and radiation response, such that the radioprotection of skin is reduced or even abolished with low doses of MISO."}
{"text": "Leukaemia cells from the peripheral blood and bone marrow of patients with acute myeloblastic leukaemia were labelled in vitro with [125I]5-iodo-2'-deoxy-uridine (IUdR). The myeloblasts were then injected into groups of mice and the survival of these cells estimated by measuring isotope loss, using whole-body counting. The isotope excretion from mice treated with various doses of cytosine arabinoside (Ara-C) and those not treated with drugs were compared. This comparison showed that the sensitivity of myeloblasts to the drug varies from patient to patient, and in one case was different for myeloblasts from bone marrow and from blood from the same patient. We compare the clinical responses of myeloblasts to Ara-C in 6 patients, who had high peripheral blood myeloblast counts, with the sensitivities of their myeloblasts to Ara-C in mice. This comparison indicates that the assay might be a useful way of predicting the response of leukaemic cells in patients to cytotoxic agents."}
{"text": "Stroke-specific outcome measures and descriptive measures of health-related quality of life (HRQoL) are unsuitable for informing decision-makers of the broader consequences of increasing or decreasing funding for stroke interventions. The quality-adjusted life year (QALY) provides a common metric for comparing interventions over multiple dimensions of HRQoL and mortality differentials. There are, however, many circumstances when \u2013 because of timing, lack of foresight or cost considerations \u2013 only stroke-specific or descriptive measures of health status are available and some indirect means of obtaining QALY-weights becomes necessary. In such circumstances, the use of regression-based transformations or mappings can circumvent the failure to elicit QALY-weights by allowing predicted weights to proxy for observed weights. This regression-based approach has been dubbed 'Transfer to Utility' (TTU) regression. The purpose of the present study is to demonstrate the feasibility and value of TTU regression in stroke by deriving transformations or mappings from stroke-specific and generic but descriptive measures of health status to a generic preference-based measure of HRQoL in a sample of Australians with a diagnosis of acute stroke. Findings will quantify the additional error associated with the use of condition-specific to generic transformations in stroke.We used TTU regression to derive empirical transformations from three commonly used descriptive measures of health status for stroke  to a preference-based measure (AQoL) suitable for attaching QALY-weights to stroke disease states; based on 2570 observations drawn from a sample of 859 patients with stroke.Transformations from the SF-36 to the AQoL explained up to 71.5% of variation in observed AQoL scores. Differences between mean predicted and mean observed AQoL scores from the 'severity-specific' item- and subscale-based SF-36 algorithms and from the 'moderate to severe' index- and item-based Barthel algorithm were neither clinically nor statistically significant when 'low severity' SF-36 transformations were used to predict AQoL scores for patients in the NIHSS = 0 and NIHSS = 1\u20135 subgroups and when 'moderate to severe severity' transformations were used to predict AQoL scores for patients in the NIHSS \u2265 6 subgroup. In contrast, the difference between mean predicted and mean observed AQoL scores from the NIHSS algorithms and from the 'low severity' Barthel algorithms reached levels that could mask minimally important differences on the AQoL scale.While our NIHSS to AQoL transformations proved unsuitable for most applications, our findings demonstrate that stroke-relevant outcome measures such as the SF-36 and Barthel Index can be adequately transformed to preference-based measures for the purposes of economic evaluation. The economic evaluation of health programs is often and increasingly a prerequisite in obtaining funding from third-party payers seeking to get the best value from a limited health budget. Where treatment is expected to impact on health-related quality of life (HRQoL), selecting an appropriate outcome measure frequently entails a trade-off between the sensitivity of available instruments for the disease or condition under study and the comparability (and therefore policy-relevance) of study results. Leaving aside the question of whether disease-specific outcome measures really are more sensitive than more generic measures, a number of difficulties arise in selecting a comparable outcome measure for use in economic evaluation.While the minimal clinically significant improvement on a descriptive measure such as the SF-36, NIHSS or Barthel could be used to partition the trial population into responders and non-responders before expressing findings in terms of cost per additional responder, such an approach would not achieve comparability of findings even in the event that every other evaluation was also to express results in terms of responders. Because descriptive measures lack weak interval properties, there is no guarantee that a 10 point improvement at the upper end of the scale is equivalent to a 10 point improvement at the lower end of the scale. The weak interval property simply requires that a given numerical change along a scale should have the same meaning regardless of the direction and location of that change  put it, and relevant dimensions of HRQoL. Richardson .We identify the 'correct' specification within each class of algorithm using standard diagnostic tests. Following Harvey , the 'coWith regards to (i), the higher the strength of association, the better the algorithm is able to predict variation along the scale. Note, however, that \"two measures can be perfectly correlated but have poor agreement\" . at the group level is all that is required. For the purposes of evaluating precision at the group level in the present study, we split the study sample into three sub-groups defined by stroke severity on the NIHSS . While (iii) is the most relevant test of predictive validity in measuring group-level treatment effects and health-state utilities, we report findings on all three criteria to provide a more complete evaluation of the strengths and weaknesses of our transformations. We conducted the analyses reported here using SPSS 15.0 for Windows ; in children with stroke.Finally, it should be emphasised that the models estimated in the present study are not intended for application in non-stroke populations. The weight attached to each item, subscale or scale entering each of our conversion algorithms reflects the covariance in our data between AQoL health states and Barthel, NIHSS or SF-36 health states. Because this covariance is likely to be quite different in stroke than in other disease-areas or the general population, our conversion algorithms may not be applicable to non-stroke populations. More generally, our findings are contingent upon the characteristics of our study population and on the coverage and sensitivity of the descriptive and preference-based measures used to generate our conversion algorithms. Note, for example, that our findings regarding the feasibility and value of TTU regression in stroke-specific outcome measures might not be generalisable to all condition-specific measures in all disease-areas. Likewise, where transformations have been derived and validated in a sample of stroke-patients with mean age exceeding 70 years, those transformations cannot be assumed valid for the purposes of predicting QALY-weights Despite these limitations, the conversion algorithms reported here represent an improvement on the regression-based conversion algorithms that have previously been validated for use in stroke ,28. MoreOur findings suggest that TTU regression can provide a useful second-best approach for deriving QALY-weights associated with stroke disease-states. While the NIHSS to AQoL transformations proved unsuitable for most applications, transformations from the SF-36 and Barthel to the AQoL provided sufficient predictive power to suggest that stroke-relevant outcomes can be transformed to preference-based measures for the purposes of economic evaluation. While a number of generic to generic transformations from the SF-36 to preference-based outcome measures are now available, the SF-36 to AQoL transformations reported here are the only published transformations to have been derived and validated in a sample of stroke patients . MoreoveThe implications for practice are two-fold. First, it is anticipated that our transformations will prove to be a valuable tool for analysts and should allow the best use to be made of the available data; improving the quality and policy-relevance of economic evaluations for stroke interventions. Second, improvements in the economic evaluation of stroke interventions should allow clinicians and policy-makers to make better decisions; potentially saving money and improving patient outcomes. Our findings also have a number of implications for research. First, researchers may wish to take account of the feasibility of TTU regression in certain condition-specific measures (but not in others) when selecting descriptive outcome measures for inclusion in clinical trials. Such considerations will be particularly important where resource constraints or patient burden preclude the direct observation of preference-based measures in the trial population. Second, researchers attempting to derive their own regression-based transformations for other descriptive measures should take particular note of the improvements in predictive validity that we were able to obtain by deriving separate transformations for clinically distinct subgroups of patients. Finally, our findings suggest that validity in predicting group-wise differences will not always translate to validity in predicting health state utilities or change scores for individual patients. Researchers responsible for the derivation of regression-based transformations might therefore wish to provide guidelines for end-users to ensure use consistent with validation data.The authors declare that they have no competing interestsDM participated in the design of the study, data analysis and interpretation of results, and drafted the manuscript. LS participated in the design of the study and interpretation of results, and suggested edits and revisions to the manuscript. JS contributed to the acquisition and interpretation of the data, participated in the interpretation of results, and suggested edits and revisions to the manuscript. All authors read and approved the final manuscript."}
{"text": "Chinese hamster ovary cells have been treated in vitro with the platinum coordination complexes cis-PAD or CHIP and with radiation, either alone or in combination with different doses and time intervals. The isobologram method has been used to make a graphic comparison of these combined-modality data in terms of additivity and enhancement. The data showed enhancement of the radiation effect by these platinum complexes in many combinations, and a truly synergistic effect in one case. This method of analysis points to the limited usefulness of the parameter dose-modifying effect (DMF) since the most synergistic combination did not have the highest DMF."}
{"text": "We have measured mitotic indices and 3H-thymidine-labelling indices for the colonic epithelial tumours induced in rats by the administration of dimethyl-hydrazine (DMH). The fraction-of-labelled-mitoses (FLM) technique has been used to estimate the duration of the cell-cycle phases. In general, mitotic and labelling indices in the tumours are similar to those in the proliferation zone of the normal crypt epithelium; lesions considered to be least well differentiated on histological grounds appear to have the lowest mean labelling index. Benign tumours and the different types of malignant tumours have mean cell-cycle times about half those of the normal mucosa."}
{"text": "Recent studies have suggested a correlation between the rate and incidence of apoptosis and the radiation response of particular cell lines. However, we found that increasing the rate of induction of apoptosis in the fibroblast line 208F, by transfecting it with human c-myc, did not lead to a change in its clonogenic survival dose-response for either gamma-irradiation or 125I-induced DNA damage. It was also found that expression of mutant (T24) Ha-ras in the 208F line appeared to decrease the level of apoptosis per mitosis after irradiation and inhibited the formation of nucleosomal ladders, but did not affect either the onset of the morphological features of apoptosis or the clonogenic survival dose-response of the cells to either gamma-irradiation or 125I-induced DNA damage. Our findings suggest that it may be incorrect to make predictions about the radiosensitivity of cells based only on knowledge of their mode of death."}
{"text": "PG hydrolyses thehomogalacturonan of the plant cell wall and is considered an important pathogenicityfactor of many fungi. PGIP is a specific inhibitor of fungal PGs and is thought to beinvolved in plant defence against phytopathogenic fungi. SPR was used either to study theeffect of the PG glycosylation on the formation of the complex with PGIP, and as asensitive affinity capture of an interacting peptide from a mixture of PG fragmentsobtained by limited proteolysis. Mass spectrometry allowed to characterise the interactingpeptide eluted from the sensor surface.A combination of surface plasmon resonance (SPR) and matrix-assisted laser-desorptionionization-time-of-flight mass spectrometry (MALDI-TOF-MS) was used to study theinteraction between"}
{"text": "We would like to report on our experience of illustrating our operation notes with pre-, per- and post-operative digitalimages."}
{"text": "The administration of a single bolus of anti-IgM antibody to foetal lambs early in pregnancy produces prolonged B-cell depletion. The present study investigated this depletion by examining the effect, on B-cell development in the ileal Peyer's patches, of varying the timing and dosage of antibody administration and by supplementing anti-IgM with surgical splenectomy. The capacity of a 1 mg bolus of anti-IgM to deplete Peyer's patches of B cells was lost if its administration was deferred until two thirds of the way through pregnancy, but persisted beyond this time if weight-adjusted doses were used. Splenectomy of the foetus performed at an earlier age failed to extend the age at which a 1 mg dose of antibody remained effective. As the concentration of murine immunoglobulin in foetal serum was greatly reduced after 21 days, it is inferred that ongoing suppression of B-cell development is not dependent on the continued presence of murine immunoglobulin. The enduring nature of suppression could be attributable to a limited period during which differentiation of B cells from stem cells normally occurs, although further studies will be needed to investigate this and other possible explanations for the effect of anti-IgM treatment on prenatal B-cell development in sheep."}
{"text": "We have developed a computer-implemented, multivariate Markov chain model to project tuberculosis (TB) incidence in the United States from 1980 to 2010 in disaggregated demographic groups. Uncertainty in model parameters and in the projections is represented by fuzzy numbers. Projections are made under the assumption that current TB control measures will remain unchanged for the projection period. The projections of the model demonstrate an intermediate increase in national TB incidence  followed by continuing decline. The rate of decline depends strongly on geographic, racial, and ethnic characteristics. The model predicts that the rate of decline in the number of cases among Hispanics will be slower than among white non-Hispanics and black non-Hispanics a prediction supported by the most recent data."}
{"text": "The recent development and publication of evidence-based clinical practice guidelines (CPGs) for acute low back pain (LBP) has resulted in evidence-based recommendations that, if implemented, have the potential to improve the quality and safety of care for acute LBP. While a strategy has been specified for dissemination of the CPG for acute LBP in Australia, there is no accompanying plan for active implementation. Evidence regarding the cost-effectiveness of active implementation of CPGs for acute LBP is sparse. The IMPLEMENT study will consider the incremental benefits and costs of progressing beyond development and dissemination to implementation.Cost-effectiveness and cost-utility analyses alongside the IMPLEMENT cluster randomised controlled trial (CRCT) from a societal perspective to quantify the additional costs (savings) and health gains associated with a targeted implementation strategy as compared with access to the CPG via dissemination only.The protocol provided here registers our intent to conduct an economic evaluation alongside the IMPLEMENT study, facilitates peer-review of proposed methods and provides a transparent statement of planned analyses.Australian New Zealand Clinical Trials Registry ACTRN012606000098538 The recent development and publication of evidence-based clinical practice guidelines (CPGs) for acute low back pain (LBP) has resulted in evidence-based recommendations that, if implemented, have the potential to improve the quality and safety of care for acute LBP . While aThe purpose of the present paper is to describe methods for the cost-effectiveness analysis alongside the CRCT. Detailed descriptions of methods for development of the targeted implementation strategy and design of the CRCT in the IMPLEMENT study are given elsewhere .It is now well established that development and dissemination of CPGs will not necessarily produce improvements in clinical practice . Clinicaet al. [Despite this imperative, a recent review of 63 economic evaluations and cost analyses conducted alongside rigorous experimental studies of guideline implementation strategies published between 1966 and 1998 concluded that the available economic evidence was lacking in methodological rigour and often drew conclusions that 'must clearly be treated with suspicion' . A signiet al. . The actet al. [et al. conclude that 'it is very likely that the extended implementation strategy incurs extra costs without producing health gains, hence it is very likely to be not cost-effective' [Hoeijenbos et al.  calculatfective' . While cet al. [While the principles of economic evaluation for health care interventions are now well-established, the literature provides relatively few examples of well-executed economic evaluations of implementation strategies and the characteristics of CPGs raise several issues in the estimation and interpretation of cost-effectiveness ,12. The et al.  suggest The costs of guideline development may be substantial and that development and dissemination alone might have relatively little impact on practice patterns . Compariet al. [The second issue concerns the potential for repeated use of various components of the evaluated intervention. The information embedded in a CPG and an implementation strategy is 'non-rival' such that a single use does not diminish the quantity or quality of information available for subsequent use. The development of a CPG therefore amounts to a one-time investment that may find a repeated use in other populations, in subsequent cohorts of practitioners, or in other contexts. Likewise, an implementation strategy may find repeated use in other populations/contexts, in subsequent cohorts, or perhaps even for implementation of another CPG in another disease-area. Drummond et al.  note theet al. [A number of recent findings suggest that cost-effectiveness studies in the public domain may represent a biased sample of the population of economic evaluations ,15. It iet al.  suggest e.g., lower the 'response' required to be classified as a 'responder'), extend the time-horizon  and/or revise the unit cost attached to particular categories of resource use  [Published trial protocols typically include a section headed 'economic analyses' when such analyses are planned, but the description of methods is often insufficiently detailed to achieve the purpose of a protocol. Without detail, it is not possible to distinguish planned analyses from post-hoc 'mining' or 'gaming' and analysts can freely substitute between outcomes (at zero) . Each ofThe impact of moves to improve transparency and rigour in the conduct of modelled and trial-based evaluations will vary depending on the extent of discretion exercised by sponsors over research methods and dissemination of findings, the complexity of the disease-process, and the extent to which evidence gaps necessitate a reliance on assumption and/or lower level evidence . For impThe IMPLEMENT study is a CRCT, with the clusters being a sample of 92 general practices of one or more GPs drawn from a sampling frame of 1,000 general practices within the state of Victoria, Australia. Participating practices will be randomised to either a control group or an intervention group. Enrolling an average of 25 patients per practice will yield 2,300 patients for inclusion in intention-to-treat analyses. A detailed description of the design of the CRCT and of proposed methods for sample selection, randomisation, and analysis of clinical outcomes are provided elsewhere [i.e., whether implementing CPG for acute LBP is cost-saving as compared with dissemination alone), and to determine whether the implementation strategy dominates dissemination alone . The time horizon for inclusion of relevant costs and consequences is set at three months, consistent with the final scheduled follow-up of patients from the CRCT. That is to say, the economic evaluation is explicitly 'within-trial' and any subsequent extrapolation beyond the trial period will be treated as a separate research task.Cost-effectiveness and cost-utility analyses will be conducted alongside the CRCT to quantify the additional costs (savings) and health gains associated with the implementation strategy as compared with dissemination alone from a societal perspective. Specific secondary aims will be to determine whether the incremental costs of the implementation strategy are outweighed by incremental cost-savings associated with any change in practice  of Australia endorsed a CPG for acute LBP . There iIn addition to access via the existing dissemination strategy, the intervention group will receive active implementation of the CPG for acute LBP. The GPs randomised to the intervention arm will receive an implementation strategy specifically designed to address the barriers and enablers for implementation of the CPG. The intervention will concentrate on delivering the CPG's key messages, namely that diagnostic x-rays are rarely necessary in the management of acute LBP and that remaining active reduces pain and disability. The intervention will consist of a series of facilitated face-to-face small group workshops. These workshops will involve a combination of didactic lectures and small group interaction. The delivery of the intervention will be co-ordinated by a project officer and delivered by members of the research team and external facilitators.The program logic of the evaluated intervention and the symptomatology of acute LBP suggest that specific dimensions of HRQoL, such as pain-related disability, physical function, and physical pain are most relevant in capturing variation in health outcomes. However, it is possible that a differential effect might arise between the evaluated intervention and the comparator with respect to dimensions of HRQoL other than physical disability or physical pain. The outcome measures specified below will therefore provide broad coverage of HRQoL.The measures chosen to assess patient outcome are commonly used in trials of interventions for acute LBP and provide broad coverage of HRQoL, including those dimensions of HRQoL that are most likely to be relevant in identifying an effect attributable to the intervention.The RDQ is among the most widely used and well-validated measures of LBP-specific disability. The RDQ has high validity and reliability for use over the telephone and is recommended for inclusion in core sets of measures used in LBP . The RDQAn 11-point scale (0 = no pain to 10 = worst pain ever) has acceptable reliability and validity for self-reported assessment of pain .The AQoL can be used as either a psychometric instrument, yielding a descriptive measure of HRQoL, or a multi-attribute utility instrument that yields a preference-based measure of HRQoL. The AQoL descriptive system includes five latent dimensions with each dimension reflected in three items: illness , independent living , social relationships , physical senses  and psychological well-being . Four of the five dimensions and 12 of the 15 items contribute to the AQoL's preference-based measure of HRQoL, with the illness dimension excluded because it was deemed indicative of an underlying health condition rather than the impact of that health condition on HRQoL . The AQoFollow-up of patient level outcomes is scheduled for seven days and three months after their initial GP consultation for acute non-specific LBP. Table While the patient level outcomes described above are expected to capture all relevant dimensions of health outcome, there are a number of advantages in expressing the results of cost-effectiveness analyses in cost per quality adjusted life year (QALY) terms. Between-group differences in preference-based HRQoL weights derived from the AQoL will be combined with the period of time over which such differences persist to calculate effectiveness in QALY terms. Intervention effects with respect to AQoL scores will be estimated using methods specified for the main analysis of patient level clinical outcome measures, controlling for the same set of pre-specified set of potential confounders . In the et al. note that some costs may simply confirm a result that would be obtained by consideration of a narrower range of costs [Incremental costs will reflect all resource use associated with development of the implementation strategy, delivery of the implementation strategy, and any subsequent changes in practice and subsequent health effects. All research and evaluation costs will be excluded from the cost analysis. Two questions arise in specifying the minimum dataset for the cost analysis. First, can any cost items be excluded from the base-case analysis without biasing our estimate of incremental costs? And, second, for which included costs should we directly collect data from either GPs or patients? Drummond of costs . Volunteet al. note the importance of identifying capital outlays that should be amortised over the lifetime of the asset [Cost items associated with development of the implementation strategy include the cost of recruiting informants to assist development of the intervention, the cost of time in focus groups for informants and facilitators, the opportunity cost of interview and meeting rooms, the cost of time and equipment for analysis and interpretation of focus group data, and the cost of consultation with the GP advisory committee. Drummond he asset . CertainCost items associated with delivery of the implementation strategy include administrative costs associated with coordinating small group workshops, production of materials for workshops, the opportunity cost of venue use, the opportunity cost of travel time, and attendance at workshops for GPs, opportunity cost of pre- and post-workshop reflection for GPs, and labour costs associated with preparation/delivery/facilitation of workshops.Cost items associated with change in clinical practice include direct and indirect health care costs, such as use of x-rays, over-the-counter or prescription analgesics, allied health or GP consults, and the time of volunteer or paid caregivers. Practice change is also expected to impact on direct and indirect costs outside the health sector, including waiting time and travel time to attend treatment, productivity gains due to a change in specific disability, and time lost from work associated with treatment.In measuring resource use associated with development of the implementation strategy, delivery of the implementation strategy, and any subsequent changes in practice and subsequent health effects, data will be collected from the research team, from the enrolled practitioners and from the enrolled patients. Scheduled observations on resource use are listed in Table Resource use associated with the development of the implementation strategy will be costed based on financial and administrative records, as well as a detailed description of the development process obtained from the project manager and project officers. This will require recall over a relatively short period of time as to proportion of an equivalent full-time salary that project staff spent in development of the implementation strategy . Administrative and financial records will provide data as to the number of informants, total person hours spent in focus groups and interviews for informants and facilitators, use of interview and meeting rooms, total person time for analysis/interpretation of findings, and total person hours for advisory committee members.Resource use associated with the delivery of the implementation strategy will be estimated from administrative and financial records detailing resource use associated with the production of materials, total person hours spent in organising and facilitating workshops, total hours GP attendance, venue location and total hours venue hire, and practice location for attending GPs. Time spent by GPs in pre- and post-workshop reflection or self-education will be estimated based on a description of the intervention (rather than self-report) and varied in sensitivity analysis.Resource use associated with a change in clinical practice and subsequent health effects will be based on patient self-report. While GPs may be in a position to report the percentage of LBP patients referred for x-ray, patients' use of allied health care and their use of over-the-counter analgesics cannot be obtained from enrolled practitioners. It is well-known that patient self-report becomes increasingly unreliable as the period of recall increases. \"For example, one study found that 10% of patients failed to report that they had been hospitalized when they were interviewed approximately five months after discharge. Even if subjects remember that they have seen a physician or have gone to a hospital, they often will not know what services they received .\" For loUnit costs for health service resource use will be as per the Manual of Resource Items for use in submissions to the Commonwealth of Australia's Pharmaceutical Benefits Advisory Committee . Resource.g., average wage rates, cost of services such as childcare or cleaning services required to replace role of homemaker) is frequently used to value the unpaid work of retirees, homemakers, and the unemployed. For example, the Bureau of Transport Economics [Production losses are most frequently valued via the human capital approach, whereby the actual gross earnings of those in paid employment are used to estimate the value of time absent from work due to treatment or illness . Note, hconomics  estimateconomics  and averconomics , and theconomics .et al. employed a friction cost approach to the estimation of productivity gains/losses in their study of guideline implementation for non-specific LBP [Due to the relatively short duration for an episode of acute non-specific LBP and the relatively short duration of follow-up, the difference between human capital and friction cost  estimateific LBP , productAll costs will be inflated to current Australian dollars for the year of study completion. While costs and benefits associated with delivery of the implementation strategy and any subsequent within-trial changes in practice are expected to accrue within a 12 month period, costs associated with development of the implementation strategy are expected to accrue up to 24 months prior to costs associated with delivery of the implementation strategy and any subsequent within-trial changes in practice. All costs and benefits will be converted to present values using an annual discount rate of 5% in the base-case, and annual rates of 3% and 7% in sensitivity analysis.Results from the economic evaluation will be expressed as: additional costs (savings) per point difference in RDQ at seven days and three months; additional costs (savings) per point difference in usual pain at seven days and three months; and additional costs (savings) per QALY gained.Cost-effectiveness acceptability curves (CEACs) will be used to quantify and visualise sampling and parameter uncertainty. The CEAC is derived from the joint density or joint distribution of incremental costs (\u0394C) and incremental effects (\u0394E) for the intervention of interest against a comparator, and represents the proportion of the density where the intervention is cost-effective for a range of willingness to pay thresholds (\u03bb). The joint density will be obtained via non-parametric bootstrapping from the distribution of observed cost/effect pairs. Because the base-case analysis will include all cost items listed above, a separate CEAC will be calculated using best estimate and upper/lower bound estimates for travel time, time of volunteer caregivers, productivity gains and for other uncertain parameters such as the discount rate. Sensitivity analysis on the CEAC will also adjust estimates of incremental costs and incremental benefits for practice characteristics and patient characteristics to consider the external validity of study findings.Publication and peer-review of protocols for economic evaluation is advisable for much the same reasons as has been advocated elsewhere for trial protocols . PublicaEthical approval for this trial was obtained from the Monash University Standing Committee on Ethics in Research involving Humans (2006/047).Sally Green is a member of the editorial board of Implementation Science. The remaining authors declare that they have no competing interests.DM participated in the design of the trial-based economic evaluation and drafted the protocol. SF, JM, DO'C and SG participated in the design of the trial-based economic evaluation and suggested edits and revisions to the protocol. All authors read and approved the final manuscript."}
{"text": "Changes in the immune competence and levels of suppressore elements were assessed by mitogen stimulation and in vitro antibody production, after resection of a transplantable sarcoma. Spleen cells from tumour-resected animals were found to have depressed responses to conA as well as to the antigens SRBC and DNP-LPS. This inability to respond was gradually overcome and, by Day 21 after resection, spleen cell competence had returned to normal levels. Suppressor cells isolated from the spleens of tumour-resected animals were capable of suppressing the conA response and PFC response of normal syngeneic spleen cells in vitro. The ability to suppress the conA response of normal cells disappeared by Day 1 after resection, while the ability to suppress the anti-SRBC and anti-DNP PFC response of normal cells disappeared by Day 8 and Day 14 respectively. Serum from tumour-resected mice was also found to be suppressive to the conA response of normal spleen cells. The inhibitory material responsible for suppression eluted with the Ig-containing fraction on Sephadex G-150. This inhibitory material gradually disappeared from the serum of tumour-resected mice and was no longer apparent by Day 14. Therefore, it appeared that the return of normal lymphocyte function after tumour-resection was concomitant with the disappearance of splenic suppressor cells and suppressive serum factor."}
{"text": "An overview is presented of the different aspects of the role ofanalytical chemistry in process monitoring and control. On-linemonitoring is currently the most attractive option in this area,especially with unsegmented-flow techniques. In addition toallowing automation of these systems, the variety of ways in whichcalibration and recalibration can be performed allows theiradaptation to any situation by using extremely simple, home-mademanifolds. The most relevant designs are presented and criticallydiscussed in this paper."}
{"text": "A method is presented for the description of a heterogeneous cell population with respect to the volume and density of its cellular components, based on computer analysis of the cell-volume spectra of density-gradient fractions. Display programmes were developed to produce either a perspective plot or an isofrequency contour plot (\"fingerprint\") of the two-parameter data. The use of sequential density and velocity gradients permitted the separation and study of the properties of any subpopulation. We describe the results of an analysis of cellular heterogeneity in an ovarian carcinoma cell line and in 2 cases of ascites cells from human ovarian carcinoma. The proliferative state (labelling index) and growth potential (culture clonogenicity) of cells from one malignant ascites have been \"mapped\" in terms of density/volume parameters. The results are discussed in terms of their impact on the view of human ovarian carcinoma as a stem-cell system."}
{"text": "Photoradiation therapy of cancer in the presence of haematoporphyrin derivative is based on a retention of porphyrin in malignant tissue. After long term incubation of NHIK 3025 cells in the presence of 25 microgram ml-1 haematoporphyrin derivative, one fraction is easily removed from the cells by washing with a serum-rich medium. Another fraction remains bound to the cells for a prolonged time. The former does not contribute to the photosensitivity of the cells while the latter, the tightly-bound component, results in a photosensitivity proportional to the cellular contents of porphyrin. Transformed cells are shown to be slightly more sensitive and to retain 25-50% more haematoporphyrin derivative than non-transformed cells. Cytological effects of light absorbed by the tightly-bound component have been studied. The growth of treated cells is similar to that of control cells after a dose-dependent post irradiation lag period. A relatively slow leakage of lactate dehydrogenase (LDH) out of the cells takes place after treatment. The treatment induces a significant increase in the frequency of sister chromatid exchanges (SCE). We conclude that photoactivation of the tightly-bound fraction of haematoporphyrin derivative induces less damage to the outer cell membrane and probably more intracellular damage than irradiation of cells after a short period in contact with the derivative."}
{"text": "Tumour blood flow was characterised in a 'tissue-isolated' rat tumour model, in which the vascular supply is derived from a single artery and vein. Tumours were perfused in situ and blood flow was calculated from simultaneous measurement of (1) venous outflow from the tumour and (2) uptake into the tumour of radiolabelled iodo-antipyrine (IAP). Comparison of results from the two measurements enabled assessment of the amount of blood 'shunted' through the tumours with minimal exchange between blood and tissue. Kinetics of IAP uptake were also used to determine the apparent volume of distribution (VDapp) for the tracer and the equilibrium tissue-blood partition coefficient (lambda). lambda was also measured by in vitro techniques and checks were made for binding and metabolism of IAP using high-pressure liquid chromatography. VDapp and lambda were used to calculate the perfused fraction  of the tumours. Tumour blood flow, as measured by IAP (TBFIAP), was 94.8 +/- 4.4% of the blood flow as measured by venous outflow, indicating only a small amount of non-exchanging flow. This level of shunting is lower than some previous estimates in which the percentage tumour entrapment of microspheres was used. The unperfused fraction ranged from 0 to 20% of the tumour volume in the majority of tumours. This could be due to tumour necrosis and/or acutely ischaemic tumour regions. For practical purposes, measurement of the total venous outflow of tumours is a reasonable measure of exchangeable tumour blood flow in this system and allows for on-line measurements. Tracer methods can be used to obtain additional information on the distribution of blood flow within tumours."}
{"text": "The novel fluorinated 2-nitroimidazole SR-4554 is undergoing preclinical development as a magnetic resonance spectroscopy and imaging probe for hypoxic tumour cells. We have used electron energy loss spectroscopic analysis (EELS) to show selective reduction and differential subcellular localisation of SR-4554 in human ovarian multicellular spheroids. SR-4554 was demonstrated to be metabolised by these A2780 cells under hypoxic but not under normal aerobic cell culture conditions. The EELS technique illustrated that the relative amount of drug within the cytoplasm of cells from both the inner region (150-160 microns from edge) and outer edge of the spheroid did not differ significantly after an initial 3 h incubation with drug. In contrast, an 8-fold differential between the amount of drug retained in the cytoplasm (primarily ribosomes and endoplasmic reticulum) of cells from the inner vs outer regions of the spheroids was observed following a subsequent 2 h 'chase' culture in drug-free medium. Within cells from the hypoxic region of the spheroid, SR-4554 was mainly associated with the endoplasmic reticulum, nucleus and the cytoplasmic side of intracellular vesicles and also to a lesser extent with the nuclear periphery. Interestingly, the drug was only weakly associated with the mitochondria and plasma membrane of the cells. The characteristics of cellular and subcellular distribution of SR-4554 are consistent with the hypothesis that 2-nitroimidazole compounds undergo hypoxia-mediated enzymatic reduction to reactive species. These reactive species are selectively retained in the cells in which they are metabolised through covalent association with subcellular components. These findings provide additional support for the clinical development of the drug as a non-invasive probe for tumour hypoxia and at the same time illustrate the utility of the EELS technique for examining the heterogeneity of drug distribution both between and within cells."}
{"text": "Vector-borne diseases for which transmission occurs exclusively between vectors and hosts can be modeled as spreading on a bipartite network.Ixodes ricinus ticks on mice and lizards from two independent studies are well described by a scale-free distribution compatible with an asymptotically vanishing epidemic threshold. The commonly used negative binomial, instead, cannot describe the right tail of the empirical distribution.In such models the spreading of the disease strongly depends on the degree distribution of the two classes of nodes. It is sufficient for one of the classes to have a scale-free degree distribution with a slow enough decay for the network to have asymptotically vanishing epidemic threshold. Data on the distribution of The extreme aggregation of vectors on hosts, described by the power-law decay of the degree distribution, makes the epidemic threshold decrease with the size of the network and vanish asymptotically. Many natural, social and technological systems can be described in terms of self-organized networks of interacting entities. These networks often display topological properties, such as scale-free degree distributions, community structure and small-world phenomenon, which set them apart from simpler networks such as lattices and random networks see e.g. .In particular, the spreading of a transmissible disease can be studied by modeling the population as a network of individuals, in which an edge is placed between two individuals if there is the possibility of transmission between them. It was shown In some cases of practical interest modeling the propagation of the disease requires the introduction of a bipartite network In this work we introduce another context in which bipartite networks provide the natural framework to study epidemic spreading, namely those vector-borne diseases in which transmission occurs exclusively between vectors and hosts. The aim of this study is twofold: first, we show that the analysis of bipartite networks performed in Ixodes ricinus on their hosts. These ticks can transmit the pathogens responsible for Lyme disease (Borrelia burgdorferi) and the tick-borne encephalitis (TBE) virus  to have a scale-free distribution of contacts  To determine the degree distribution of the bipartite network we analyzed field data on the distribution of the number of ticks (nymphs and larvae) found on hosts (mice and lizards), represented in the model by the degree distribution of host nodes. Exhaustive empirical surveys have shown that macroparasites, and in particular ticks, are aggregated across host populations. This aggregative behavior has important implications for the population and evolutionary dynamics of the parasite and its host right tail of the distribution better than the commonly used negative binomial distribution in both empirical datasets. The power-law distribution is compatible with both datasets , B. burgdoferiApodemus spp. and Podarcis spp. The animals were infested only by immature ticks Ixodes ricinus. The number of mice and lizards examined are reported in The \u201cTuscany\u201d dataset contains infestation data from field work conducted in a natural reserve in Le Cerbaie hills, Pisa province, central Italy. This area is characterized by Mediterranean vegetation, an optimal habitat for ticks and their hosts The \u201cSlovakia\u201d dataset refers to the distribution of larvae and nymphs on mice, obtained from The power-lawThe goodness-of-fit tests were based on the empirical distributions of the Kolmogorov-Smirnov statistic obtained by Monte Carlo methods as explained in"}
{"text": "Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold does suitable for use of multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed."}
{"text": "The construction of a microcomputer-controlled electrode switch foruse in potentiometric determinations is described. This can be coupled to most of the analytical equipment usually found in laboratories, to enable a setting up of automatic systems capable of performing sequential determinations with several ion-selectiveelectrodes. The assessment of its analytical usage and behaviour are discussed."}
{"text": "Prostatic intraepithelial neoplasia (PIN) has been considered as a precursor of prostatic cancer. Few reports have dealt with the long-term follow-up of PIN lesions, and there is still a lack of proof that PIN is a true premalignant lesion. The objective of this study was to evaluate PIN in the transition/central zone as a marker for subsequent development of prostatic cancer. The PIN status of tissue specimens from 789 men without prostate cancer was determined in 508 transurethral resections and 281 transvesical prostatic enucleations. All slides were reviewed blind and independently by two pathologists. The patients were followed for an average of 11 years, and the incidence of subsequent cancer and cause-specific survival were analysed. Thirty-six cases of clinical prostatic cancer occurred among the cohort of 789 men through follow-up. No association between the presence of PIN in the transition/central zone and subsequent cancer development was found. There was also no difference in survival related to PIN status among the subsequent cancer patients."}
{"text": "Serial transplantation of an HCG-producing human testicular teratoma in immune-deprived mice is described. The xenografted tumour was compared to the tumour of origin in histology, immunohistochemistry  autoradiography, marker production and growth rate. It is concluded that the xenograft retained the characteristics of the original tumour with the exception of a reduction in HCG-producing elements at transplantation beyond 5 serial passages."}
{"text": "Pre-concentration of analytes, or matrix removal to overcomeinterferences using mini- or micro-columns of exchange media prior to atomic spectrometric detection is becoming increasingly more common. This paper is a review of some of the more recent applications of chelating, ion exchange and other resins and gelsthat have been used to accomplish this."}
{"text": "This paper addresses some serious issues about personnel morale,fears and hopes associated with and attributed to the laboratoryrobot. The introduction of the laboratory robot into the laboratoryis examined from a managerial perspective. Human-rights androbot-rights issues are identified and addressed. Real worldexamples of how the integration of two high through-put robotsaffected the routine of a major industrial food laboratory arediscussed."}
{"text": "In this study, the immunohistochemical expression of a new inducible elastase inhibitor, SKALP (skin-derived anti-leucoproteinase)/elafin, in the tissue of squamous cell carcinoma and uninvolved oesophageal mucosa was studied using a polyclonal rabbit anti-serum against SKALP/elafin. The results were compared with the immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and the TUNEL assay in serial sections. In non-malignant oesophageal mucosa, the expression of SKALP/elafin was localized in the cells of the stratified zone overlying the PCNA-positive basal zone. In oesophageal cancer, the incidence of the expression was significantly related to the degree of the differentiation of the tumour. Characteristically, the expression was almost limited in tumour cell nests that had a clear squamous phenotype. In tumour cell nests, the expression of SKALP/elafin was localized in the cells overlying PCNA-expressing cells and no expression was found in the cells that expressed PCNA; DNA fragmentation was often observed in the same cell layers as those in which SKALP/elafin immunoreactivity was found. This enzyme inhibitor is speculated to be involved in the induction of the cell differentiation and apoptosis of human squamous cell carcinoma cells of the oesophagus."}
{"text": "Human bronchoalveolar macrophages were separated from other free lung cells by density sedimentation on Percoll gradients. They were then tested for cytotoxicity against the human lung adenocarcinoma cell line A549, using a Selenomethionine-75 post-labelling assay. The cytotoxicity of the macrophages increased as the effector:target cell ratio was increased, approaching 100% at 20:1. There was no significant difference in the cytotoxicity of macrophages isolated from the lungs of bronchial-carcinoma or non-carcinoma patients. The highly cytotoxic nature of the macrophages was not due to selection of a more potent cytotoxic subpopulation of macrophages on the Percoll gradient, nor to a generally elevated activation of the macrophages due to the pathological conditions in the patients' lungs. An attempt to determine whether low concentrations of macrophages could potentiate target-cell growth proved negative. Cytotoxicity of macrophages for cultured lung target cells was not restricted to A549 cells and is not in accordance with the view that defective bronchoalveolar macrophage cytotoxicity contributes to the emergence of bronchial neoplasia."}
{"text": "Dear Sir,Fibrolipomas belong to the family of fat-containing lesions and are benign tumor variants of lipomas characterized by the presence of adipose tissue and abundant amounts of fibrous tissues. They are well-separated from the surrounding tissues and usually occur in adults. These le2A 62-year-old female presented with a giant mass in the abdominal wall . The firet al. in the back region.[Neural fibrolipoma is a benign tumor comprised of hypertrophied, fibrofatty tissue with intermixed nerve tissue and fibrolipomatous hamartoma of the nerve usually seen in infants and children. Althoughk region. For a lik region. In the f"}
{"text": "These are the first fully evaluated gold(III) complexes. The activity and reactions   of the diacetato-complex bear a resemblance to cisplatin, and some of the relevant chemistry is    discussed. Preliminary screening data for C,P-chelated tertiary phosphine derivatives of gold(III) are presented.A review is given of the background to and results of the succesful pharmacological testing of         [AuX"}
{"text": "The Bayesian methodology described in this paper has the inherentcapability of choosing, from calibration-type curves, candidateswhich are plausible with respect to measured data, expertknowledge and theoretical models (including the nature of themeasurement errors). The basic steps of Bayesian calibration arereviewed and possible applications of the results are described inthis paper. A calibration related to head-space gas chromatographicdata is used as an example of the proposed method. Thelinear calibration case has been treated with a log-normaldistributed measurement error. Such a treatment of noise stresses theimportance of modelling the random constituents of any problem."}
{"text": "The main difference between the reviewed paper and my scientific point of view is the acceptance of bisphosphonate therapy (BT) in daily practice for patients with advanced prostate cancer. Bisphosphonate therapy has been shown to alleviate pain which certainly has an impact on patients' quality of life and skeleton-related events (SRE) at 15 months and two years follow-up . Reduction in fractures translates directly into diminished hospitalization, costs and improves the patients' well-being.Contrary, the authors mean that the use of bisphosphonates is not established.Nevertheless, taxan-based chemotherapy (docetaxel) is the first treatment shown to increase overall survival in patients with hormone-resistant prostate cancer and is today's standard treatment of patients in Western countries. Secondary hormone treatment and administration of bisphosphonates are other established alternatives for palliation of symptoms in patients with hormone-resistant prostate cancer. The existing data support this general statement, but use of bisphosphonates should be restricted to certain conditions such as recommended by the NUCG : BT should be considered in patients with advanced prostate cancer as part of the palliative compassionate care treatment to reduce pain, SRE and use of opiates. Taxan-based chemotherapy should have priority without the combination of BT. The efficacy of combined treatment should be tested in trials such as the ongoing NEPRO study . Patients with fractures should get BT every four weeks and orally calcium/vitamin D supplement."}
{"text": "Mortality rates from cancer of the prostate in successive periods from 1908 to 1978 in Australia, and 1911 to 1977 in England and Wales, have been examined for trends with time and birth cohort. Age-specific rates and a proportional hazards model, designed to isolate the effect of birth cohort from those of calendar year and age, were used in the analysis. During the period of study, age-standardized mortality rose more than 5-fold in Australian men compared to just over 3-fold in men in England and Wales. In both countries the increases occurred almost entirely before 1960, with relative stability in age-standardized rates since then. The trends in mortality with year of birth were similar in the two sets of data. The risk of death from prostate cancer increased with successive birth cohorts to reach a peak in men born around 1865-1880 in Australia and men born around 1876-1896 in England and Wales. Males born later experienced a continuing reduction in rates, with the exception of age groups between 50 and 69 in which a further increase has appeared, starting with cohorts born after 1910. On the basis of current knowledge of the aetiology of prostate cancer, possible relationships between changes in sexual practices and prostate-cancer risk in successive generations have been explored. It is suggested that lowered sexual activity during the Great Depression may account for the recent cohort-based increases in mortality in middle-aged men."}
{"text": "A previously described defect of in vitro monocyte maturation in patients with squamous-cell carcinoma of the lung (SCC) has been investigated further. The maturation of patients' monocytes in pooled normal human serum was significantly better than in autologous serum. Conversely, the maturation of normal control monocytes was significantly depressed in patients' serum. The defect has been shown to be due to the presence of an inhibitory factor, rather than the lack of a necessary component in the patients' serum. Artificially aggregated gamma-globulin inhibited monocyte maturation in vitro, but the presence of immune complexes in the serum of many patients with SCC did not correlate well with the depression of in vitro maturation of monocytes from the same patient. Similarly, pregnancy-associated alpha 2-glycoprotein, in increased amounts in the serum of patients with SCC, showed no correlation with monocyte maturation. The addition of soluble extracts of tumour, but not of surrounding normal lung tissue significantly inhibited monocyte maturation. The results suggest that the defective monocyte maturation in patients with SCC is at least in part due to serum inhibitory factors, which are likely to be a heterogeneous group."}
{"text": "To assess the impact of preventive measures by the food industry, we analyzed food monitoring data as well as trends in the incidence of listeriosis estimated through three independent sources: the National Reference Center of Listeriosis; a laboratory-based active surveillance network; and two consecutive nationwide surveys of public hospital laboratories. From 1987 to 1997, the incidence of listeriosis decreased by an estimated 68%. A substantial reduction in the proportion of Listeria monocytogenes-contaminated products was observed at the retail level. The temporal relationship between prevention measures by the food industry, reduction in L. monocytogenes-contaminated foodstuffs, and reduction in listeriosis incidence suggests a causal relationship and indicates that a substantial part of the reduction in illness is related to prevention efforts."}
{"text": "Two cohorts of women born in 1914-18 and 1929-33 who participated in a cervical screening programme have been followed for over 40 years. Age-specific incidence rates of squamous carcinoma of the cervix by rank of smear and length of interval between smears are reported. The younger cohort, who had undergone more frequent screening, had lower rates of invasive disease. From these incidence rates, estimates of false-negative rates and regression rates for carcinoma in situ have been made. The false-negative rate was estimated to be about 15%. Regression seemed more frequent in younger than in older women. For the younger cohort it was estimated to be 72% and in the older 47%. A comparison of the rates of in situ carcinoma with those of invasive disease suggests that the screening of the younger cohort reduced the rate of invasive disease to at least one-half or one-third of what it would have been if screening had commenced later. Rates of disease appear less dependent on age than previously thought and are consistent with causation by an infective agent."}
{"text": "Lonidamine or 1-[ methyl]-1H-indazole-3-carboxylic acid, studied in a battery of in vitro and in vivo tests currently used for the screening of anti-tumour agents affecting cell division, has been shown to have a narrow spectrum of anti-tumour activity. The significance of this finding is discussed in the light of previous investigations suggesting that lonidamine affects mitochondrial function and not cell replication. Hyperthermia has been shown to sensitize tumour cells to lonidamine. This observation indicates that in combination with hyperthermia lonidamine has some potential for the treatment of cancer; moreover, it suggests that hyperthermia might reproduce a metabolic condition occurring in some stages of the disease. The blood levels corresponding to the anti-tumour action of lonidamine in animals are in the range of those detected in patients treated with the drug."}
{"text": "This paper describes an automatic system which measures the effectof temperature variations on the response of ion-selective electrodes (hysteresis curves). The system is managed by a computer program which plots hysteresis curves following a pre-established temperature cycle, from setting and controlling the temperature of thewater-bath, to acquiring the response potentials of up to five electrodes after temperature stabilization."}
{"text": "Emphasis is given to the effect of tumour burden on production of the monokines and of the eicosanoids and on the production of these compounds by the tumour cells. Finally, the therapeutic implications drawn from animal studies and clinical trials is discussed.Cytokines and eicosanoid products of macrophages play an essential role in expression of antitumour activity of macrophages either in a cell-to-cell contact system between the effector and the target cell or as cell-free soluble products. In this review the relationship between three main monokines, namely TNF-\u03b1, IL-1 and IL-6 and the interrelationship between these monokines and eicosanoids (PGE"}
{"text": "Although most diseases due to pathogenic mycobacteria are caused by Mycobacterium tuberculosis, several other mycobacterial diseases-caused by M. ulcerans (Buruli ulcer), M. marinum, and M. haemophilum-have begun to emerge. We review the emergence of diseases caused by these three pathogens in the United States and around the world in the last decade. We examine the pathophysiologic similarities of the diseases  and common reservoirs of infection (stagnant or slow-flowing water). Examination of the histologic and pathogenic characteristics of these mycobacteria suggests differences in the modes of transmission and pathogenesis, though no singular mechanism for either characteristic has been definitively described for any of these mycobacteria."}
{"text": "This paper describes the epidemiology of Hodgkin's disease occurring in parts of the United Kingdom between 1984 and 1986. The cases were carefully diagnosed and the data rigorously cross-checked as part of the larger Leukaemia Research Fund Data Collection Survey of all lymphoid and haematogenous malignancies. The age-specific rates show the lack of an older adult second peak. Spatial variation is examined in some detail. At county and district levels there is little heterogeneity in the distribution of cases. However, at the electoral ward level there were real differences for the younger age group (0-34)."}
{"text": "One of the vital                        activities performed by telomeres is the protection of chromosome ends. This                        allows cells to distinguish the tip of linear chromosomes from sites of DNA                        damage, and to prevent end-to-end chromosome fusions. The protective function                        of telomeres is lost when telomeres become critically short; a condition that                        is frequently found in aging cells . In mamm"}
{"text": "A mathematical model was developed to improve understanding of the biodistribution and microscopic profiles of drugs and prodrugs in a system using enzyme-conjugated antibodies as part of a two-step method for cancer treatment. The use of monoclonal antibodies alone may lead to heterogeneous uptake within the tumour tissue; the use of a second, low molecular weight agent may provide greater penetration into tumour tissue. This mathematical model was used to describe concentration profiles surrounding individual blood vessels within a tumour. From these profiles the area under the curve and specificity ratios were determined. By integrating these results spatially, average tissue concentrations were determined and compared with experimental results from three different systems in the literature; two using murine antibodies and one using humanised fusion proteins. The maximum enzyme conversion rate (Vmax) and the residual antibody concentration in the plasma and normal tissue were seen to be key determinants of drug concentration and drug-prodrug ratios in the tumour and other organs. Thus, longer time delays between the two injections, clearing the antibody from the blood stream and the use of 'weaker' enzymes (lower Vmax) will be important factors in improving this prodrug approach. Of these, the model found the effective clearance of the antibody outside of the tumour to be the most effective. The use of enzyme-conjugated antibodies may offer the following advantages over the bifunctional antibody-hapten system: (i) more uniform distribution of the active agent; (ii) higher concentrations possible for the active agent; and (iii) greater specificity (therapeutic index)."}
{"text": "As a popular simulation of photon propagation in turbid media, the main problem of Monte Carlo (MC) method is its cumbersome computation. In this work a table-based random sampling simulation (TBRS) is proposed. The key idea of TBRS is to simplify multisteps of scattering to a single-step process, through randomly table querying, thus greatly reducing the computing complexity of the conventional MC algorithm and expediting the computation. The TBRS simulation is a fast algorithm of the conventional MC simulation of photon propagation. It retained the merits of flexibility and accuracy of conventional MC method and adapted well to complex geometric media and various source shapes. Both MC simulations were conducted in a homogeneous medium in our work. Also, we present a reconstructing approach to estimate the position of the fluorescent source based on the trial-and-error theory as a validation of the TBRS algorithm. Good agreement is found between the conventional MC simulation and the TBRS simulation."}
{"text": "This paper describes the development of fully-automated synthesis systems for preparing and isolating various kinds of pharmaceuticalcompounds. The systems are versatile, and are able to performmost of the chemical reactions currently used in organic chemistry,with the exception of hydrogenation which requires high pressure.An additional benefit is the very user-friendly software."}
{"text": "A randomized controlled trial (RCT) comparing primary-care-centred follow-up of breast cancer patients with the current standard practice of specialist-centred follow-up showed no increase in delay in diagnosing recurrence, and no increase in anxiety or deterioration in health-related quality of life. An economic evaluation of the two schemes of follow-up was conducted concurrent with the RCT. Because the RCT found no difference in the primary clinical outcomes, a cost minimization analysis was conducted. Process measures of the quality of care such as frequency and length of visits were superior in primary care. Costs to patients and to the health service were lower in primary care. There was no difference in total costs of diagnostic tests, with particular tests being performed more frequently in primary care than in specialist care. Data are provided on the average frequency and length of visits, and frequency of diagnostic testing for breast cancer patients during the follow-up period. \u00a9 1999 Cancer Research Campaign"}
{"text": "The activity of theophylline and disodium cromoglycate was tested on adriamycin-induced histamine release in vitro and on adriamycin cardiotoxicity in vivo. Both substances significantly inhibited the release of histamine induced by 100 micrograms ml-1 of adriamycin on rat peritoneal cells and produced significant protection against adriamycin-mediated acute and chronic cardiotoxicity in mice. N-acetylcysteine, a free radical scavenger, successfully used in the prevention of the cardiomyopathy, was also found to be an inhibitor of histamine release induced by adriamycin and compound 48/80 on rat peritoneal cells. This study further supports the hypothesis that the release of histamine may be involved in the pathogenesis of anthracycline cardiotoxicity."}
{"text": "The incidence of ovarian, cervical, lung and prostatic cancer was higher in second-generation Irish living in England and Wales than in all other persons in England and Wales. A higher incidence of ovarian cancer was not found in first-generation Irish. Differences in socioeconomic status did not explain these patterns."}
{"text": "This report highlights the association of a tumour in an acalculous gall bladder with an anomalouspancreatico-biliary junction (PBJ) and a type IVa choledochal cyst. Cholecystectomy and Rouxen-Y hepatico-jejunostomy (RHJ) was performed after division of the common bile duct (CBD)and excision of the dilated segment. The details of the case are presented and the role of an abnormalPBJ in gall bladder carcinogenesis is discussed."}
{"text": "As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials  provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored."}
{"text": "The glycosaminoglycan (GAG) content of stomach carcinoma tissue was compared with that of non-neoplastic mucosa. GAG synthesis was also studied, by an analysis of 35S-labelled material after incubation of tissue segments in medium containing 35SO4. No significant difference was found between the amount of GAG and its components in the medullary carcinoma tissue and in non-neoplastic mucosa, but GAG synthesis of the carcinoma tissue was at a much higher rate than that of the non-neoplastic mucosa. In the autoradiograph, high 35S uptake in the carcinoma cells was observed. The GAG content of the scirrhous-carcinoma tissue was about twice that of medullary carcinoma."}
{"text": "The ADC data transfer and manipulation routinewas written in Assembler code and in high-level language; thegraphics package and data treatment package is in Basic. For thevarious sampling speeds, all of the program can be written usingBasic-Assembler or completely in Assembler if a high samplingrate is needed. Several numerical treatment methods for chemicalkinetics have been utilized to smooth the data from experiments.A microcomputer-interfaced data acquisition system for chemicalkinetics  hasbeen developed. Analogue signals from instruments used in kineticsexperiments are amplifed by a wide-range adjustable high-gainoperational amplifier and smoothed by an op-based filter, and thendigitized at rates of up to 10The computer-interfaced system for second-order chemical kineticstudies was applied to the determination of the rate constant of thesaponification of ethyl acetate at 35\u00b0C. For this specific problem,an averaging treatment was used which can be called an intervalmethod. The use of this method avoids the diffcully of measuringthe starting time of the reaction. Two groups of experimental dataand results were used to evaluate the systems performance. All of theresults obtained are in agreement with the reference value."}
{"text": "The incidence of lymphomata in CBA mice is low and furthermore is unaltered by transplantation at the early blastocyst stage and being born from the lymphoma-prone AKR. The number of C-type murine leukaemia virus particles in CBA derived in this manner and milk-fostered by AKR mice in no way differs from normal CBA. The results suggest that the oncogenic Gross virus does not pass through either the transplacental or transmammary routes, or alternatively that viral replication in the CBA was in some way inhibited. Both possibilities have still to be distinguished."}
{"text": "In the development of test methods for solid dosage forms, manual test procedures for assay and content uniformity often precede the development of automated test procedures. Since the mode of extraction for automated test methods is often slightly different from that of the manual test method, additional validation of an automated test method is usually required. In addition to compliance with validation guidelines, developers of automated test methods are often asked to demonstrate equivalence between the manual and automated test methods. There are problems associated with using the traditional zero-difference hypothesis tests (such as the Student's t-test) for demonstrating equivalence. The use of the Westlake Interval and Schuirmann's Two One-sided test as more rigorous methods of demonstrating equivalence is discussed."}
{"text": "Although it is now widely endorsed that children should as far as possible rate their own health related quality of life (HRQL), there are situations where proxy information on child HRQL may be useful, especially where a child is too ill or young to provide their own HRQL assessment. There is limited availability of generic HRQL scales that have a parallel child and parent version and that are reliable, valid, brief, comprehensible and suitable for use in UK populations. The aims of this study were therefore to develop and validate a parent version of the anglicised Manchester-Minneapolis Quality of Life child form (MMQL-UK (CF)) and to determine the level of association between the child and parent versions of this form.This study was undertaken concurrently with the anglicisation and validation of the MMQL, a measure of HRQL developed for use with children in North America. At that time, no parent version existed, so the MMQL form for children (MMQL-UK (CF)) was used as the basis for the development of the MMQL-UK parent form (PF). The sample included a control group of healthy children and their parents and five exemplar groups; children diagnosed with asthma, diabetes or inflammatory bowel disease and their parents, children in remission from cancer and their parents and children in public care and their carers. Consistency of the MMQL-UK (PF) components were assessed by calculating Cronbach's alpha. Validation of the parent questionnaire was undertaken by comparing MMQL-UK (PF) component scores with comparable components on the proxy PedsQL\u2122 quality of life scales, comparing MMQL-UK (PF) component scores between parents of healthy and chronic disease children and by comparison of component scores from children and their parents or carers. Reproducibility and responsiveness were assessed by retesting parents by follow-up questionnaires.A total of 874 children (completing MMQL-UK (CF)) and 572 parents or carers (completing MMQL-UK (PF)) took part in the study. The internal consistency of all the MMQL-UK (PF) components exceeding the accepted criterion of 0.70 and the construct validity was good with moderate correlations being evident between comparable components of the MMQL-UK (PF) and the proxy PedsQL\u2122. Discriminant validity was demonstrated with significant differences being identified between parents of healthy children and those with chronic conditions. Intra-class correlations exceeded 0.65 for all MMQL-UK (PF) components demonstrating good reproducibility. Weak to moderate levels of responsiveness were demonstrated for all but social functioning. The MMQL-UK (PF) showed moderate parent-child correlation with the MMQL-UK (CF) for all components. The best correlations were seen for those components measuring the same construct .The MMQL-UK (PF) showed moderate to good correlations with the MMQL-UK (CF) component scores. The MMQL-UK (PF) will be of use when comparing child and parent/carer perception of the impact of a child's condition on their HRQL or where the child is too ill or young to provide their own report. The measurement of health-related quality of life (HRQL) is increasingly becoming part of the overall assessment of a patient's health both in the clinical and the research setting, as it provides a more complete picture of the health of the patient. Measuring HRQL includes assessing the patient's perceptions of their physical, emotional and social health and function that can supplement clinical information on their health status.It is now widely endorsed that children as far as possible should rate their own HRQL ,2. HowevThere are conflicting views regarding the benefits of using proxies for measuring HRQL. There is some doubt as to whether proxy reports provide an accurate reflection of the child's HRQL ,6-8. PatWhen measuring the HRQL of children it may be necessary or desirable to obtain reports from their parents . CliniciIn spite of this, may measures of child HRQL do not include parallel parent versions ,18. For This questionnaire was originally developed in the US for use with child cancer survivors . The oriPedsQL\u2122 measurement system is a modular approach to measuring HRQL in children and adolescents and their parents which is rapidly becoming established in the US and Europe ,22. AnglThis study was carried out in the context of a wider study to anglicise and shorten the Manchester-Minneapolis Quality of Life Survey for children (MMQL-UK (CF)). The MMQBefore wider administration of the MMQL-UK (PF) could take place, the phrasing of the questions from the child form had to be modified to make them adult oriented. This was done by qualitative methods. An opportunistic sample of 15 parents of school children (age range 10\u201318) were recruited for interviews from a local school known to one of the researchers (PU) for development of the MMQL-UK (PF). During the interviews parents were asked to comment on the wording and structure of the questionnaire as well as completing a draft parent form. Interviews were carried out either at the home or at Swansea University, depending on the preference of the parent.The newly developed MMQL-UK (PF) was then compared with the shortened and anglicised version of the MMQL-UK (CF). This paper concentrates specifically on the validation of the MMQL-UK (PF) and comparison with the child (CF) version. The Anglicisation and validation of the MMQL-UK (CF) is reported elsewhere . AlthougChildren and their parents or carers who met the inclusion criteria . The control group were healthy children (and their parents) who were not currently using health care resources for any serious condition. Participants were given a screening questionnaire prior to participation that included a section about health status. Anyone who was identified as having a health problem was excluded from participation in the study. Permission to approach schools was obtained from the Directors of Education in each Local Education Authority, before selecting schools via multi-stage sampling. Information was sent to head teachers of sampled schools, inviting their school to participate. A researcher visited schools expressing an interest, to discuss the project further and arrange for data collection. Written information for parents, parental consent forms and parent questionnaires were supplied for each child to take home. Parents were asked to complete their questionnaires at home and return them to school by a specified date, along with consent for their child to complete the questionnaires. It was emphasised that completion of questionnaires should not involve consultation with the child. For those children that had parental consent, re-explanation and completion of questionnaires followed in class a week later, under the supervision of the researcher.In both subject and control groups, children with moderate to severe learning difficulties and children and parents for whom English was not their first language were excluded from the study.The study was approved by the Welsh Multi-centre Research Ethics Committee (MREC). Informed consent was sought from all children (subjects and controls) and their parents or those with parental responsibilities (for children less than 16 years of age), following oral and written explanation of the study.Data were analysed using the Statistical Package for Social Sciences (SPSS) version 11.4.The internal consistency of the MMQL-UK (PF) components were assessed by item-total correlations and Cronbach's alpha . QuestioThe construct validity of the MMQL-UK (PF) components were assessed by comparing them with the appropriate parent PedsQL\u2122 quality of life scales. If the components were valid measures of HRQL, they would be expected to show significant small to moderate levels of correlation with each of the PedsQL\u2122 scales, with the largest correlations being seen between the PedsQL\u2122 scales measuring physical, social, emotional and school function and the comparable MMQL-UK (PF) components.The discriminant validity of the MMQL-UK (PF) was assessed by comparison of component scores between parents whose children were being treated and the parents of the control group. Our a priori hypothesis was based on identifying moderate to large differences in effect size between each exemplar and the control group . If the The relationship between the MMQL-UK (CF) and MMQL-UK (PF) was determined using Pearson's correlation. If the two reports measure the same concept, then moderate correlation would be expected between the component scores of the MMQL-UK (CF) and the MMQL-UK (PF).Following initial completion of the MMQL-UK (PF) by parents of the exemplar group children, they were asked to complete a second 'retest' questionnaire the next time their child visited clinic. This was a maximum of three months after the first assessment. In addition to completing the MMQL-UK (PF), the parents of children were asked to rate whether they thought their child's health had changed  since the first questionnaire was completed. Those parents reporting no change were included in the reproducibility analysis. Reproducibility was assessed using intra-class correlation co-efficient .The responsiveness of the MMQL-UK (PF) was assessed by using the scores of the exemplar group parents who reported a change in their child's health. The response ratio (mean change in scores for subjects reporting a change divided by the standard deviation of the subjects reporting no change) was used to quantify the responsiveness . The larIn order to have a parallel proxy report, question selection for the parent form replicated that for the child form. A total of 29 questions were selected for the anglicised and shortened MMQL-UK (CF) and MMQL-UK (PF) with five proposed components: physical appearance, school functioning, social functioning, emotional functioning and physical functioning.874 children and 572 parents completed the MMQL-UK (CF) and MMQL-UK (PF). The internal consistency of the MMQL-UK (PF) was excellent, with all components exceeding the accepted criterion of 0.70  was good, with significant correlations being evident between the MMQL-UK (PF) and the proxy PedsQL\u2122 on those scales measuring similar constructs, i.e physical functioning, emotional functioning, social functioning and school functioning (see Table Table Intra-class correlations ranged from 0.65\u20130.91 for the MMQL-UK (PF) components demonstrating good reproducibility for the questionnaire ) was successfully developed based on the anglicised and shortened child version which has been recently validated in the UK (MMQL-UK (CF)). The parGood internal reliability was found for the MMQL-UK (PF), with alphas exceeding 0.70 for all the components, thus making them acceptable for group comparisons . ConstruDiscriminant validity was demonstrated for the MMQL-UK (PF) proxy report with differences being noted in HRQL by parents of healthy children and children with chronic health conditions and carers of children in local authority care. The reproducibility and responsiveness of the MMQL-UK (PF) were indicated by good test-retest results. The relationship between the MMQL-UK (CF) and MMQL-UK (PF) was confirmed by moderate correlations indicating that the two reports measure the same concept.The availability of a proxy report is important as there may be occasions when a child is either unable or unwilling to complete a HRQL measure. However interpretation of proxy reports should be undertaken with caution as they may not accurately reflect the child's view, particularly for some components. However if they are used in conjunction with a clinical consultation or other objective assessments they could potentially provide useful information on the health of the child .It should be recognised that both child and proxy ratings have value but the question is to clarify how differences in perception of HRQL arise between the child and the proxy . It has It is recommended that parent proxy reports be available for child HRQL measures, a condition that the PedsQL\u2122 also fulfils. The availability of proxy-reports in addition to child reports may be more desirable than reports from the child alone. In medical consultations, the clinicians often look to the parents for guidance regarding medical decision making in relation to their children . The parFurther studies are needed to determine the accuracy of the MMQL-UK (PF) proxy reports compared with the MMQL-UK (CF) child reports in other conditions and different age groups of children. The usefulness of the MMQL-UK (PF) in assessing longitudinal outcomes of children also warrants further attention.This study established the reliability and validity of a new MMQL proxy report (MMQL-UK (PF)). The MMQL-UK (PF) showed good correlations with the child form (MMQL-UK (CF)) in healthy children, those in public care and those suffering from chronic conditions.Health related quality of life (HRQL), Minneapolis-Manchester Quality of Life Instrument (MMQL), Child Form (CF), Youth Form (YF), Parent Form (PF), Inflammatory Bowel Disease (IBD), Bone Marrow Transplant (BMT), Acute Lymphoblastic Leukaemia (ALL), Multi-centre Research Ethics Committee (MREC), Statistical Package for Social Sciences (SPSS), United Kingdom (UK)The author(s) declare that they have no competing interests.HAH was the primary author on the manuscript and was responsible for methodological and statistical support throughout the study and analysis of the final study results. JGW secured funding and led the study, provided methodological support throughout and was involved in writing the manuscript. PU was the primary researcher, was responsible for co-ordinating and managing the study on a day-to-day basis, for data collection and collation, data analysis and input into writing the manuscript. WYC provided methodological and statistical support throughout the study, was involved in the final study analysis and was involved in writing the manuscript. AM provided clinical support for the study, was involved in designing the study and was involved in writing the manuscript. CE was involved in designing the study, provided methodological support throughout and was involved in writing the manuscript. SJ was involved in designing the study and was involved in writing the manuscript. MEM Jenney provided clinical support, was involved in designing the study, provided methodological support throughout and was involved with writing the manuscript. ITR provided methodological and statistical support throughout the study. All authors read and approved the final manuscript."}
{"text": "The morbidity of high-dose chemotherapy has been considerably reduced by the use of autologous peripheral blood progenitor cell reinfusion. Most studies have used myeloid colony-stimulating factors after stem cell reinfusion, making it difficult to determine the relative contribution of each of these variables to the early recovery of blood cells. The financial implications of colony-stimulating factor use are an area of concern as dose intensification in chemosensitive malignancies is increasingly employed. We have studied 19 consecutive patients receiving high-dose chemotherapy with and without filgrastim  after stem cell infusion to examine its effect on the kinetics of blood cell recovery, the complications of myelosuppression and the associated costs. Analysis of the two treatment groups reveals that administration of filgrastim 10 micrograms kg-1 day-1 following stem cell reinfusion does not further accelerate haemopoietic recovery, fails to reduce the incidence of neutropenic fever or antibiotic usage and significantly increases the cost of the procedure. The results of this study do not support the routine use of filgrastim after high-dose chemotherapy and peripheral blood stem cell reinfusion."}
{"text": "Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features."}
{"text": "Movement regularities are inherently present in automated goal-directed motions of the primate's arm system. They can provide important signatures of intentional behaviours driven by sensory-motor strategies, but it remains unknown if during motor learning new regularities can be uncovered despite high variability in the temporal dynamics of the hand motions.We investigated the conservation and violation of new movement regularity obtained from the hand motions traced by two untrained monkeys as they learned to reach outwardly towards spatial targets while avoiding obstacles in the dark. The regularity pertains to the transformation from postural to hand paths that aim at visual goals.In length-minimizing curves the area enclosed between the Euclidean straight line and the curve up to its point of maximum curvature is 1/2 of the total area. Similar trend is found if one examines the perimeter. This new movement regularity remained robust to striking changes in arm dynamics that gave rise to changes in the speed of the reach, to changes in the hand path curvature, and to changes in the arm's postural paths. The area and perimeter ratios characterizing the regularity co-varied across repeats of randomly presented targets whenever the transformation from posture to hand paths was compliant with the intended goals. To interpret this conservation and the cases in which the regularity was violated and recovered, we provide a geometric model that characterizes arm-to-hand and hand-to-arm motion paths as length minimizing curves (geodesics) in a non-Euclidean space. Whenever the transformation from one space to the other is distance-metric preserving (isometric) the two symmetric ratios co-vary. Otherwise, the symmetric ratios and their co-variation are violated. As predicted by the model we found empirical evidence for the violation of this movement regularity whenever the intended goals mismatched the actions. This was manifested in unintended curved \"after-effect\" trajectories executed in the absence of obstacles. In this case, the system was \"perturbed\" away from the symmetry but after several repeats it recovered its default state.We propose this movement regularity as a sensory-motor transformation invariant of intentional acts. The primate arm-hand system has many more degrees of freedom (d.o.f.) than the three-dimensional physical space in which the system operates. Such excess lends primates great flexibility to interact with the external environment and gives rise to highly versatile behaviours. Any goal-oriented task can be performed in a variety of ways. Even under highly constrained laboratory conditions several repeats of the same motion can be highly variable after the motion has been fully automated. To the naked eye every repeat may seem similar to the previous trial but when examined at a millisecond time-scale resolution, different patterns of variability can be revealed. In spite of the many possible ways that exist to perform voluntary reaches, and of the variability of movement parameters manifested in any family of reaching actions, research in the field of motor control has unveiled a number of regular movement patterns that suggest conservation of some underlying quantities possibly driven by sensory-motor integration strategies to achieve some higher-level goal.Examples abound in motions that are performed under temporal constraints aiming for a particular maximum speed or particular movement duration. Among them the first to be noted was the speed-accuracy trade off known as Fitts' law, discovered by Paul Fitts in 1954 [ring law .Other known regularity of human movements is the symmetric (\"bell-shaped\") nature of the speed profiles of point-to-point straight motions noted earlier  and modeInvariably these studies however have treated the movement time as a free variable and pre-set the duration of the reach a priori. This has also been the case in animal movement research, which has reproduced the speed profile regularity ,8 in higIn reach to grasp motions that required the bending and twisting of the hand along the motion paths to match some location and orientation in space, the arm system defaulted to the co-articulation of 4 rotational joints roughly projecting to three physical dimensions for transport of the hand and 1 for rotations of the hand. The subjects performing such motions invariably conserved the relationship between the transport and the rotational errors . This coAs one assesses more natural behaviours, movement regularities unveiled in one context do not necessarily transfer to another context. Another known example has been the somewhat controversial human movement pattern known as the 2/3 Power Law. This movement regularity reveals a non-linear relationship between the tangential hand speed and the curvature of its trajectory during curved motions -14. SuchStudies involving motor learning may provide a more natural scenario to test the movement regularities described thus far in fully automated reaches, or in motions with specific spatio-temporal requirements. In most experiments describing such phenomena, the arm has been constrained to move on a plane and/or to move under a pre-defined temporal structure that a priori sets bounds on the total duration of the motion and/or on the motion's maximum speed. It is unknown whether the untrained system, moving naturally at its own pace while learning new dynamics would also manifest movement regularities. In natural settings unconstrained motions of the arm would recruit many of the rotational d.o.f. in the proprioceptive space of sensed postural configurations and the motions would generally be more variable. Would other subtle invariants emerge under such conditions? More importantly, are there motion invariants that remain conserved across different families of reaching actions? Under what conditions such invariants would be violated and repaired? We address these questions here in two untrained monkeys as they learned to avoid obstacles when their hands aimed at visual targets in the dark.Two rhesus macaque monkeys were first trained to perform memory-guided straight reaches directed to visual targets in the dark. Targets were located on a vertically-oriented board figure . A blockThe structure of the paradigm was A-B-A', where A represented the automated straight reaching block, B was the block of curved reaches around obstacles and A' was the last block of straight reaches after exposure to many highly fast and curved OB-avoidance-motion repeats. The experimental paradigm and other aspects of the learning process have been described elsewhere . Here weSince these experiments monitored the two animals over several months until their new reaches turned automated, here we focus on the time period when the animals were still learning. The criteria for learning vs. automatic came from (1) the jerkiness vs. smoothness of the new speed profiles along the curved hand paths, and (2) the ease with which the animals switched from one experimental block to the next. The presence of jerky hand speed profiles when switching from A to B, or from B to A' indicated that the OB-avoidance motor program was still fragile, i.e. undergoing learning .Since our main interest rests on the effects that the high variability inherent in the learning process may have on movement regularities, we will focus on the behavioural data from the earlier days of training. The data was gathered from experimental sessions where the transition from A to B, or from B to A' was not direct. In those days it took many trials to transition from straight paths with smooth speed profiles to curved paths which would also develop smooth speed profiles (going from A to B); or it would take many trials to transition from curved paths with smooth speed profiles to straight paths with smooth speed profiles (going from B to A'). In particular, in the transition from B to A' unintended curved hand trajectories in the absence of OB were coined \"after-effect\" trajectories from OB-avoidance and we studied the evolution of those trajectories in depth here.The motions of the performing arm were recorded using electro-magnetic sensors (Polhemus Fastrak 120 Hz resolution). The hand sensor was mounted on a piece of Plexiglas, affixed to a custom-made glove and placed on the surface of the moving hand, one cm from the wrist line. The rest of the sensors were mounted on a piece of Plexiglas and affixed to a primate jacket at the shoulder, upperarm and forearm.The monkeys were seated in a primate chair. Since concurrent neural recordings were being obtained, their head was not moving and their eyes were fixating straight ahead. They moved their arm freely in three dimensions and received a juice reward after each successful trial. Successful trials had the following structure . The present study focuses on locations to the right and to the left of the fixation point as these evoked the highest changes in curvature and timing.The subjects were not penalized if the hand collided with the OB(s), as we were interested in the evolution of such trials. However, not enough trials where they hit the OB(s) could be gathered for analyses as both animals were naturally very proficient at successfully avoiding the OB(s) while maintaining eyes fixated in the dark. The data reported here comes from trials where no collision with the OB(s) occurred.All experimental procedures were conducted according to the \"Principles of laboratory animal care\"  and were approved by the California Institute of Technology Institutional Animal Care and Use Committee.We assessed the effects of task condition and target location on the curvature of the hand trajectories. To this end we measured the deviation of the hand trajectory from the Euclidean straight line and used this as a bending index (denoted \u03ba).The starting and final location of each hand trajectory was joined by the corresponding straight line. The hand trajectories were re-sampled (100 points) to obtain a fine temporal partition at equally spaced points without distorting the spatial path. This was necessary for numerical integration to compute the area and the perimeter ratios explained below and to treat the curve as a geometric object independent of its temporal profile. The latter is justified by empirical evidence indicating that during voluntary motions, primates conserve the hand paths regardless of the motion's speed ,11,19-21normal to this plane at each position was compared to that corresponding to the plane from the previous position in order to measure the twisting of the curve along the hand motion's trajectory . To better visualize this relative to an ideal OB-avoidance modelled geodesic we show in figure We also measured the degree of twisting along the hand paths. At each point along the trajectory the tangent vector to the curve (the velocity vector) and the vector perpendicular to it (the acceleration vector) span a plane (known as the osculating plane ). This pTwo-way ANOVA  as the dependent variable) was used to assess significance in the differences across experimental blocks. Within each block we also performed an ANOVA to ask if the target location had a systematic and significant effect on the bending (or on the twisting) parameter.time length to reach the maximum speed from the start of the reach (denoted tau); the time length to reach the maximum acceleration (denoted \u03b1) and the total duration (denoted t). In particular we were interested in the evolution of the magnitude of the acceleration relative to the magnitude of the velocity. Where and when along the curve traced by the hand were these quantities maximal? Was there any evidence that the system was using a particular critical temporal point as a reference while timing the reaches?We measured in each trajectory the timing of several kinematics parameters occurring at different points of the motion. These critical temporal markers were: the We had previously reported that the speed profiles during the learning phase of the new OB-avoidance motion were jerky, with multiple accelerations and decelerations phases and highly variable in duration ranging from 1,500 ms to 700 ms for the same target . Motivatt we used two-way ANOVA with target location and experimental condition as the two factors, and the temporal-dynamics parameters as the dependent variable in each case.To assess the effects of target-dependent curvature/torsion and learning on tau, \u03b1 and We defined two trajectory ratios:area ratio was defined as the quotient between the partial area under the curve in the first portion of the movement, up to the point of maximum bending \u03ba, and the total area enclosed between the curve and the line. Figure (1) The perimeter ratio was defined as the quotient between the partial perimeter -the sum of the path length and the length of the line connecting the initial hand position and the target up to the point of maximum bending- and the total perimeter given by the total sum of the lengths of the hand path and the initial hand position-to-target line.(2) The the Appendix and qualitatively congruent with previous data from various laboratories showing the conservation of voluntary arm postural and hand paths [It is important to note that the assessment of these quantities in the context of motor learning was motivated by a previous finding involving human subjects. In that study humans performed similar three-dimensional point-to-point straight reaches under visual memory guidance in the dark. Both aforementioned ratios were time-invariant, i.e. remained conserved for multiple speeds along paths of similar curvature. The conservation was in that case also independent of the frame of reference used to cue visual guidance . This wand paths ,10,19-21The novelty of the questions addressed in the present experiments rests in two facts: (1) the animals were untrained to perform the task of interest; (2) there were dramatically different arm force patterns to achieve multiple families of curved hand trajectories.We obtained from each hand trajectory the area and perimeter ratio and used the Friedman test  to assesWe found significant effects of target location and experimental condition in both animals alpha 0.01) on the bending and twisting of the hand trajectories. In the straight-reaching block the target location affected both trajectory parameters significantly. These results extended from the straight-reaching to the OB-avoidance block. There was a significant effect of the block-condition. Figure  on the bThe time to reach the first velocity peak: Each target location in space had a characteristic value of tau specific to that location in each task. This parameter was highly consistent at each location despite the fact that in each experimental block, the repetitions of the reach were made to randomly presented targets. Figure t. This result extended to other families of reaches in the present study.Figure The time to reach the maximum acceleration: The temporal profiles of the magnitude of the acceleration revealed that the hand trajectories in general had several acceleration peaks. We obtained the percentage of the total movement duration time that it took to reach the absolute maximum acceleration for each condition and plotted the distribution of this parameter across all target locations and reach repetitions. Since the total length of the path relates to the overall duration of the reach, we also examined the distance delta travelled to the first velocity peak, as the hand completes the first pulse of the reach.p < 10^-6, dip = 0.09). A mixture of Gaussians fit yielded 55% of trials with the maximum acceleration reached earlier at 10% of the total time and 45% of the trials with the maximum acceleration reached later at 20% of the total time.In straight reaches the distribution of the percent of time that it took to reach the absolute maximum acceleration along the curve turned out to be strongly bimodal according to the Hartigan's dip test ,26 for bFurther analyses of all trial-times in each class revealed that each class of trials was composed of reaches to all target locations (uniformly distributed across space) and trials performed uniformly at all times (early and late) in the block. These results ruled out a possible effect of target location preference  or an effect of fatigue . This bi-modal distribution defined two trial classes in the straight reaches, one in which the peak acceleration preceded the peak velocity and the other in which the peak acceleration followed the peak velocity. The distribution of time stamps in these trials revealed an alternating strategy whereby it took mostly one or two trials across all repetitions to switch from one trial class to the other. This is depicted in figure dip = 0.03, p = 0.6, failed bimodality test) as well as 2 OB(s) .The OB avoidance block yielded a very different picture with a unimodal uniform distribution of the percent of the total time that it took to reach the maximum acceleration \u03b1. This was the case when avoiding 1 . Avoiding 1 OB also failed the bimodality test . However learning to avoid 2 OB(s) yielded a significantly non-unimodal distribution . Figure Figure The total time of the motion: The movement duration relates to the total length of the trajectory so we measured both quantities and the other spatio-temporal parameters in each block. The OB-avoidance total path length ranged between 37 cm and 79 cm for ipsi-lateral targets and between 39 cm and 105 cm for contra-lateral targets. The partial distance delta travelled up to the first velocity peak varied between 10 cm and 36 cm for straight reaches and between 11 cm and 60 cm for curved reaches around 1 and 2 OB(s). The total movement duration time t in ms ranged between 420 ms and 1,600 ms for ipsi-lateral targets and between 500 ms and 1000 ms for contra-lateral targets. It was highly variable at the beginning of the learning, for example in a single session it evolved from 1,600 ms until it became stable at 700 ms in the most affected ipsi-lateral target.Automated straight reaches showed consistent movement duration for each location despite the randomness of the target presentation. This contrasted with the earlier trials of the OB-avoidance learning block where the total duration was highly variable yet with a consistent monotonically decreasing trend at each randomly cued target location. The last portion of the OB-avoidance block was characterized by a more consistent duration in each target location. For each target location we observed statistically significant differences between the automated straight and OB-avoidance reaches. Likewise, there were significant differences within the OB-avoidance block when we compared earlier and later trials of the block, with a significant effect of target location . Table Despite significant differences in all trajectory parameters as a function of target location; and as a function of the learning stage of OB-avoidance, the area and the perimeter ratios pooled across all target locations and repeats for each animal formed a unimodal distribution clustered tightly around 1/2. This distribution was similar for both quantities and remained so despite striking differences in temporal dynamics figure  or hand The similarity of the area and the perimeter ratios denoting their co-variation was confirmed by the Friedman's test  yieldingDuring the early trials of the third block of straight reaches (A') both subjects manifested motion trajectories similar to those observed during OB-avoidance. Their hand paths were curved and the temporal profiles along the hand paths were highly variable. A distinct difference was that the consistency of the parameter tau was no longer present. Eventually the simultaneity of the delta-tau pair quantified during the first pulse of automated straight reaches was regained in this block. Attaining this synchronicity however, took many trials (at least 5 per each of the 14 targets). At that stage we found as in the A-block, similar bimodal distribution of the percent of time to reach the maximum acceleration relative to the maximum speed, and a unimodal distribution of the distance delta travelled to reach the first velocity peak. Figure This work investigated (1) if there were new movement regularities conserved across various families of goal-directed voluntary reaches; and (2) if the regular patterns across reaches would remain conserved despite high motion variability during the natural learning of a new procedural act. We found that during intended goal-directed reaches, despite significant statistical effects of target location and learning stage on many relevant spatio-temporal movement parameters, there was a new symmetry linked to hand trajectories. This symmetry was captured by two ratios of the hand trajectories, which significantly co-varied across space and remained invariant to changes in temporal dynamics, to changes in hand path curvature and to changes in the arm postural paths required to achieve differently curved hand trajectories across the three-dimensional physical space.It is important to notice that all research questions addressed here are part of a research program investigating the cross roads between geometry and temporal dynamics during unconstrained intentional actions. This program aims at further developing the idea of an internal model of the body's temporal dynamics ,29 by prIt is generally believed that an internal representation of movement variables -such as position and velocity- is maintained in the neural activity (whether in intrinsic joint and muscles or extrinsic coordinates) and used to update and monitor the state of the system. Such representations are thought to be stored as internal models -31 that when they occur [It is accepted that these internal models can be characterized by dependence on a motion state -a mapping between motor commands and resulting limb motions-rather than by a dependence on the times ey occur . Empiricey occur ,34. No eThe present work uncovered a bimodal distribution of maximum acceleration-magnitude relative to maximum velocity-magnitude suggesting that relative timings are indeed important to learn new curved point-to-point reaches. Each bump of the unveiled bimodal distribution reflected separable acceleration timing relative to the maximum speed, suggesting that -generally for both automated straight and automated curved timings-the peak velocity can serve as a critical reference point.when these states occur. In particular the relative timings of these states' critical points  appear to play an important role in the learning of new curved reaches. Models of motor learning that treat time as a free parameter and that leave out such relative-temporal dependencies will not account for these empirical results of unconstrained three-dimensional complex reaches performed at the subjects' own pace.These data demonstrate that in addition to a dependency on the motions' states, the system's performance in general straight and curved reaches also manifests a dependency on the times where and when in the path the hand attains the speed maximum. The temporal analyses had revealed the speed maximum as a possible critical point of reference to time the reach. The spatial analyses revealed that these critical points largely depended on the reliable path length -used to update relative distances during learning.In both automated straight and curved OB-avoidance reaches studied here the hand path length remained consistent despite the temporal learning and despite the arm's redundant d.o.f. Motivated by these empirical results, in all 3 cases ) we examined the portion of the total path length that it took the hand to reach maximum velocity (denoted delta in cm) and that lasted tau ms. These parameters indicate The questions addressed in this work were motivated by our geometric characterization of intentional arm-hand motions. In each case we had previously characterized the curve to reach a target as the shortest-distance path with respect to a task-dependent Riemannian distance metric. In curved reaches for the -associations, we had proposed that these parameters could play a key interchangeable role in predicting ahead sensory-motor temporal lags . We systThe hand path curvature played a significant role on this motor-learning process as it determined the cases in which the learning of the new motion timing was based on the adjustments of the distances travelled by the hand at a fixed time-length in relation to the maximum speed. In this regard it was important to divide the hand trajectory into different critical temporal land marks defining different segments along the motion path. This further relative-timing refinement revealed that later points along the temporal path were more affected by the error-correction process. This process was driven by the trial-by-trial adjustments of the distance travelled by the hand after the maximum speed had been attained, prior to reaching the intended target. Eventually the hand converged to a smooth timing and travelled two segments. The overall motion then consistently lasted a similar time length.We speculate that it is possible that during the later portions of the movement trajectory sensory-motor feedback was used to correct errors between intended and actual executed dynamics. This was evidenced in the later corrections of the jerky speed profiles, which disappeared as the earlier delta became consistent. In contrast to the later corrections, in the earliest pulse of the trajectory  information on the distance-to-be-travelled seemed more adequate than actual motor feedback (possibly not yet fully available) to estimate adjustments in the upcoming dynamics and to achieve  a systematically consistent overall timing. In this earlier portion of the reach the system may have placed a tighter bound on the variability of the length of time devoted to the segment. This was evidenced in the low variability of the parameter tau throughout the learning process.Regarding the interactions between geometry and relative-timing, the rate of change of the distance accumulated along the highly curved hand path in principle interacts with the acceleration of the curve at each point (the vector perpendicular to the velocity vector tangent to the curve). If there had been extreme changes in distance travelled, the hand would have fallen out of the intended direction along the path and collided with the OB(s). Yet this was not the case during curved-timing learning. Throughout the learning process -despite different dynamics - the curvature of the path and its overall length were systematically conserved across random repeats to the same target.Path length conservation facilitated distance-based adjustments when learning the curved timing. The unveiled bimodal distribution of delta manifested during the adjustment phase contained trials from all targets. This uniformity ruled out an explanation of the non-unimodal distribution solely based on the subjects' biases due to comfort  or effort . The composition of the classes showed mostly an alternating distance-adjusting strategy where if trial n was in the short-length trial class then trial n+1 would most probably be in the long-length trial class. This systematisation suggested that the system was running two learning processes simultaneously, one short-term based on trial-by-trial error corrections and one long-term quantified across days of training. We had previously tracked longitudinally the long term learning  and see , but theThe present results fully agree with previous reports, which had suggested different time scales for motor learning in the context of a different force-field paradigm . In the The data from both animals showed that whenever the intended path geometry and tau were consistent, the symmetries and their co-variation held. We found that the uncovered invariant of hand motions was violated whenever the executed motion path miss-matched the intended path. This was the case during the de-adaptation trials where different forces were still present in the arm system from the previous experimental block. To describe this new phenomena we borrowed the term \"after-effects\" from the well known motor learning paradigm that uses force fields to alter arm dynamics . In our During the de-adaptation trials tau was highly variable at each target location. This was in contrast to the other blocks of automated straight reaches, and OB-avoidance learning where this temporal landmark of the hand trajectory remained consistent. In those cases, we had found that the variability of tau was negligible compared to the variability of delta. We had quantified the systematic consistency of tau even during the striking changes in overall temporal dynamics from motor learning, yet during de-adaptation tau varied significantly between the mean values of the 2 motor programs for straight and curved paths.During de-adaptation trials the parameter delta also had comparable variability to that of the parameter tau. An immediate sensory-motor strategy was not evident in these trials at first. The inevitable arm state seemed to have over ruled the intended sensory-motor transformation strategy. Yet eventually, after many trial-and-error repeats, with no apparent systematic pattern of variability in the hand trajectories, the system regained synchrony of delta and tau, and the bimodal trial-distribution of \u03b1 was again quantified. Perhaps systematic de-adaptation patterns could have been identified in the arm muscles domain, but our recordings of the arm kinematics at 120 Hz limited our ability to address different sources of noise and their possible meanings with regards to important lower-level control strategies.The invariance of the uncovered symmetry may reveal a higher-level sensory-motor transformation and integration strategy common to several families of reaches performed by the primate arm system. The learning progression from the straight to the curved timings revealed important features. The non-unimodal distribution of \u03b1 in the automated straight reaches disappeared when learning the curved timing. As the system built a new curved temporal profile, the \u03b1-distribution turned unimodal and the \u03b4-distribution turned non-unimodal. Upon examination of relative timings at the end of the learning process, we discovered that the newly automated curved trajectories had similar non-unimodal relative-timings structure as the automated straight trajectories. The spread of the clusters had however changed and the centres shifted. In the new curved timing there was a contraction of the time-length separation between the speed and the acceleration maxima.The OB-avoidance learning strategy was closely tied to the rate of change of the distance accumulated along the first pulse of the reach in relation to the overall path length: i.e. the percentage of the path covered. The path length remained stable (low variability) throughout the curved-timing learning process both in the postural and in the hand domains. This stability in the face of so many possible postural configurations suggested an initial geometric strategy based on relative distances rather than on relative timings. At the end of the learning process however figure , the strWe speculate here that in visuo-motor acts the learning of complex curves in high dimensions and their projection to three-dimensional space may initially rely on sensing the distances covered by the end effector (proprioceptive sense of posture) and estimating ahead  the remaining distance for various segments. Eventually, through trial and error performance, aiming for a faster, less time-segmented motion, the system may learn to rely on the relative timings, as was manifested in the transfer from automated straight to automated curved reaches. There is evidence that smoothness maximization is important to the motor system [r system ,36, yet In our previous work  the longWe have previously proposed ,11 that According to our geometric model, under normal conditions, the learning of new dynamics along new curved paths would entail building an association between the general notion of distance (in a sensory space) to be travelled along a geodesic direction  and the time lag that it would take for sensory-motor feedback to return and be utilized to complete the segment. Once the motor program became automated, the time lag (which we sense from movement) and the distance  would be interchangeable, so we could have a representational model of the dynamics in a \"Least-Action-Principle\" sense; i.e. we could have a representational, time-invariant geometric model of the dynamics motion path. To the na\u00efve system distance and time would be separable but to the automated system they would be equivalent. Whenever this association-map became ambiguous or misaligned (as during de-adaptation or brain injury ), such cmemory-guided reaching contexts that adult human Parkinson's and Parietal patients also violated this invariant, yet they could repair the symmetries and their co-variation when the appropriate source of sensory guidance was provided to cue the spared systems. The deficit/repair pattern of the symmetry was specific to the injured site and so was the preferred source of sensory guidance. The present work complements the patient data and strongly suggests that this movement regularity is not merely a by-product of the primate arm's biomechanics and its compliance with the physical laws of motion. We believe that this invariant reflects compliance with intended sensory-motor transformation strategies of the primate brain and conclude that it is a manifestation of mental laws governing the control of voluntary arm movements.We have previously found in similar The author declares that they have no competing interests.All authors read and approved the final manuscript. EBT designed the task, programmed the motion capture recording system, designed the questions addressed in this paper, designed the analyses and modeled the phenomena prior to the experiments. EBT trained the subjects, carried on the experiments, collected and analyzed the data and wrote the paper. EBT did not build the experimental set up which was part of the Andersen laboratory at CALTECH. In addition to this, as part of a broader question, Professor Richard Andersen posed the question of curved trajectories in relation to the Posterior Parietal Cortex and provided the idea of using obstacles to evoke hand path curvature.dq = -G-1\u2207r\u00b0 f\u0394\u03c4 (i) described in [Paths generated with the gradient-flow-driven equation ribed in  conserve1-shoulder, and q2-elbow rotations. Parameterization of the surface is compatible with the metric and projects geodesics paths on the Q-Cost to geodesics paths on the X-Cost surface according to equation (i) (fully described in [xtarget pulled back into the corresponding qtarget in Q according to the gradient rule. This gradient flow minimizes the remaining (non-Euclidean) distance between current posture in Q and final target in X subject to any additional priorities and constraints that the task at hand may demand [Figure ribed in ,11) whicy demand ,11. ThisIn the toy-model example of Figure The metric in X is pulled back into the metric in X is The cost function in this case is 2r\u00b0 f along the path. This is measured by In Figure Figure The results illustrated here in lower dimensions extend to higher dimensions for a more realistic characterization of this problem Figure f-map from postures to hand position. The star marks an abducted posture used later in (D) to simulate a reach. Figure i is given as a visually sensed desired distance quantity and \u03b4i is the distance traversed that changes as the gradient flow changes the hand position, (*) is the sign which alternates as each segment is completed to drive the term towards 0 [Figure owards 0 .The distance-based formulation presented here can be converted to a time-based formulation of relative-temporal segments tracking differences between angular and linear velocities and accelerations. In addition the \u03bb-terms can be defined by other smooth-differentiable real-valued functions to represent different tasks. Since the gradient is a linear operator, the gradient of the sum  equals the sum of the individual gradients of each segment. Thus the segmented learning process can be modelled using the general gradient equation (i) and the excess segment-terms that make the motion jerky can be turned to 0 as the system learns to smooth out the timing. Likewise, more complex realistic multi-segmented motions in posture space can be geometrically characterized using the gradient approach. In such cases the limb segments can be synchronized or de-synchronized using a higher level temporal coordination scheme. Figures primate arm motions of several kinds ; (2) the simulated situations in which these symmetries and their co-variation would break down also existed in the empirical case. In the model this violation was predicted for non-isometric mapping of the gradient flow. In the after-effect data the invariants were indeed violated when the system mismatched the intended straight and the actual curved motion-path flow. The real system however, eventually recovered the symmetries and their similarity thus suggesting a default preference for a sensory-motor transformation strategy. This strategy seemed congruent with what the model had specifically predicted under local isometric embedding.Notice that this general gradient-flow solution could be applied to other non-brain problems. Thus, it is not implied here that this is the brain solution to this set of problems. What seemed striking were two findings: (1) this arbitrary model predicted area-perimeter related symmetries that held in actual This suggests that under normal circumstances the geometric transformations that give rise to actual motion paths from the primate arm can be on average well characterized by the local isometric embedding of the proposed PDE. Furthermore despite motor noise the symmetries from the data manifested invariance to straight or curved timings. The actual trajectories could be on average well characterized by different families of length minimizing curves and still preserve the similarity of the time-invariant symmetric ratios so long as -regardless of the sensory space geometry-the transformation from visual to body coordinates was distance-preserving (isometric).Both in the model and in the veridical paths the ratios were shown to be independent of the curvature and timing. Previous empirical data had shown the speed invariance of voluntary postural and hand reaching paths ,10,38,39Supplementary material contains a glossary of geometric terminology and a proposed computational method to further pursuit the study of this invariant symmetry in more complex motions.Click here for file"}
{"text": "Changes of breast-cancer (BC) mortality for all women in England and Wales between 1911 and 1975, and for the social-class gradient during the 1950s, were not related to changes in child-bearing. The changes in BC mortality for all women were associated with changes in consumption of fat, sugar and animal protein 1-2 decades earlier. A decline in mortality around 1935 was not obviously related to changes in fat or sugar, but dietary data were sparse. The social-class gradient of BC mortality almost disappeared during the 1950s; rates declined for the upper classes but increased for the lower. These opposite changes could have resulted from the opposite changes in diets of the upper and lower classes which occurred in the early 1940s. In contrast, the geographical variation of BC mortality within the United Kingdom, by region or by urban-rural aggregate area, was closely correlated with child-bearing but poorly correlated with diet. The poor correlation with diet might be a consequence of the small range of variation of diet between regions of the United Kingdom. The regional gradient of BC mortality was low in 1961, a decade after the period of food rationing when regional variation in diet would have been reduced. This suggested that diet did contribute to the regional variation of BC mortality within the United Kingdom, perhaps jointly with contributions from child-bearing."}
{"text": "Radioimmunoassay methods for the determination of oestradiol-17 beta and prolactin have been examined for their reliability and applied to the measurement of hormone concentrations in the plasmas from male and female rats. Prolactin was detectable in all samples (greater than 7 ng RP-1 ng/ml) but the concentration of oestradiol-17 beta was below the sensitivity of the method (greater than 0-10 ng/100 ml) in ovariectomized females. Plasma oestradiol-17 beta concentration rose gradually from metoestrus to proestrus and fell to barely detectable levels in oestrus. Plasma prolactin concentration was very variable even for rats in the same stage of the oestrous cycle but values were minimal in the afternoon of diestrus and a surge in secretion occurred in the afternoon of proestrus. In addition to the stage of the oestrous cycle, the prolactin concentration was influenced by mode of blood collection, degree of haemolysis and choice of serum or plasma. There was no correlation between the concentration of prolactin and that of oestradiol-17 beta in the same sample of plasma."}
{"text": "The classification of polymer samples from their infra-red spectrahas been achieved by the application of a fuzzy c-means clusteralgorithm. The generation of a fuzzy classifier allows thecharacterization of samples which are a combination of more thanone pure polymer."}
{"text": "The 5-year survival of women with localized (early-stage) cervical cancer is much higher than for women with non-localized (late-stage) cancer, but women with localized cancer tend also to be younger than those with advanced cancer. A new method of presenting the long-term survival is suggested, and the registrations of cervical cancers in South Wales are analysed in terms of average age at registration and average age at death. The observed average age at death was very close to 59 years regardless of stage (and age) at diagnosis, and calculations of expected ages at death of the whole populations suggest that more than half the advantage in survival shown by early stage cancers over late stage cancers is due to diagnosis of the former in younger women."}
{"text": "Virology Journal and the authors of this article [The Editor-in-Chief of  article  acknowle"}
{"text": "An Israeli Jewish population group consisting of 1298 cases of breast cancer and 1816 cases of benign mastopathy hospitalized in 1960-64 and 10,604 properly selected control women was studied with respect to the relationship of breast diseases to ethnic origin, educational background and socio-economic status. It was found that the percentage of Israeli-born and Orientals was higher in the benign mastopathy group than in the cancer group. For the Westerners the opposite was true. Educational level and socio-economic status were considerably higher in patients than in controls, regardless of ethnic origin. They were also higher in Westerners than in Orientals and among the Orientals higher in Iraqis than in Yemenites. The population groups with high breast cancer incidence rate appear to be on a higher educational and socio-economic level than those with a low incidence rate."}
{"text": "Cultured cells established from the bone marrow of a child with null-cell acute lymphoblastic leukaemia (ALL) have been studied. After 8 months in vitro, the cytological, cytochemical and immunological properties of the cultured cells were very similar to those of the patient's cells. Many of the cultured cells had morphological and cytogenetic abnormalities often found in acute leukaemia. The cells were EBNA-negative. This unique culture of ALL-derived null cells might provide information as to the aetiology and origin of malignant cells."}
{"text": "Proteinuria is a defining criterion for the diagnosis of pre-eclampsia. The amount of protein lost per day has been thought by some to predict both maternal and fetal outcome. The systematic review of 16 primary papers including over 6700 patients by Thangaratinam and colleagues published this month in BMC Medicine suggests otherwise. This finding may influence our management of pre-eclampsia. Proteinuria has been proposed and studied as both an indicator of severity of disease and as a predictor of outcome in pre-eclampsia. Many clinicians still make major management decisions based on the degree of proteinuria in such patients. The systematic review by Thangaratinam and colleagues  publishePre-eclampsia affects 2 to 3% of all pregnancies and is responsible for about 60,000 maternal deaths every year, mainly in poor countries , while iProteinuria is a defining dysfunction of pre-eclampsia . QuantitThe severity of the proteinuria in pre-eclampsia has been regarded by some as a predictor of adverse outcomes for the mother . Others The review by Thangaratinam et al  reportedDespite the rigor and efforts to determine the quality of the studies included in the current review, practice differences, equipment changes, and definitions of pre-eclampsia could have influenced the diagnosis (and management) of pre-eclampsia over the time period of the studies used. Thirty years ago changes in systolic pressure and diastolic pressure during gestation were being used to define pre-eclampsia  and if the diagnosis of pre-eclampsia is differently defined in different studies the validity of the result may be diminished.A very important potential confounding factor to consider in studies of the kind reviewed, is that the test result (in this case severe proteinuria), particularly in the earlier studies, may have dictated management. In the USA at least, proteinuria of 5 g or more per 24 hours is one of the diagnostic criteria for severe pre-eclampsia . If womeDespite these limitations, this metanalysis appears to confirm what clinicians have suspected for a long time. The degree of proteinuria alone does not have a strong association with adverse outcome. Maternal and fetal clinical condition and gestational age, complemented by hematologic and biochemical parameters, should for the time being remain the primary determinants for timing delivery in women with pre-eclampsia.As the results of observational studies may systematically over- or underestimate the predictive value of tests as discussed above, a randomized trial of knowledge versus no knowledge of the level of proteinuria to guide management would be justified.The authors declare that they have no competing interests.MAB and GJH drafted the manuscript and MAB revised it for important intellectual content. MAB and GJH have both given final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for the content.The pre-publication history for this paper can be accessed here:"}
{"text": "In a population-based case-control study in the Uppsala-Orebro Health Care Region of Sweden, the histories of cancer among parents of 517 histologically confirmed cases of papillary and follicular carcinoma and of a similar number of sex- and age-matched controls were compared. The parental history of cancer was compiled through information from death certificates and from the nationwide Cancer Register. The incidence of malignancies in a cohort of parents of cases of thyroid cancer was also compared with the incidence in the whole Swedish population. A maternal history of cancer was more common among women with follicular carcinoma than among their controls . Parents of probands with papillary carcinoma had an increased risk of thyroid cancer , and mothers of probands with follicular carcinoma had an increased risk of stomach cancer  compared with the general population. Cancer of the lung, breast, and pancreas were less common than in the general population. Familial cases of thyroid cancer were not limited to the papillary type. An inheritable pattern of carcinogenesis is possible for certain differentiated non-medullary thyroid cancers, but shared environmental exposures may also explain the parent-child associations of cancer in this study."}
{"text": "This paper reports on the evaluation and testing of a home-made device. Data-acquisition, treatment of transient signals and the hardware and software involved are discussed. Some practical aspects are developed in order to power the autonomy of procedures using the device. Kinetic and multi-signal calculations are considered in order to cover the actual tendencies in continuous-flow analysis. Somepractical advantages versus the use of classical chart recorders or commercial computerized-instrument devices are pointed out."}
{"text": "It is of great practical importance to develop simple methods for theautomatic detection ofthe controlled state of the analytical methodbeing applied. The key point is to find quantities that greatly affectthe quality of the analytical results and that can be easily estimatedduring the measurement process from the measured data. Thesignal-to-noise ratio has proved to be such a quantity in gaschromatographic methods. The statistical properties of theestimation of the signal-to-noise ratio from gas chromatographicdata have been investigated. The suggested practical method forestimating the signal-to-noise ratio proved to be biased from amathematical statistical point of view, but the bias is usually notgreater than 10%. It has been shown by practical examples that thesignal-to-noise ratio affects the quality of the analytical results andit is easy to estimate its value from practical data."}
{"text": "An introductory clinical trial of the anti-oestrogenic agent IC146474 in late or recurrent carcinoma of the breast is described.Forty-six patients have been treated, of whom 10 have shown a good response. This is of the same order as that seen with oestrogens and androgens.The particular advantage of this drug is the low incidence of troublesome side effects."}
{"text": "Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin IX might be a suitable photosensitizer in Barrett's oesophagus and adenocarcinoma, we determined the activities of porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) in various malignant and premalignant as well as in normal tissues of the human oesophagus. A PDT power index for ALA-induced porphyrin accumulation, the ratio of PBG-D to FC normalized for the normal squamous epithelium of the oesophagus, was calculated to evaluate intertissue variation in the ability to accumulate porphyrins. In malignant and premalignant tissue a twofold increased PBG-D activity and a marginally increased FC activity was seen compared with normal squamous epithelium. A significantly increased PDT power index in Barrett's epithelium and adenocarcinoma was found. Our results suggest that, after the administration of ALA, porphyrins will accumulate in a greater amount in Barrett's epithelium and adenocarcinoma of the oesophagus because of an imbalance between PBG-D and FC activities. The PDT power index here defined might be a useful indicative parameter for predicting the susceptibility of these tissues to ALA-PDT."}
{"text": "Xenopus, manipulated to be of comparable size, exhibited stagespecificantibody expression. The production of adult-type higher-affinity anti-DNPantibodies proved to be independent of the age and size of the individual and isconcomitant with the completion of metamorphosis. The appearance of new antibodyspecificities at such a time suggests that their expression occurs with the cell turnoverand renewal during a period of morphological changes.Tadpole and adult"}
{"text": "Social relationships are robust predictors of better health and greater longevity in aging adults. The current study examined a relatively understudied aspect of relationship quality - positive relations with others, a domain of eudaimonic well-being - and its independent associations with change in and incidence of mobility limitations in a sample of mid-life and older adults from the Midlife in the United States (MIDUS) study. Using data from all 3 waves of MIDUS, we examined the extent to which positive relations with others predicted smaller increases in limitations and reduced risk of onset of new limitations over a 18-20 follow-up period. Linear and logistic regression models, adjusted for demographic and health confounds, showed that higher positive relations scores predicted slower increase in limitations over time (p=.003) and reduced risk of incidence of new limitations (p=.01). These effects were also observed over and above the associations with more traditional structural and functional measures of social relationships, neither of which was significantly linked to changes in functional abilities. These results suggest that positive relations with others may act as a unique protective factor for functional decline, both in individuals with no initial functional limitations and in those with existing limitations. They also extend prior research on the potential health benefits of social relationships to include a social dimension of eudaimonic well-being. Finally, they suggest that vulnerability to functional limitations and the potential benefits of social connectedness extend to mid-life as well as older adults."}
{"text": "Recent population trends for the United States show substantial increases in racial diversity as well as an increase in the older adult demographic. Accordingly, the expansion in minority older adults suggests the importance of recognizing how race affects future care planning (FCP) in late life. The aim of this paper is to investigate the racial similarities and differences in planning behavior and intentions related to end-of-life care planning. This study utilized data from the Future Care Planning intervention based on the initial assessment with 237 older adults in rural Iowa  with 73 non-White participants. Results indicated that both Whites and non-Whites had similar levels of intentions in terms of future care. However, non-Whites were less likely than Whites to engage in multiple areas of FCP including planning behavior and preparing for end-of-life . These findings suggest a need for more targeted FCP assessments and interventions across race groups in rural contexts."}
{"text": "Ways to address the increasing healthcare needs of older people are a priority for the National Health Service (NHS) in England. The NHS England Test Bed programme was designed to trial new models of care that are supported by digital health technologies. This paper reports on findings from one Test Bed programme, the Lancashire and Cumbria Innovation Alliance (LCIA) \u2013 a partnership between NHS England, industry and Lancaster University, which ran from 2016 to 2018. A key aim of the LCIA Test Bed was to explore the extent to which supported self-care telehealth technology helped older people with long-term conditions to better self-manage their own care, promoting independence and enabling them to remain at home for longer. Each patient received a combination of health technologies over a six-month period. This paper presents results from the qualitative data that formed part of a large-scale mixed-methods evaluation. Specifically it draws on the analysis of 34 observational interviews with 17 participants with chronic obstructive pulmonary disease (COPD) to understand the role of these technologies in the self-management of their care. The data revealed that the majority of participants felt more confident about self-managing COPD as a result of their participation in the programme. These increases in confidence were the result of participants\u2019 increased knowledge and skills in managing their COPD. The paper demonstrates how patients learned to better manage their respiratory condition, the impact of this learning on their daily lives and that of their family carers, and the implications for healthcare practice."}
{"text": "We were struck reading this article by the fact that the authors did not properly address the state-of-the-art of the field in their review and were not addressing all the technologies developed over the past years to address intraoperative tumor diagnostic by MS. As a matter of fact, the authors fail to mention the SpiderMass technology. Therefore, they provide inadequate and not up-to-date citation on this discussed topic. In 2014, PRISM lab  introduced the water-assisted laser desorption/ionization MS (SpiderMass) and filed the patent (PCT/IB2015/057301) [ex vivo molecular profiles of a cohort of biopsies for example. One of the major advantages of the SpiderMass system is its low invasiveness and painless sampling, tissues being reversibly dehydrated. Another advantage and specific characteristic of SpiderMass is the very low fragmentation observed in the spectra and the possible operation in both positive and negative ion modes with good sensitivity. The system was successfully applied for cancer biopsies analysis ex vivo and then was shown for allowing real-time analysis of human skin in vivo as presented for the first time in 2015 at the ASMS conference and then published in 2016 [in vivo analysis and its potential to be used in intraoperative diagnostics. Over the past few years, the system was used to analyze genetically modified macrophage cell lines [ex vivo, allowing for correct classification (97% of specificity) of tumor type and grading [in vivo intraoperative analysis at the surgery room in a veterinary clinic on dog patients [We wish to offer our perspective and expertise concerning the review article entitled \u2018mass spectrometry-based intra-operative tumor diagnosis\u2019 written by Lorena H\u00e4nel PCT/IB201/057301 [patients . The afo"}
{"text": "Occupational diseases are broadly defined as diseases with a specific clinical diagnosis associated with work-related factors. The worldwide burden of work-related diseases and injuries is high, although there are large variations in and between countries . A work-Detecting early signs of work-related diseases could stimulate prevention . Early sConsidering the factor work in clinical care is to increase knowledge of work-related risk factors in diagnoses, selective prevention and treatment in the daily care of patients. The diagnoses of occupational diseases or work-related diseases is often complex due to its multifactorial origin and dependent on work-related, personal  and environmental factors. Work-related risk factors can worsen the prognosis and can hinder returning to work or sustaining at work. Therefore, knowledge about the work-relatedness of diseases is useful for clinicians in order to take timely and actively actions related to risk factors in the workplace; it will optimize the work participation of their patients and prevent worsening of diseases."}
{"text": "The increasing interest for microfluidic devices in medicine and biology has opened the way to new time-lapse microscopy era where the amount of images and their acquisition time will become crucial. In this optic, new data analysis algorithms have to be developed in order to extract novel features of cell behavior and cell\u2013cell interactions. In this brief article, we emphasize the potential strength of a new paradigm arising in the integration of microfluidic devices , time-lapse microscopy analysis, and machine learning approaches. Some snapshots of previous case studies in the context of immunotherapy are included as proof of concepts of the proposed strategies while a visionary description concludes the work foreseeing future research and applicative scenarios. In sucho models . Howevero models , liver  according to cell movements extracted in synthetic videos with the effect to make the ex vivo experiment more robust, to conduct synthetic massive tests, to reduce time-to therapy and patient undesired treatment effects.In this context, one of the most challenging scenarios for OOC devices is represented by cancer-immune cross-talk due to the very complex and not still completely discovered signaling modalities between immune cells and cancer insult or among clustered cancer cells. Some attempts have been presented with the aim to model cancer\u2013immune interaction  through approach  but therapproach ]. In thiapproach . Trajectapproach , automatapproach . After capproach ] can be approach . The stuapproach . Additioapproach . Motilitapproach . Furtherapproach  allow rein vivo and ex vivo like scenarios in favor of reduced invasiveness and deep understanding.The described platform is expected to open new scenarios of cell network modeling such as agent-based system  in order to simulate more advanced organs-on-chip model coupled to artificial intelligence (AI)-based algorithms and neural networks to provide more affordable organs-on-chip models of study. These AI-based OOC may potentially shorten the distances between in silico-based devices. Such a scenario allows enlarging the potentiality of OOCs experiments by increasing the mimicking capability of the platform toward in vivo like environment.Future application scenarios include the possibility to develop a hybrid system in which OOC-based environment interacts with This scenario is made possible counteracting the limitations imposed by the need of very high frame rate and high spatial resolution of the acquired images that lead to undesired effects such as phototoxicity and storage of more than Gigabytes of a single experimental data. Thanks to the exploitation of modern Deep Learning (DL) architecture , future EM and AM designed the manuscript organization and coordinated interactions among authors. All authors contributed to the manuscript preparation and revision.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Nature leads this week with a story about a proposal to fuse space-based astronomy funded by NASA with ground-based astronomy funded by the National Space Foundation (NSF). Science starts the week with a successs story about attempts to slow the spread of foot-and-mouth disease."}
{"text": "In this important paper Dr. Cheung and cols. from New York - USA, presented a modified technique of artificial urinary sphincter (AUS) placement with dorsolateral fibromuscular tissue of bulbo-spongiosus muscle (BSM) preservation.The authors proposed a technique that is associated with low rates of erosion and infection in patients with high risk of complications . BSM, also known as the bulbo-cavernosus muscle, is a paired striated muscle originating from the perineal body and fixed in a median raphe involving the bulbar urethra , 2. BSM The authors concluded that the preservation of dorsolateral fibromuscular tissue of BMS during AUS placement is an effective means to achieve a low risk of erosion with good functional outcomes with low rates of re-operation and excellent long-term continence. The study is retrospective but the description of a 74% success index is amazing and this new technique with BSM preservation is very interesting. This article presents a good overview of the surgical treatment of erectile dysfunction-related Peyronie's disease, covering the best indication of the various possible surgical alternatives. To conclude, we also emphasize that pre-operative counseling about the realistic outcomes of surgery in PD is mandatory to achieve adequate postoperative satisfaction rates."}
{"text": "Cellular aging is characterized by a build-up of oxidatively modified proteins. The steady-state level of oxidized proteins depends on the balance between the rate of protein oxidative damage and the rates of protein degradation and repair. Therefore, the accumulation of oxidized protein with age can be due to increased protein damage, decreased oxidized protein degradation and repair, or the combination of both mechanisms. The proteasomal system is the major intracellular proteolytic pathway implicated in the degradation of oxidized protein, and the peptide methionine sulfoxide reductase catalyzes the reduction of methionine sulfoxide  to methionine within proteins. A short summary on protein oxidative damage and oxidized protein degradation is given, and evidence for a decline of proteasome function with age is presented. Arguments for the implication of peptide methionine sulfoxide reductase in the age-related accumulation of oxidized protein are also discussed."}
{"text": "The late nineteenth century witnessed unprecedented advances in biomedical sciences, with the promotion in particular of physiological experimentation, bacteriological investigation, and chemical research . These finter alia, the shift from traditional materia medica to laboratory- and industry-based research; the establishment of the chemical and biological foundations of pharmacology; the gradual transformation from empirical drug discovery to rational drug design; the development of a wide variety of new drugs, as well as\u2014more recently\u2014the impact of molecular biology; and the re-evaluation of therapeutic strategies and priorities , and sheds more light upon the feedback loops that exist between bench and bedside, which are stereotypical of much pharmaceutical innovation.Al-Humadi et al. in their disease-focused review on the challenges of treating tuberculosis, with a specific emphasis on the decades between World War II and the early twenty-first century. In addition to summarizing the historical sequence of relevant drug development and use, the authors consider issues of drug resistance, drug repurposing, and problems of co-infection as factors influencing the fight against tuberculosis.A different approach is taken by Falzone et al. consider pharmacological treatments for cancer at the beginning of the twenty-first century, against the background of a series of turning points defining modern oncology: radiotherapy; the introduction of broad-based chemotherapy; targeted therapeutics; and the recent adoption of checkpoint inhibition as a novel immunomodulatory anticancer approach. Their review emphasizes the constantly changing and evolving field of drug discovery in the fight against cancer, with a focus on the biopharmaceuticals.Li et al. in their review of drugs for autoimmune inflammatory diseases, in which they describe the therapeutic trajectory from small-molecule compounds to anti-tumor necrosis factor (anti-TNF) biologics. In addition to analyzing the historical development of anti-inflammatory drugs after World War II, the authors consider the promise of novel TNF receptor-targeting entities that have already revolutionized the management of autoimmune diseases such as rheumatoid arthritis.A similar discussion on biopharmaceuticals is presented by Gu and Pei is a shorter perspective on historical aspects of Chinese herbal medicine (CHM) ranging from traditional practice to scientific drug discovery, with a focus on the antimalarial compound artemisinin. The authors suggest that a new understanding of traditional health practices using modern systematic and in silico techniques such as analytical chemistry, systems biology, network pharmacology, and computational modeling could provide promising new interpretations and applications of CHM.The final contribution by The articles included here cover only a small section of this huge subject of post-World War II pharmaceutical innovation. We hope that these papers will stimulate readers to delve further and reflect on the vast and varied relevant literature.Both authors have contributed equally to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Cyprinus carpio), hereafter referred as carp, is one of the most widely cultured fish produced for food globally. It was introduced into Australia for aquaculture in the mid-nineteenth century ] in Australia. McColl et al.  and produce viable offspring which are expected to have a high resistance to CyHV-3 disease  than in aquaculture ponds or under laboratory conditions (Kopf et al., The observation that CyHV-3 can persist in the wild without inducing carp death suggests that the expression of the disease requires environmental co-factors. Notably, the lack of recorded CyHV-3-associated mass carp deaths in Australia may simply reflect a lack of environmental co-factors rather than the absence of the virus. A recent phylogenetic study suggested that ancestors of CyHV-3 may have infected carp populations, long before the initial outbreaks of the disease were first reported (Gao et al., Invasive carp expanded in Australia to their current range and relative abundance decades ago (Shearer and Mulley, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Despite the increasing trend in catalytic studies dealing with gold-based materials, many questions remain open and the beauty of gold for the catalysis community remains alive. Apparently, the magic of this element resides in its resistance to be completely understood. Simultaneously, this mystery attracts scientists to keep working on it, to keep playing the game of revealing the beautiful secrets behind gold catalysts.Gold nanocatalysts have demonstrated excellent features for environmental catalysis including CO oxidation, clean hydrogen production, VOCs abatement, water purification, and COThe aim of this Research Topic is to celebrate the success of catalysis by gold, the extraordinary versatility of gold nanoparticles as catalytic materials, and the impact of gold-based catalysts for the development of greener and more sustainable societies.Meg\u00edas-Sayago et al. demonstrated the high efficiency of gold catalysts to conduct oxidations reactions in gas phase  and liquid phase (selective glucose oxidation). Both processes are key reactions with potential applications in the elimination of toxic gases in the former and synthesis of added-value platform chemicals in the latter. In terms of applications, the comprehensive review contribution from Carabineiro showcases the excellent performance of gold-based catalysts for two industrially relevant reactions such as the oxidation of alcohols and the oxidation of alkanes. The influence of the particle size, preparation method, and support is carefully described. Moreover, some mechanistic insights are addressed, opening some room for future catalyst improvement.In this sense, the collection of high-caliber contributions gathered in this special issue reflects the successful story of catalysis by gold and allows one to foresee the future in this field whose horizons are still under continuous expansion. This special issue reflects the versatility of nanogold catalysts in both liquid and gas phase reactions. For instance, the research article by Tabakova's review is an excellent contribution to the field of clean hydrogen production for fuel cell applications. The paper revises the most recent literature on the water gas shift reaction (WGS) and preferential CO oxidation (CO-PrOx)\u2013processes in which gold-based catalysts outstand as highly efficient materials. The review covers multiple aspects that are not standard in review papers such as design of single-atom catalysts, structure-monolithic catalysts, and strategies to design highly stable catalysts, among many other pivotal aspects of gold-based catalysts for redox reactions. Following the topic of the WGS reaction, the team of Prof. Hutchings has made an extraordinary contribution to this special issue with the research paper entitled Enhanced Activity and Stability of Gold/Ceria-Titania for the Low-Temperature Water\u2013Gas Shift Reaction . It is well-known that gold supported on ceria-zirconia is one of the most active low-temperature water\u2013gas shift catalysts reported to date but rapid deactivation occurs under reaction conditions. In this work, ceria-titania is proposed as an alternative support to highly dispersed gold nanoparticles leading to promising results in terms of activity and stability.Molina et al.). An added value of this work is the detailed discussion on how to optimize gold colloid preparation and their deposition to carbon materials that are very different in nature. The change of the continuous phase and its dielectric constant is used to assure the good dispersion of the hydrophilic/hydrophobic carbons and the successful transfer of the preformed small size colloids to their surface.Beyond oxidation reactions, this special also showcases the successful application of gold for reduction processes. The paper from Odriozola's team entitled Carbon Supported Gold Nanoparticles for the Catalytic Reduction of 4-Nitrophenol is a good example of the excellent performance of carbon-supported nanogold particles for organic nitro-compound reduction . This includes, for example, oxidation and reduction reactions in both gas and liquid phase media. The perspective also touches some of the most relevant industrial applications of gold-based catalysts commercialized so far. In addition, this perspective provides a snapshot of the current challenges triggered by nanogold catalyst limitations and also try to pinpoint the future trends expected for these materials.Finally, the perspective paper by Price and co-workers entitled \u201cThe successful story of gold based catalysts for Gas and Liquid Phase reactions: brief perspective and beyond\u201d is a nice synthetic piece of work where the fruitful application of gold-based catalysts in multiple processes is carefully addressed (As mentioned above, the spirit of this special issue is to celebrate with the catalysis community the success of one of its most acclaimed metals: gold. Overall, the set of works gathered in this special issue can be considered a fair representation of the versatility of gold-based catalyst to be a champion material in multiple applications. The editorial team hopes that this collection serves as a useful tool for the catalysis society and we hope to ignite passion for the discovery of the beautiful science hidden by this mysterious element.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "This data is useful to compare the oil prices impact on the leading oil trading countries and also compare a set of countries affected most by oil prices\u2019 fluctuations, oil-exporting countries or oil-importing countries. Since this data covers the period of latest oil-crisis, so the impact of oil-crisis could also be analysed.This data presented in this article is specifically employed from the Asian region based on the top position in the list of oil exporting and oil-importing countries around the world. Asia as the biggest continent on the earth had high consumption of energy [1]. Here we employed the daily prices of crude oil and seven oil trading countries, out of which three are oil exporting  and four are oil-importing countries , from the time period of 1-09-2009 to 31-08-2018. The data is collected from an authentic database Bloomberg. This data is related to the research paper \u201cVolatility spillover impact of world oil prices on leading Asian energy exporting and importing economies' stock returns. Energy, 188 (2019), 116002,  Energy 2The data covers the daily stock prices of three oil-exporting and four oil-importing countries, and then return of these prices are employed. The returns are calculated by taking the natural logarithm of closing prices divided by lagged closing prices.At first the graphical pictures of prices and returns are presented  to analyDescriptive analysis was performed to present a real picture about the important trends of the oil trading countries . The details of the descriptive analysis for the data are presented in Ethics approval is not applicable.The authors of the study have given their consent for the data to be used and published in this scientific article.Data generated or analysed during the study are available in the published paper which is highlighted in the aforementioned text. Moreover, raw data is linked with this data article in the (1)- Financial support from Fujian Major Social Science Planning Fund Program under grant no. FJ2017Z006.(2)- Fujian Natural Science Foundation Project under grant no. 2017J01518.There are two kind of funding supports with this data article.All of the authors have contributed equally to the design of theoretical model, to analyzing and discussing the data and to writing the data article. All of the authors read and approved this data article."}
{"text": "After the diagnosis of transsexualism is confirmed therapy commences with psychotherapeutic preparation for the conversion, and after conversion, long-term patient rehabilitation is maintained for at least two years. The indication for surgery is chronic discomfort caused by discord with the patient's natural gender, intense dislike of developing secondary sex characteristics and the onset of puberty. The surgical conversion of transsexuals is the main step in the complex care of these problematic patients . This suWe present a step-by-step male to female transsexual surgery.Surgical gender reassignment of male transsexuals resulted in replicas of female genitalia which enabled coitus with orgasm . With th"}
{"text": "A 30-year-old male with history of repaired hypospadias and anal atresia was referred for magnetic resonance imaging (MRI) of the pelvis  because of ongoing chronic prostatitis-like complaints for three months. MRI revealed a large thick-walled cystic lesion in the midline between the prostate and the (deformed) sacrum, communicating with the prostatic urethra at the level of the verumontanum via a thin neck  are cystic intraprostatic lesions located dorsocranially in the midline with communication to the prostatic urethra at the level of the verumontanum. They are embryologic remnants of the M\u00fcllerian duct system and are associated with genito-urinary abnormalities including hypospadias, intersex disorders, cryptorchidism and renal agenesis . PUCs ar"}
{"text": "The urban-rural dichotomy underpins the common approach in studying environmental conditions influencing older adults\u2019 lives characterized by post-Second World War urban migration in both Italy and the United States (US). However, the traditional opposition urban-rural dichotomy is inadequate to study how the environmental characteristics of a geographical area can account for the heterogeneous profile of its populations and its age distribution. This study aims to overcome the traditional mobility theories as an explanatory dichotomy for understanding the distribution of the age structure of a given population. The extent of a supportive network, and the connection between the place of residence to the proximity of other residential centres can be seen as potential resources for understanding the attractiveness of certain areas for older adults. A large harmonized set of demographic and socio-economic data were collected from the Italian National Institute of Statistics (ISTAT) and the American Community Survey (ACS). An analysis at the Italian municipality- and US county-level finds the population over 75 years old are overrepresented in rural areas of both countries as would be expected by available employment opportunities, but considerable heterogeneity among both urban and rural areas exist. In particular, rural more than urban settings are based on an informal support network that is argued to rely on human proximity to produce successful aging in the community. The variation in population of older adults in rural areas, therefore, might have implications on how to achieve age-friendly communities, aside from population\u2019s traditional mobility theories and formal support network."}
{"text": "Depression is a common mental disorder worldwide, and also a leading cause of disability and global burden of disease. The risk factors of depression are multi-facets; however, past studies have focused more on individual factors than ecological factors. This study aims to use a health map framework with multi-level analysis to analyze the effects of environmental factors on the incidence of depression of older adults in Taiwan. We connected 3 national datasets, including the National Health Interview Survey (NHIS), Age-friendly Dataset at city-level, and the National Health Insurance Research Databases (NHRID), to examine the relationship between environmental factors and the incidence of depression in Taiwan. The dependent variable was the new cases of depression in older adults during 2010-2016. The study variables were environment factors including 5 build environments and 8 social environments. A total of 6494 valid participants aged 50 and over were recruited from the 2009 NHIS and were followed up to 2016. There were 292 (4.5%) new incident cases of depression during 2010-2016. Results of multi-level analysis showed that only one built environment (no. of heritage sites) was associated with the incidence of depression. No social factors was found significantly in the study. It seems that factors of individual-level appear more important than that of ecological-level as the determinants of depression. Results of this study could provide an exploratory information for future research regarding the relationships between depression and environments."}
{"text": "In the last 10 years there has been increasing interest in the role of calcitonin gene-related peptide (CGRP) in primary headaches. Tension-type headache is one of the most common and important types of primary headaches, and ongoing nociception from myofascial tissues may play an important role in the pathophysiology of this disorder. CGRP sensory fibers are preferentially located in the walls of arteries, and nerve fibers containing CGRP accompany small blood vessels in human cranial muscles. It is well established that nociception may lead to release of CGRP from sensory nerve endings and from central terminals of sensory afferents into the spinal cord. It has also been shown that density of CGRP fibers around arteries is increased in persistently inflamed muscle. These findings indicate that ongoing activity in sensory neurons in the cranial muscles may be reflected in changes of plasma levels of neuropeptides in patients with chronic tension-type headache. To explore the possible role of CGRP in tension-type headache, plasma levels of CGRP were measured in patients with chronic tension-type headache. This study showed that plasma levels of CGRP are normal in patients and unrelated to headache state. However, the findings of normal plasma levels of CGRP do not exclude the possibility that abnormalities of this neuropeptide at the neuronal or peripheral  levels play a role in the pathophysiology of tension-type headache. Investigation of CGRP in other compartments with new sensitive methods of analysis is necessary to clarify its role in tension-type headache."}
{"text": "Please be advised that since publication of the original article  the authPlease see below for the correct (up-to-date) version of the figure:The authors apologize for this error."}
{"text": "The engineering design of microbioreactors (MBRs) and Organ-on-Chips (OoCs) has advanced considerably in recent years ,2. The tIn bioprocess development, the main aim of the use of MBRs is to accelerate the development work of new bioprocesses with microorganisms or mammalian cells as production organisms . The culThe aim of OoC devices is to facilitate the study of organ cell assemblies in vitro under conditions that recreate in vivo conditions of the organ in the body for recapitulating time-related cellular behavior ,5. An OoThis special issue addresses these diverse aspects of MBR design in nine expert contributions where a variety of cells and tissues are used with various aims and ambitions.The fundamental design challenges in MBRs are highlighted in two review contributions ,7. The sSeldon and Fuller  further The use of MBRs as tools for investigating tumor models is highlighted in two research studies ,9. KuhlbToh and colleagues  have devInvestigating effects of drug compounds on organ cells in in vitro microfluidic models has been mentioned recurrently to fill the need in the pharma industry for more efficient drug testing. In a study by Christoffersson and colleagues , a 3D moFreyer and colleagues  demonstrIn another MBR setup, Wrzesinski and Fey  carry ouAspects of fluid dynamics in MBRs are addressed by Tajsoleiman et al. . Due to Another important aspect of MBR design is oxygen distribution. Fernandez et al.  demonstrAll together, these nine contributions reflect state-of-the-art aspects of MBR design and highlight the inherent potential and strengths of the concept of MBRs for organ cell studies."}
{"text": "Digital communication technologies expand opportunities for social interactions and as a result have the potential to either amplify or dampen the coupling of social interactions with well-being in daily life. We use data from the 100-day Personal Understanding of Life and Social Experiences project  to examine variation in the sensitivity of older adults\u2019 daily reports of well-being to the quality of social interactions with their five closest social partners across digital  and analogue (in person/by phone) interactions. Digital interactions were more common among less-close social partners. Multilevel random coefficient models showed days with more digital interactions than normal to be characterized by a) lower well-being and b) less sensitivity in well-being to the quality of social interactions with close social partners on that day. The implications of our findings are discussed within a life-span perspective of social relationships and well-being."}
{"text": "Kynurenic acid (KYNA) is a bioactive compound that is produced along the kynurenine pathway (KP) during tryptophan degradation. In a few decades, KYNA shifted from being regarded a poorly characterized by-product of the KP to being considered a main player in many aspects of mammalian physiology, including the control of glutamatergic and cholinergic synaptic transmission, and the coordination of immunomodulation. The renewed attention being paid to the study of KYNA homeostasis is justified by the discovery of selective and potent inhibitors of kynurenine aminotransferase II, which is considered the main enzyme responsible for KYNA synthesis in the mammalian brain. Since abnormally high KYNA levels in the central nervous system have been associated with schizophrenia and cognitive impairment, these inhibitors promise the development of novel anti-psychotic and pro-cognitive drugs. Here, we summarize the currently available structural information on human and rodent kynurenine aminotransferases (KATs) as the result of global efforts aimed at describing the full complement of mammalian isozymes. These studies highlight peculiar features of KATs that can be exploited for the development of isozyme-specific inhibitors. Together with the optimization of biochemical assays to measure individual KAT activities in complex samples, this wealth of knowledge will continue to foster the identification and rational design of brain penetrant small molecules to attenuate KYNA synthesis, i.e., molecules capable of lowering KYNA levels without exposing the brain to the harmful withdrawal of KYNA-dependent neuroprotective actions. N-methyl-D-aspartate receptor (NMDAR). In addition, KYNA non-competitively antagonizes the \u03b17-nicotinic acetylcholine receptor (\u03b17nAChR) . Research interests in the KP find a unifying rationale in the ever-increasing demonstrations that the majority of the compounds formed along the pathway play a role in modulating fundamental aspects of biology  the absolute availability of tryptophan and/or L-kynurenine (KYN), (ii) the competition that exists between the kynurenine monooxygenase/kynureninase-dependent branches of the catabolic KP cascade   , in complex with the amino group donor/substrate kynurenine, or with the amino group acceptor/co-substrate oxaloacetate   . This rekat1 gene variant isolated from spontaneously hypertensive rats (SHR) is characterized by a missense mutation that leads to a Glu-to-Gly amino acid substitution at the C-terminal side of the sliding \u03b1-helix in the KAT I N-terminal arm (Kwok et al., The structural information on KATs summarized here strengthens the initially hypothesized fundamental role of a discrete region of the N-terminal arm of KATs in controlling substrate/inhibitor access into and binding inside the active site (Rossi et al., The analysis of KYNA synthesis from an integrated structural biology/neuropharmacology standpoint will drive the lead optimization process aimed at further improving the pharmacodynamics, bioavailability and specificity of action for the most potent hKAT II inhibitors developed thus far, as a prerequisite to their safe use in pathological situations characterized by abnormally elevated brain KYNA levels. However, due to the potential adverse effects associated with the irreversible inhibition of KATs, the future challenge for the field is the identification and/or the structure-based design of molecules capable of reversibly associating with specific KAT targets (Nematollahi et al., heme demolition, and XA deficiency has been associated with direct oxidative damage to insect midgut epithelial cells (Lima et al., Anopheles gambiae 3-hydroxykynurenine transaminase (Rossi et al., Plasmodium male gametogenesis, which takes place in the mosquito upon a parasite-infected blood meal (Billker et al., in vivo analyses, it has been proposed that KAT II could be the main determinant of XA synthesis in the CNS (Sathyasaikumar et al., At the same time, by revealing the determinants of substrate specificity in specific KAT isozymes, a combined structural biology/biochemistry approach could provide new small molecule tools to better characterize the interplay between the alternative branches of the KP in physiological conditions and in human diseases. A paradigmatic example of the applicability of such an approach is its recent use to study the roles of XA in the CNS. In light of the pro-apoptotic and neurotoxic potential associated with 3-HK (Okuda et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Given the high current prevalence of dementia and expected increases in the coming years, it is increasingly important to understand and address the process of transitioning from driving to non-driving among older drivers with dementia and the potential role of self-regulation . The purpose of this Alzheimer\u2019s Association-funded study was to examine differences in self-regulation between older drivers with and without dementia. Fifty-two active drivers age 65 or older , completed a validated self-regulation questionnaire and standardized assessment of cognition, vision, and psychomotor skills. The dementia group reported some awareness of cognitive challenges (lower driving-related abilities to remember things and concentrate on multiple things at a time than the comparison group). Similarly, the dementia group performed significantly worse on memory tasks and complex reaction time in the objective assessment. Both groups were confident they could drive safely where they needed to go. However, the dementia group reported being less comfortable driving in several situations . Despite lower driving comfort among the dementia group, there were few differences in self-regulation between the groups. The only statistically significant difference was that more of the dementia group had reduced their driving in the past year. There were no differences in self-regulation between groups for any of the specific driving situations for which the dementia group reported feeling less comfortable. Full study results will be presented along with implications for programs and future research."}
{"text": "Bactrocera dorsalis) infestations. The data was collected from the experiment. Fifty chili varieties (Capsicum spp.) were planted in the screen house and subjected to antixenosis and antibiosis tests. The antixenosis test was evaluated using choice and no-choice methods. The data observed was the number of oviposition punctures by fruit fly on the chili fruits. The antibiosis test was conducted on chili fruits using the Fitness Index method. The data observed were the percentage of pupa (%), the weight of pupa (mg), duration of larva-pupa (day), and duration of pupa-imago (day).This article contains the data on chili antixenosis and antibiosis to fruit fly ( The antixenosis response of chili to fruit fly (An antibiosis experiment was set up according to Hennessey et\u00a0al."}
{"text": "In the original article, there was an error regarding the cost of medically unexplained symptoms (MUS).A correction has been made to the Abstract:\u201cMedically unexplained symptoms (MUS) are common in both primary and secondary health care. It is gradually being acknowledged that there needs to be a variety of interventions for patients with MUS to meet the needs of different groups of patients with such chronic long-term symptoms. The proposed intervention described herewith is called The BodyMind Approach (TBMA) and promotes learning for self-management through establishing a dynamic and continuous process of emotional self-regulation. The problem is the mismatch between the patient's mind-set and profile and current interventions. This theoretical article, based on practice-based evidence, takes forward the idea that different approaches  are required for people with MUS. The mind-set and characteristics of patients with MUS are reflected upon to shape the rationale and design of this novel approach. Improving services for this population in primary care is crucial to prevent the iterative spiraling downward of frequent general practitioner (GP) visits, hospital appointments, and accident and emergency attendance (A&E), all of which are common for these patients. The approach derives from embodied psychotherapy (authentic movement in dance movement psychotherapy) and adult models of learning for self-management. It has been developed from research and practice-based evidence. In this article the problem of MUS in primary care is introduced and the importance of the reluctance of patients to accept a psychological/mental health referral in the first instance is drawn out. A description of the theoretical underpinnings and philosophy of the proposed alternative to current interventions is then presented related to the design, delivery, facilitation, and educational content of the program. The unique intervention is also described to give the reader a flavor.\u201dAdditionally, a correction has been made to the Introduction, paragraph one:\u201cMedically unexplained symptoms (MUS) are a thorny issue in primary care. Despite the differing nomenclature, the recent DSM-5 terms it as somatic symptom disorder (SSD) but is yet to achieve general usage. Many general practitioners (GPs) appear to reliably recognize MUS without the need for standardized assessments (Rasmussen et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
{"text": "Industry 4.0-based human-in-the-loop cyber-physical production systems are transforming the industrial workforce to accommodate the ever-increasing variability of production. Real-time operator support and performance monitoring require accurate information on the activities of operators. The problem with tracing hundreds of activity times is critical due to the enormous variability and complexity of products. To handle this problem a software-sensor-based activity-time and performance measurement system is proposed. To ensure a real-time connection between operator performance and varying product complexity, fixture sensors and an indoor positioning system (IPS) were designed and this multi sensor data merged with product-relevant information. The proposed model-based performance monitoring system tracks the recursively estimated parameters of the activity-time estimation model. As the estimation problem can be ill-conditioned and poor raw sensor data can result in unrealistic parameter estimates, constraints were introduced into the parameter-estimation algorithm to increase the robustness of the software sensor. The applicability of the proposed methodology is demonstrated on a well-documented benchmark problem of a wire harness manufacturing process. The fully reproducible and realistic simulation study confirms that the indoor positioning system-based integration of primary sensor signals and product-relevant information can be efficiently utilized in terms of the constrained recursive estimation of the operator activity. In the age of digital transformation, human operators are still applied in manufacturing processes. The Operator 4.0 concept aims to create human-cyber-physical production systems (H-CPPS) that improve the abilities of the operators\u2019 thanks to the dynamic interaction between humans and production systems . Smart sTracing hundreds of primary activities is critical due to the enormous variability and complexity of products. As every operator performs sequentially a specific set of actions over a period of time, our goal is to develop a sensor system that continuously estimates the time consumption of these elementary activities. We model the time consumptions of these actions by activity time models and compare the estimated activity times to the performance of operators and generate early warnings when their productivity decreases.For the cost-effective and robust measurement of assembly times, sensors were developed to record the timestamps related to the activity when the components are pushed into the fixtures by operators. As the activities of operators depend on the type and number of the built-in components, the production flow is tracked by an indoor positioning system (IPS). For the localization of the products and identification of the status of the conveyor system, Ultra-Wide band (UWB) IPS technology is applied with its low energy demand for transmitting information over a broad bandwidth (>500 MHz) and its accuracy with the range of 30\u201350 cm, which is significantly better than the one-meter uncertainty of Bluetooth Low Energy (BLE)-based solutions ,12.a priori knowledge concerning the activity times, the estimated parameters were optimally projected on to a set of linear constraints by quadratic programming [To integrate measurements originating from the IPS, a varying number (10\u2013100) of active or passive fixture sensors, and other information sources of the production management system, a multi-sensor data fusion (MSDF) algorithm has been developed. Multiple sensors provide redundancy enabling the robust recursive estimation of the unmeasured primary activity times of the operators. To constrain the model parameters to lie within a reliable region and incorporate important gramming . This cehttps://www.abonyilab.com/soft-sensors).The development of the proposed fault-detection algorithm is motivated by the analysis of an industrial wire harness manufacturing process which is a typical complex modular product manufacturing system ,15. To eThe remaining part of the paper is structured as follows. The developed IIoT-based sensor system is shown in In the present section, first the conveyor and the modular production systems are characterized, then the fixture sensors and the indoor positioning system as information sources are described. This is followed by the mathematical formulation of the multi sensor data fusion-based recursive estimation model and finally by the local estimation and monitoring with regard to the activity times of operators.The development of the proposed fault-detection algorithm is motivated by the analysis of an industrial wire harness manufacturing process. Wire harnesses are produced by a typical complex modular production system ,15. The k-th production cycle.The key idea is that in the case of modular production, the expected activity times are estimated based on the Bill of Materials (BoM) of the manufactured products. The manufacturing is modular meaning that the products m1,\u2026,mNm . The strnowledge  as presehttps://www.abonyilab.com/soft-sensors).To ensure fully reproducible results, only openly available information on wire harness manufacturing technologies was utilized during the development of this case study. To stimulate further research, the resultant algorithm of the developed model of the production system and the details of the products and sensor placements are publicly available on the website of the authors :i-th activity depends on how many elementary activities of a given type should be performed  Indoor Positioning System (IPS) technology with its low energy demand for transmitting information over a broad bandwidth (>500 MHz) and accuracy within the range of 30\u201350 cm, which is significantly better than the uncertainty of one meter that the BLE based solutions posses [As s posses ,12, was In comparison with outdoor environments, sensing location information in indoor environments requires higher precision which is a more challenging task because various objects reflect and disperse signals. Ultra-Wideband (UWB) is an emerging technology in the field of indoor positioning  that hasThe concept of identification of the products at workstations to extract product-relevant information from the Bill of Materials (BoM) and other structured information sources are widely used to support production management , value sMultiple sensors provide redundancy which enables the robust recursive estimation of the unmeasured primary activity times of the operators. Therefore, the estimation problem is defined as a sensor-fusion task . The prek-th cycle of the conveyor:The fusion center receives and synchronizes all the The linear structure of the developed production-monitoring model (see Equation ) is adeqWhen the observation errors of the workstations are assumed to be independent, the covariance of the The central estimation enhances the confidence of the nominal model which improves the performance of fault detection based on the reconciliation of the local measurements .Based on When the positive-definite weighting matrix function .The covariance matrix of the estimation error The recursive estimation of the primary activity times The recursive estimation consists of prediction and correction steps as follows.At the prediction step the state vector and its covariance matrix is calculated based on information available at the The correction step utilizes the measured a priori knowledge of the activity times, the estimated parameters were optimally projected on to the set of linear constraints by quadratic programming [To constrain the model parameters to lie within a reliable region and incorporate important gramming .The local (operator-related) projection of the unconstrained estimate ncreased .The following section demonstrates how the estimated and expected primary activity times are used for production monitoring.To validate the reliability of the proposed model, the distribution of the activity times collected from real production lines was studied. As is illustrated in The identifiability of the model is determined by the rank of the covariance matrix The information content of the available data can be evaluated based on the eigenvalues or determinant of the covariance matrix When only one product is produced, The production of 1000 products was studied. The production sequence contained all 64 types of products with an average batch size of 10 products/batch. The rank of the covariance matrix ored see .When the raw material, design or the processing of a component in a cost-cutting or quality-improvement project is changed by the supplier, this change may influence the activity times of the operators. Such operator-independent loss in performance can occur when a shorter length of wire increases the time required to lay and arrange the cables. In this case study, such effects are monitored. In the studied case, the new wires between the As The means of detecting individual losses in operator performance losses and sensor faults (due to delayed registration and IIoT communication) were also studied.In terms of fault detection, the prediction error used in Equation  can be uwth block matrix of The global performance of the model is reflected byBased on the analysis with regard to the rank of the ng error ,32 . One weakness of this procedure is that it assumes that conditions were comparable over the two time intervals. A more problematic issue is what happens when a significant change occurs in the process and product. For such applications precedent-based targeting models can be over simplistic. Activity-based targeting is particularly appropriate when the clear drivers of performance are known .Automatic monitoring and targeting schemes attempt to compare performances very short time intervals  which is ideal for fault detection. The most important key performance indicators (KPIs) of the production system are the station times which reflect how well the production line is balanced. The concept of calculating the station time is depicted in Human-in-the-loop cyber-physical production systems are transforming the industrial workforce. Due to the enormous variability and complexity of products, the tracing of hundreds of activity times on production lines is a critical problem. To handle this problem a software-sensor-based activity-time and performance measurement system was proposed. To ensure a real-time connection between operator performance and varying degrees of product complexity fixture sensors were utilized and designed and an indoor positioning system used to merge this multi-sensor data with product-relevant information.The presented sensor fusion algorithm combines all sensory and production data such that the estimates of the activity times have less uncertainty than would be possible when these sources were used individually. The estimation of the activity times is based on a linear-in-parameters model. The linear structure of the developed production-monitoring model is adequate as the time consumption of the activities linearly depend on how many primary activities should be performed and what is the number of the built-in components.The number of parameters of activity time estimation models is comparable to the number the number of measurements, the identifiability of the parameters of the model has to be carefully analyzed. For this purpose, we studied the Fisher information/covariance matrix of the estimation problem. The identifiability of the model and the information content of the available data can be evaluated based on the rank, the eigenvalues and the determinant of the covariance matrix. When the rank is smaller than the number of measurements , only a subset of the parameters is identifiable. As the placement of the sensors significantly influences the identifiability of the parameters, tools of D-optimal experimental design can be used to optimize the proposed system.The determination of the optimal number of sensors and features has crucial importance as redundant sensors can generate correlated features which decrease the efficiency of the algorithm. The analysis of the eigenvalues of the covariance matrix can highlight these negative effects. As this analysis is identical to Principal Component Analysis (PCA) of the multisensor data, the proposed methodology can utilize the reduced and transformed uncorrelated features, which results in a Principal Regression-based process monitoring algorithm. The second approach of avoiding correlated features is the application of feature selection algorithms that should be based on the previously discussed experimental design optimization task.As the estimation problem can be ill-conditioned and poor raw sensor data can result in unrealistic parameter estimates, constraints were introduced into the parameter-estimation algorithm to increase the robustness of the software sensor.The proposed model-based performance monitoring system tracks the recursively estimated parameters of the activity-time estimation models, while the sensor-relevant fault detection functionalities are based on the modeling errors which can be evaluated by classical residual-based fault detection algorithms.The applicability of the proposed methodology is demonstrated on a well-documented benchmark problem of a wire harness manufacturing process. The presented example demonstrated the benefits of multiple sensors as they provide redundancy which enables the robust recursive estimation of the unmeasured primary activity times. The fully reproducible and realistic simulation study also confirmed the efficiency of the proposed constrained estimation algorithm regarding fast convergence and giving reliable estimates.The results illustrate that indoor positioning system-based integration of product-relevant information and sensor signals and can be efficiently utilized to design on-line performance management systems.The developed benchmark problem can be used to study fault detection and sensor placement algorithms which is the objective of our further research."}
{"text": "Nature leads off this week with by speculating on the possible science policy consequences of the soon-to-be-inaugurated Bush administration. The top Science story this week is the announced budget increase for the National Institutes of Health (NIH)."}
{"text": "The monitoring of the activity of alpha-amylase and amyloglucosidase is an important tool for studying their role in the hydrolysis of starch. Here we introduced an improved method capable to measure the activity of alpha-amylase and amyloglucosidase from different sources based on a quantitative starch-iodine assay. The developments of the assay sought the consistent preparation of the reagents, the rescale of the assay and the adjustment of the sensitivity. This was complemented by a glucose yield assay for amyloglucosidase that allowed a secondary source of information when insoluble starches were studied. The proposed method showed high precision in long-term use (RSD\u2009<\u20096.3%). Furthermore, all experimental conditions can be adapted according to the equipment available at each laboratory, transforming this method in a broadband analytical tool for screening alpha-amylase and amyloglucosidase activities.\u2022Tailorable assay based on the starch-iodine staining for the determination of alpha-amylase and amyloglucosidase activities.\u2022Enhanced consistence of reagent preparation.\u2022High intra-day and inter-day reproducibility. Specifications TableStarch is a widespread raw material with several application fields that cover food (including confectionery and drinks), feed, pharma, chemical, and paper industries . In moste.g. phenol). On the other hand, the measurement of the substrate\u2019s consumption is possible using the starch-iodine staining. This method is based on the binding of iodine to terminals of the starch\u2019s polymeric chain .Fig..Fig.2 \u2265 The present method describes an improved experimental protocol that can be used to monitor the activity of two amylolytic enzymes: alpha-amylase and amyloglucosidase. This method intends to facilitate the implementation of a new routine determination of alpha-amylase and amyloglucosidase activities in any laboratory that could deal with amylolytic enzymes by providing all the necessary experimental details and conditions that could maximize the performance of the method. The long-term use of the method also showed a high-precision for both intra-day and inter-day measurements. In the case of amyloglucosidase, it is also possible to measure glucose yield using a protocol similar to the one applied to the enzyme activity. Furthermore, this improved method is very flexible and allows a broadband application, being able to be easily adjusted according to the requirements of each study or the equipment and instrumentation available at each laboratory."}
{"text": "The following information is missing from the Funding statement: The work by Quijano-Sanchez has been supported by the Spanish Ministry of Science and Innovation grant FJCI-2016-28855."}
{"text": "The development of age-friendly cities and communities has become an important area of work in the fields of public health, ageing and public policy. This development reflects several larger trends including the complexity of demographic change and the recognition of the role of the environment in healthy ageing.In 2017, there were an estimated 962\u00a0million people aged 60\u00a0years or older worldwide, that is, around 13% of the global population. This part of the population is growing at an annual rate of about 3% and further growth is almost inevitable.Age-friendly city guide in 2006.In 2006, the World Health Organization (WHO) initiated a programme specifically targeting the health of urban residents aged 60 years and older, linking the challenges of urbanization and ageing. This collaborative programme aimed to identify which features of the built and social urban environment are essential in creating sustainable and supportive environments for older residents, and culminated in the publication of the An age-friendly city was defined as a place that encourages active ageing by optimizing opportunities for health, participation and security to enhance quality of life as people age.The network has reached several of the guide\u2019s objectives, such as generating greater recognition of the implications of population ageing on urban planning and involving stakeholders at multiple governmental levels.With increasing population ageing and urbanization, the development of age-friendly environments is a topic that demands the attention of both researchers and policy-makers. Two approaches hold the potential to move age-friendly city research forward: integration of determinants of ageing at multiple levels and the dynamics of urban environments. The guideA recent publication builds on these findings by exploring the prevalence of the tendency \u201cto focus on the characteristics of ageing individuals and their immediate milieu, while paying little attention to the interaction between the micro-individual traits and the macro-level workings.\u201dAn example of how micro and macro processes are intertwined in the age-friendly city context is that of the prioritization of working-age families in urban renewal processes. This prioritization marginalizes older people from urban renewal, which implicitly creates a cultural bias towards age-segregated residential landscapes.While many studies investigate micro-level indicators of age-friendly cities, such as accessibility or individual safety, relatively few studies investigate how large socioeconomic and sociospatial developments impact ageing communities and the cities they live in. An example is the seesaw effect between urban greenness and urban density: both an increase in the amount of urban green areas and the development of more compact cities have been linked to better health.As with many other public health challenges, a systems approach may be a promising strategy to analyse such effects. Two sample research questions exemplify this integration of cross-level interactions. First, what multilevel processes of sociospatial transformation are driving urban change and how do these forces impact the health of ageing urban populations? Second, how can we use system-based approaches to simulate the effect of prevention and early identification policies specific to urban environments on the trajectories of ageing and well-being? To answer these questions, engaging in current debates in the fields of urban geography and complex system science is necessary and can provide new perspectives.A second important approach to consider relates to the temporal character of urban environments. Cities are dynamic and constantly evolving,An example is the effect of life-course neighbourhood exposures on health. The life-course perspective informs understanding of how at later periods in life, health is affected by earlier experiences. This perspective also draws attention to historical circumstances and periods that are vital in shaping people and places.Two sample research questions are relevant to this approach. First, how are life-course histories of ageing individuals connected to the sociospatial histories of urban environments, and how does this combined effect influence health? Second, how do individual space-time constraints and temporal rhythms of activities affect health and health behaviour in ageing urban populations? Answering these questions will not only contribute to a better understanding of how the space-time of individuals and places relate to current health, but will also provide better insight on how age-friendly developments are influenced or limited by other historical urban developments. Building the evidence base this way will provide both researchers and policy-makers with tools to better design age-friendly communities.The public health challenges of ageing and urbanization are likely to intensify in the coming decades. Age-friendly cities still hold potential for both researchers and policy-makers. This potential should be further explored as the age-friendly city will never be an achieved condition, but an offer of an open horizon to work towards sustainable and age-friendly environments."}
{"text": "As our society continues to age and family size decreases, there is increasing concern about lack of caregiver availability. This may be especially important in the context of end-of-life decision-making. The goal of this study was to characterize the size and composition of the family network of adults at the time of death using a population-based register study. All adults in Denmark who died of natural causes 2009-2016  were linked to living adult family members . While the majority of decedents were linked to multiple family members (median =5), 21.6% had no identified living family at the time of their death. Kinlessness was especially common among older women and those with dementia. In addition to supporting caregiving families at the end-of-life, we must also recognize that there are many kinless individuals who may benefit from early formal care planning services to facilitate end-of-life decision-making."}
{"text": "A sixteen-year-old patient consulted for right hip pain, with limited mobility and no fever. Standard radiograph of the hip shows widening of the joint space with organized calcifications of the roof of the acetabulum (A). CT scan showed many intra-acetabular osteochondroma (B). The hip was approached anteriorly, without dislocation of the femoral head. Multiple free chondromes and some adherents to the acetabulum were found (C). The diagnosis was confirmed by anatomopathological study. The follow-up was good with recovery of mobility. Primary synovial chondromatosis is a benign synovial dystrophy, characterized by the formation of cartilaginous nodules (chondromas) that may ossify secondarily in a joint or synovial sheath. Its evolution is slow and asymptomatic at its beginning. It is a cause of lameness in children and often poses a problem of differential diagnosis with rheumatic arthritis."}
{"text": "The goal of PCC is to enhance quality and bring meaning to the lived experience in long-term care. This requires attention to patterns of life, and the creation of residential experiences within the environment. Ten case studies of homes participating in a pay-for-performance PCC program in the Midwest reveals how environmental affordances may be critical in the implementation and sustainability of PCC. Data collected through an in-depth environmental assessment revealed multiple strategies and attributes related to organizational, operational, and environmental practices. This presentation will demonstrate a diagrammatic and empirical comparison of the environments of those early in the process and those who have fully implemented and sustained PCC practices. Specific features will be highlighted and patterns discussed."}
{"text": "Correction to: BMC Evol Biolhttps://doi.org/10.1186/s12862-018-1309-8Following publication of the original article , we haveOne of the authors (WM) notes that he has also been involved in the development of state-of-the-art software, data management and mining tools; some of them were commercialized by HKL Research.None of commercial software was mentioning in the paper but because knowledge gained during research may be in future used in commercial software, WM has disclosed a financial interest in this research as WM is the co-founder of HKL Research and a member of the board.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed."}
{"text": "Scientific Reports 10.1038/s41598-018-25664-6, published online 08 May 2018Correction to: The Acknowledgements section in this Article is incomplete.\u201cThis work was funded by the National Institute of Oceanography and Applied Geophysics (OGS), by the University of Trieste (UNITS) and by the FORMAS grant 214-2013-1600 to Nina Kirchner. We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. Parts of the computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at PDC Center for High Performance Computing at KTH. The authors would like to thank the anonymous reviewers for their valuable comments and suggestions to improve the quality of the paper.\u201dshould read:\u201cThe research reported in this work was supported by Oceanography and Applied Geophysics (OGS) and CINECA under HPC-TRES program award number 2016-03, by University of Trieste (UNITS) and by the FORMAS grant 214-2013-1600 to Nina Kirchner. We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. Parts of the computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at PDC Center for High Performance Computing at KTH. The authors would like to thank the anonymous reviewers for their valuable comments and suggestions to improve the quality of the paper.\u201d"}
{"text": "An attempt is made to assess the present knowledge about the methods of determining mercury (Hg) exchange at the air-water-soil interface during the past 20 years. Methods determining processes of wet and dry removal/deposition of atmospheric Hg to aquatic and terrestrial ecosystems, as well as methods determining Hg emission fluxes to the atmosphere from natural surfaces (soil and water) are discussed. On the basis of the impressive advances that have been made in the areas relating to Hg exchange among air-soil-water interfaces, we analyzed existing problems and shortcomings in our current knowledge. In addition, some important fields worth further research are discussed and proposed."}
{"text": "This interdisciplinary symposium focuses on the Voices in Motion (ViM) choir, a novel social intervention to address issues of stigma and social isolation among older adults with dementia and their caregivers. ViM is an intergenerational choir for community-dwelling older adults with dementia (PwD) and their caregivers. Local high school students participated in the choir and added to the lively social interactions. Two professionally directed ViM choirs were fully implemented in 2018-2019 with a public performance in the Fall and Spring seasons. This symposium brings together multiple methodologies to investigate the effects of choir participation on cognition, social connections, stigma, and quality of life for the dyads. Results in the individual papers demonstrate the positive impact of choir participation on dyads (n=26) for measures that includecognition , well-being and quality of life (Sheets), and social connections (Smith). Taken as a whole, the papers indicate that this social intervention offers an effective non- pharmacological alternative approach for older adults with dementia. Choir participation has important and significant impacts on psycho-social well-being and quality of life. The body of evidence presented points to the importance of intergenerational programs that are dementia-friendly and that support meaningful participation by older adults with dementia in the broader community. Discussion focuses on implications for social policy with attention on the replication and sustainability of the program."}
{"text": "Instituto Estadual de Florestas), regulatory deliberation 86/2005 of the state of Minas Gerais, law 12040/1995 of the state of Minas Gerais, law 18030/2009 of the state of Minas Gerais, Brazilian law 9985/2000, and some laws/decrees that created municipal protected areas. The data was used to analyze the influence of the ecological fiscal transfers (EFT) in the policy-making process of adopting protected areas by municipal governments in the state of Minas Gerais. It has the potential to be reused in other studies to analyze the EFT at the local level. The related research article that uses this database was published under the title \u201cEcological Fiscal Transfers for Biodiversity Conservation Policy: A Transaction Costs Analysis of Minas Gerais, Brazil\u201d [1].This dataset was collected in the state government of Minas Gerais, Brazil ( The data were gathered from the State Government of Minas Gerais under the Brazilian law on access to public information . Also, additional data were collected from laws/decrees of the municipal governments that created PAs.The dataset contains raw and analyzed data of protected areas (PAs) created by municipal governments in the state of Minas Gerais from 1966 to 2013. The data files (do-files) were deposited at Mendeley , environmental protected area (APA), biological reserve (REBIO), natural monuments (MONA), municipal forest (FLOMA). The categories of protected areas are classified into two groups: sustainable  and integral protection . The name and the measurement of the variables used in the study are described in 2To perform the analysis to understand the influence of EFT in the policy-making process of adopting PAs by municipal governments , a compr"}
{"text": "Injury and injury prevention of the drivers, passengers, and vulnerable road users are one of the most important issues in vehicle accidents and cannot be overlooked. The challenges of this issue focus on the following aspects: (a) the accident conditions causing injuries and mechanisms of these injuries; (b) the effect of characteristics of an injured person, e.g., age, gender, and types of vulnerable road users, and the development of computational models for the injured-included accidents; and (c) the methods and designs for injury prevention. In this special issue on injury analysis and prevention in vehicle safety, we have invited a few papers that address such issues.The first paper  develops experiments to study the thoracoabdominal injuries suffered from caudocephalad impacts using pigs. 21 adult minipigs divided into three groups are tested in different impact velocities, and the mechanical responses are then analyzed. The second paper  investigates the effect of neck muscle active force on whiplash injury of the cervical spine to indicate that the neck active force influenced the head-neck dynamic response and whiplash injury during a collision, especially in a low-speed collision. The third paper  studies the effect of the neck muscle activation on head and neck injuries to find out that the activation of neck muscles can lower not only the head horizontal acceleration under different impact intensities but also the head angular acceleration in medium- and high-speed impacts. The forth paper  uses a numerical method to study the risk factors affecting lumbar spine injuries. The effects of coefficient of friction, impact velocity, cushion thickness and stiffness, and cushion angle on the risk of lumbar spine injuries are analyzed.The fifth paper  investigates the dynamic response and head injuries of standing subway passengers during collisions based on the MADYMO models to provide guidance for the safety design of the subway and some advices for standing subway passengers. The sixth paper  analyzes the injury of the riders upon car-electric bicycle accident. After accident reconstruction, data acquisition, data verification, and screening of 57 car-electric bicycle accidents wherein riders are hit to the engine hood and thrown to the air, the data obtained from the remaining 53 cases were analyzed. The seventh paper  focuses on the head and brain injuries of one new vulnerable road user which is a rider using electric self-balancing scooters. The eighth paper  develops the age-specific lower extremity finite element model for simulating pedestrian accidents. The development of the age-specific lower extremity models will lead to an improved understanding of the pedestrian lower extremity injury mechanisms and injury risk prediction for the whole population in vehicle-pedestrian collision accidents.The ninth paper  analyzes the effects of curtain airbag (CAB) on occupant kinematics and injury indexes in a rollover crash. The simulation results indicated that the occupant kinematics and most injury indexes were improved with the help of CAB in such rollover scenario. The tenth paper  investigates the relationships between the front-end styling features of SUVs and head injuries at the styling design stage for pedestrian protection performance improvement and product development efficiency. The eleventh paper  designs a conceptual bumper energy absorber coupling pedestrian safety and low-speed impact requirements. The new X-shape energy absorber can meet both pedestrian safety and low-speed impact requirements well by altering the main deformation modes according to different impact energy levels."}
{"text": "We present the results of theoretical studies of formation and evolution of the current sheet in a colliosionless plasma during magnetic reconnection in relativistic limit. Relativistic magnetic reconnection is driven by parallel laser pulses interacting with underdense plasma target. Annihilation of laser created magnetic field of opposite polarity generates strong non-stationary electric field formed in between the region with opposite polarity magnetic field accelerating charged particles within the current sheet. This laser-plasma target configuration is discussed in regard with the laboratory modeling of charged particle acceleration and gamma flash generation in astrophysics. We present the results of 3-dimensional kinetic simulations and theoretical studies on the formation and evolution of the current sheet in a collisionless plasma during magnetic field annihilation in the ultra-relativistic limit. Annihilation of oppositively directed magnetic fields driven by two laser pulses interacting with underdense plasma target is accompanied by an electromagnetic burst generation. The induced strong non-stationary longitudinal electric field accelerates charged particles within the current sheet. Properties of the laser-plasma target configuration are discussed in the context of the laboratory modeling for charged particle acceleration and gamma flash generation in astrophysics. Various impulsive phenomena in space plasmas can be attributed to MR such as solar flares6, coronal mass ejections8, pulsar winds11, open and closed planetary magnetospheres14 and gamma-ray bursts18. In laboratory plasmas, MR is related to the nuclear fusion plasma dynamics22 and the weakly ionized plasmas23.Magnetic reconnection (MR) is a fundamental process in astrophysical and laboratory plasmas which provides a mechanism to convert the magnetic field energy to the energy of plasmas and charged particles accompanying with the topology variation of the magnetic field linesAgile and Fermi-LAT in 2010 is tightly related to MR27. According to refs.\u00a028, the underlying mechanism of gamma-flares in the Crab Nebulas is based on the electron acceleration during magnetic reconnection in the relativistic limit. The features of the time dependence of gamma-flares indicate that the electron acceleration occurs in non-stationary electric field. Modeling of such the phenomena under the conditions of terrestrial laboratories is an intriguing problem.The observations of high-energy gamma rays from the Crab Nebula reported by 32 to provide a framework where MR can be investigated in the regimes of interest for astrophysical environment. One of the pioneering experiments on MR studying in laser-plasmas was proposed by Nilson et al.33 with two nanosecond laser beams and a planar solid target. Li et al.34 irradiated a thin plastic (CH) foil with two or four 1-ns long OMEGA laser beams. Both experiments observed the plasma jets with keV energy in the reconnection region. Recent experimental works with intense and high-energy laser pulses have shown plasma outflows with keV electrons and plasmoid generation in current sheets formed during reconnection on the time scale of nanoseconds35. Fan-like plasma outflows with MeV electrons and a plasmoid were obtained in a similar setup with Al foils by Dong et al.36. Lezhnin et al. presented the results of the magnetohydrodynamics simulations of driven magnetic reconnection on colliding magnetized laser-produced plasmas37. In the presence of a very powerful (petawatt) short laser pulse MR transits into the collisionless relativistic regime. Several numerical studies have been performed in the relativistic regime. Ping et al.39 reported a fast reconnection driven by two ultra-intense laser pulses using 3D kinetic simulations and the corresponding change of the topology structure was observed. MR driven by nonthermal and relativistic electron beams have been discussed recently in refs.\u00a043. Magnetic reconnections under the extreme condition of QED critical field are proposed in refs.\u00a045.The dynamics of laser produced plasmas has been shown in refs.\u00a046. Recent numerical studies with particle-in-cell (PIC) simulations presented clear signatures of the particle acceleration in the magnetic annihilation regime50.In ultra-relativistic regime, the MR acquires novel features. Due to the relativistic constraint on the electron velocity, the variation of the magnetic field cannot be sustained by the upper limit of the electron current. The magnetic annihilation is principally dominated by the displacement current and the corresponding inductive electric field. This so-called dynamic dissipation of the magnetic field was first proposed by S. I. SyrovatskiiIn this paper, we present the results of kinetic simulations on the collisionless relativistic MR regime in the 3D configurations. The purpose is to investigate the electron acceleration via the MR generated electric field. We consider the configuration in which two sub-petawatt short laser pulses interact with the hydrogen plasma target comprising two density steps. The magnetic fields with opposite polarities generated by the laser driven electron current is expected to annihilate in the low density region due to the transverse expansion of the magnetic field. In such the non-adiabatic region where the magnetic field freezing-in breaks, the plasma cannot react collectively anymore. The fast annihilation creates strong electric field accelerating electrons up to high energy.The paper is organized as follows. First we describe the simulation setup. Section of Electron Current Filaments and Strong Magnetic Field Generation presents the results of the kinetic simulations showing two electron current filaments generated by two laser pulses interacting with underdense plasma target and the associated magnetic field configuration produced by these electron current filaments. The next section is devoted to the description of opposite magnetic polarities merging resulting in the magnetic X-line formation and its evolution to thin current sheet. Then we discuss the excitation of the electromagnetic burst and the corresponding charged particle acceleration. The dynamics of the electrons and the typical trajectories are presented. Reconnection of the magnetic field lines in collisionless plasmas is closely related to the Hall effect resulting in the transverse electric field and current excitation. The Hall effect and the quadruple magnetic field formed in the vicinity of the X-line are considered. The tearing mode-like instability leading to the current sheet break-up into magnetic islands is described. The last part contains discussions and conclusions.Two linearly polarized Gasussian pulses with the peak intensity of 51. Due to the self-focusing effect of the laser field, et al.52 as: The laser pulses generate plasma channels in the underdense hydrogen target since the power of the pulses is higher than the relativistic self-focusing threshold, Figure\u00a0The radius of the magnetic dipole structure depends on the radius of the plasma channel With the expansion of the channels, the size of the magnetic dipoles also increase in the transverse direction. As illustrated in Fig.\u00a0The When the two regions with opposite polarity magnetic field merge, the so-called X-line structure in MR is formed. Fig.\u00a053, second type Fermi acceleration by turbulence54, the reflection in magnetic islands55 and the direct acceleration by reconnection electric field56. Here we proposed the regime of dynamic dissipation of the magnetic field and electromagnetic burst in the ultra-relativistic regime. Recalling the Ampere-Maxwell law\u00a0As mentioned in the previous section, the current sheet is formed due to the particle acceleration in the region where the magnetic fields with opposite polarities annihilate. The particle acceleration in the X-line of MR has been interpreted by several mechanisms including fast shock wave57. Here we employ the main conclusions suitable for our case. The electric and magnetic field around the reconnection region can be approximately described as: The dynamics of the particles in the vicinity of the X-line has been discussed in ref.\u00a0In the ultra-relativistic case, the scale-length (Larmor radius) characterizing the electron trajectory is 60). The Hall effect is closely related to the in the transverse electric field and current excitation, seen in the quadruple magnetic field formed in the vicinity of the X-line. With the magnetic field annihilation and the inductive field increasing, it generates in-plane currents due to the decoupling between electrons and ions. The plasma transversely drifts according to the distribution of the magnetic fields and the inductive electric field with the drift velocity The Hall effect manifests the basic properties of the magnetic reconnection in collisionless plasmas (e.g. see refs.\u00a061. However, in incompressible plasmas where the density does not change but the magnetic islands can be formed, as in the tokamak plasmas where the plasma incompressibility is provided by strong toroidal magnetic field20 or in the EMHD magnetic reconnection where the electron density remains unchanged due to electric charge separation electric field effects59. Since in the case under consideration the charge separation electric field also contributes to the electron density evolution the relationship between the electron density distribution and the magnetic field configuration is quite complicated. The filamentation and the breaking consistent with the electron trajectories shown in Fig.\u00a0The current sheet is unstable and it may break-up into filaments due to the development of the tearing mode instability. The corresponding schematics are shown in Fig.\u00a062. The regime proposed can be used for formulating the program of forthcoming experiments, including the research in laboratory astrophysics60. The diagnostics for the backward accelerated electron beam will be one of the signatures for the relativistic magnetic reconnection. Furthermore, the growing of the displacement current generates a low frequency wave which has a characteristic wavelength about In conclusion, we investigate the magnetic reconnection driven by laser-plasma interaction by using the 3D kinetic simulations. It presents the formation and evolution of the current sheet in a collisionless plasma during magnetic field annihilation in ultra-relativistic limit. The accelerated electron beams generated in the gas jet plasma create strong magnetic fields. The annihilation of opposite magnetic polarities is accompanied by an electromagnetic burst generation whose strong non-stationary electric field accelerates the charged particles within the current sheet. It is found that the displacement current plays important role in the ultra-relativistic MR to induce the significant growth of the longitudinal electric field. In the vicinity of the magnetic null line, charged particle acceleration is observed. Since the inductive electric field moves in the forward direction with respect to the propagating of the laser field, the electrons, which are accelerated in the backward direction, experience only an instantaneous kick. Therefore the corresponding electron bunch has a relative small energy spread. The dynamics of the particles accelerated by this field in the region in the vicinity of the X-line has been studied. Narrow energy spectrum electron beam is obtained which will be useful in explaining the radiation spectrum obtained in the astrophysics. One of the intriguing problems standing in astrophysics for a number of years is explanation of the detected gamma-ray spectrum pointing towards a very narrow particle spectrum, which is one of the arguments against the shock-acceleration regime. Our results of the mono-energetic bunch generation provide a clear signature to support the particle acceleration via MR regime. Due to the development of the tearing-like mode instability, the current sheet breaks into separated pieces. It leads to formation and evolution of the secondary magnetic islands in the current sheet. The requirement of the laser energy can be expected to be fulfilled by the upcoming facilities like ELI-Beamlines64 in 3D cases. Two linear-polarized laser pulses with the peak intensities of The simulations are performed with the relativistic electromagnetic code EPOCH"}
{"text": "Triceps nerve-to-deltoid nerve transfer requires the identification of the axillary nerve in the quadrilateral space. This may be difficult especially for residents-in-training. The senior author is a Professor of Hand Surgery at a teaching institution and has devised a new technique of identification of the axillary nerve and its cutaneous branch using surface land-marks and on-table ultrasonography.The axillary nerve and the quadrilateral space is first identified using anatomical landmarks. The ultrasound probe is the used to identify the quadrilateral space and the axillary nerve which appears as hyper-echoic oval-shaped structure. The ultrasound probe is then moved to scan the cutaneous branch of the axillary nerve as it branches-off the main nerve trunk. Finally, the cutaneous branch is traced superficially till it becomes subcutaneous. This point is marked and the skin incision is made along this marked point. During surgery, the cutaneous branch is followed retrograde to the axillary nerve in the quadrilateral space.Ultrasound guidance for localization of various nerves is now routinely done by anesthetists in the Operating Room. This localization is used for nerve blocks and in patients with brachial plexus injuries. Hence, the ultrasound machine and the expertise are already available in the operating room; and no special arrangements with the Radiology Department are needed.A technique of identification of the cutaneous branch of the axillary nerve using anatomical landmarks and ultrasonography is described. The localization is accurate and is of help in patients undergoing triceps nerve-to-deltoid nerve transfer. The senior author (MMA) is a Professor of Hand Surgery at a teaching institution and has devised a new technique of identification of the axillary nerve and its cutaneous branch using surface land-marks and on-table ultrasonography. The technique may also be helpful for experienced surgeons in difficult cases such as obese patients and in case who had previous surgery in the arm. We describe the technique using demonstrative case. The work has been reported in line with SCARE criteria .2The patient is positioned in the prone position. Localization of the axillary nerve and its cutaneous branch is done prior to prepping and draping. A longitudinal line is drawn from the postero-lateral acromion to the olecranon. A second transverse line is drawn from the axillary fold to intersect the first line at 90\u00b0 angle. Anatomically, the quadrilateral space should be 2\u2009cm cranial to this point of intersection . This po3Previous authors mentioned that the easiest way to identify the axillary nerve in the quadrilateral space is through retrograde dissection of the cutaneous branch of the nerve .With ultrasound guidance, we found it is easier and more reliable to scan the main axillary nerve trunk in the quadrilateral space and then trace the cutaneous branch antegrade without ultrasound guidance, localization of the cutaneous branch of the nerve may be difficult especially in obese patients and in patients with previous surgery in the arm. Furthermore, residents-in-training usually take a long time localizing the cutaneous branch even in straight-forward cases. Hence, the above ultrasound-guided technique for pre-operative nerve localization is now preferred at our teaching institution.Ultrasound guidance for localization of various nerves is now routinely done by anesthetists in the Operating Room. This localization is used for nerve blocks  and in p4A technique of identification of the cutaneous branch of the axillary nerve using anatomical landmarks and ultrasonography is described. The localization is accurate and is of help in patients undergoing triceps nerve-to-deltoid nerve transfer.None.None.The study was approved by the research committee, National Hospital (Care), Riyadh, Saudi Arabia.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by Editor-in-chief of this Journal on request.All authors contributed significantly and in agreement with the content of the manuscript. All authors participated in data collection and in writing of the manuscript.Not relevant here.M M Al-Qattan.Not commissioned, externally peer reviewed."}
{"text": "Pharmacists worldwide, including Saudi Arabia, are now increasingly expected to play a more patient-centred role. The transition of pharmacists from a dispensing role to a more patient-centred clinical role requires the adoption of innovative learning techniques in pharmacy teaching and learning to transform the future pharmacy workforce. One such innovation in pharmacy education is simulation-based pharmacy teaching. The use of simulation in pharmacy education allows pharmacy students to not only improve their clinical knowledge and skills, but also serves as a tool to improve their critical thinking that is a pre-requisite in sound clinical decision-making. Given the importance of patient-oriented teaching in pharmacy education, the majority of institutions offering pharmacy education in the developed countries have successfully integrated simulation-based teaching in their respective curricula to meet both patient and practice needs. However, most of the universities offering undergraduate pharmacy programs in the developing world, including Saudi Arabia, have limited application of patient-focused teaching in their respective programs. This article aims to highlight the importance of introducing simulation-based teaching in pharmacy education in Saudi Arabia. Pharmacists worldwide are now increasingly expected to play a more patient-centred role. For example, in the United Kingdom (UK), the White paper titled \u201cA vision for pharmacy in the new National Health Service\u201d (NHS) outlined the UK government\u2019 vision for community pharmacy . It callThe transition of pharmacists from a dispensing role to a more patient-centred clinical role requires the adoption of innovative learning techniques in pharmacy teaching and learning to transform the future pharmacy workforce. One such innovation in pharmacy education is simulation-based pharmacy teaching. Simulation has been defined as \u2018(an) event or situation made to resemble clinical practice as closely as possible\u2019 . The useGiven the importance of patient-oriented teaching in pharmacy education, the majority of institutions offering pharmacy education in the developed countries have successfully integrated simulation-based teaching in their respective curricula to meet both patient and practice needs. For example, the council responsible for accrediting pharmacy education in the USA has approved up to 20% use of simulation in the practical component of pharmacy practice education . HoweverPharmacy education in Saudi Arabia started in 1959 for the first time with the introduction of a four-year bachelor of pharmacy and medicinal chemistry program . The iniAlthough the academics in Saudi Arabia intend to align the PharmD curriculum on the lines of PharmD program offered in Canada and USA, this alignment is not possible without addressing some of the barriers to successful implementation of PharmD program in Saudi Arabia. Some of these challenges include lack of qualified clinical faculty coupled with a limited number of hospital training sites  and non-Simulation-based clinical teaching can address some of these challenges. Simulation-based labs can accommodate a maximum number of students without the fear of slashing the number of students\u2019 intake in the training program. The controlled and risk-free environment for patients in simulation labs allow students to work on different patient scenarios that may not be presented to them during their traditional clinical placement. Furthermore, simulation labs led by qualified faculty can also ensure the delivery of a standardized training program to all students. The clinically oriented PharmD program in Saudi Arabia promises to open new horizons for future pharmacists by allowing them to play an active role in the expanding healthcare system. However, successful implementation of the PharmD program in Saudi Arabia faces many challenges. Given the importance and utility of simulation-based teaching in pharmacy practice, academic institutions in Saudi Arabia should move towards integrating simulation in their curricula to overcome these challenges and to better prepare the future pharmacy workforce in the current era of constant change."}
{"text": "This paper presents learning analytics data for measuring the impact of study satisfaction on students' academic self-efficacy and performance. For this purpose, a specially designed questionnaire was developed and distributed across 124 undergraduate students. Preliminary analysis using descriptive statistics for items and confirmatory factor analysis is provided. The analysis provides evidence for the relation between students' satisfaction, self-efficacy, and academic performance, and evaluates the role of academic information resources in fulfilling students' information needs. These data are of importance for researchers and practitioners involved with budgetary decisions in academic collections as well as the influence of research specific (rather than training specific) information resources in student satisfaction. Therefore, the objective of this dataset is biforld. First it aims to provide raw survey data for measuring students' academic satisfaction, self-efficacy, and performance. Second it aims to provide evidence on the impact of study satisfaction on students' academic self-efficacy and performance. A hard copy questionnaire was developed and administered to students who attended an undergraduate course at a Greek regional university. An outline of basic insights using descriptive statistics and confirmatory factor analysis is provided in the sections that follow.2The survey was conducted during the second semester of the academic year 2017\u20132018 and included a total number of 124 undergraduate students in Greece. Consent was given by the school board and the data collection procedure was compliant with the privacy policy of the University. Hard copy response forms were distributed to all students of the academic program and no sampling was performed. The distribution was done in classroom before lecture and the forms were collected by a volunteer student and provided back to the researcher in a closed envelope. Section A: Demographics: five (5) variables .Section B: Self-assessment of academic satisfaction, self-efficacy, and performance: nine (9) items obtained from established scales in the literature Section C: Self-assessment of information resources usage: ten (10) variables . This can also be considered an outcome variable.Section D: Self-assessment of information needs fulfillment: one (1) variable . Items from Sections A to C have been also utilized by other studies in the literature In order to provide a meaningful structure and usefulness to other researchers, especially in relation with latent factors involved with the design of the questionnaire, we followed all the procedural remedies for confirmatory factor analysis discussed in Ref.\u00a0To evaluate cases of multicollinearity between factor items and outcome variables, the item-correlation matrix  is proviThe factor correlation matrix between the three identified factors  and the two outcome variables of interest  is provided in This dataset shows that factors such as study satisfaction combined with a sense of self-efficacy may act as an essential mechanism for improving students' academic performance and the overall satisfaction with their studies. On the other hand, academic information resources usage assessment is continually improving affecting students' academic performance as well, especially in cases of research-oriented instruction. This dataset can help researchers and institutions  to comprehend the important role and the impact of academic program satisfaction to students' academic self-efficacy and performance. With the ongoing trend in the deployment of learning analytics, the outcomes showcase that potential investments in academic information services to support the educational and research process may result in an improvement in students' academic performance. The latter is important to administrators and policymakers considering the important budgetary decisions related to the allocation of funds for academic subscriptions of teaching and learning vs. research-oriented material. Enrichment activities of the presented data could also target areas of improvement related to assessment and other primary sources of academic achievement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors."}
{"text": "Correction to: Cell Death & Disease10.1038/s41419-019-1856-y, published online 13 August 20191], it was realized that an error was made in typesetting which resulted in a change in the ordering of the last two authors. The correct ordering of the authors for the paper is as follows:Following publication of this article We apologize for any inconvenience this may have caused the readers."}
{"text": "Dear Editor,Cutaneous infections by herpes simplex virus (HSV) and varicella zoster virus (VZV), both of which belong to the alpha subfamily of herpes viruses, are relatively common.A 78-year-old man presented to our dermatology clinic with multiple painful vesicular lesions located on the left forearm and left hand (C6\u20138 dermatomes) and left lumbar region (T12 dermatome), for four days . Prior tHSV and VZV are DNA viruses that share some biologic attributes but, at the same time, differ significantly; such differences may explain why concurrent reactivation is rare.4Concurrent reactivation of VZV and HSV is possible in both immunocompetent and immunosuppressed patients, although it is more common in the latter group.We report a case of concurrent reactivation of VZV and HSV in an immunocompetent elderly male with no clinical history of herpes simplex but with serologic evidence of past infection. The combination of high sensitivity and specificity, low contamination risk, and speed has made real-time PCR technology an excellent testing method for diagnosing many infectious diseases. The closed system for amplification and detection used with real-time PCR virtually eliminates amplicon contamination.Simultaneous infection with VZV and HSV was suspected due to the atypical clinical presentation. Dermatologists must be aware of this possibility to assure the correct diagnosis is obtained and that the appropriate treatments are performed.None declared.Miguel Costa-Silva: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; obtaining, analyzing and interpreting the data; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.Joana Sobrinho-Sim\u00f5es: Approval of the final version of the manuscript; conception and planning of the study; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the manuscript.Filomena Azevedo: Approval of the final version of the manuscript; conception and planning of the study; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the manuscript.Carmen Lisboa: Approval of the final version of the manuscript; conception and planning of the study; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied; critical review of the literature; critical review of the manuscript.None declared."}
{"text": "While the differential diagnostic clinical work-up of patients with neurodegenerative diseases contains magnetic resonance imaging (MRI) as one of the core elements, the search of neuroimaging-based biomarkers in neurodegeneration is still an ongoing process, although tremendous advances could be reached in the last two decades. The additional value of advanced MRI, including but not limited to the potential use as a technical biological marker and phenotype characterization at the individual level with absolute quantification of regional alterations, remains a subject of investigation by multiparametric MRI protocols, including volumetry/morphometry of T1-weighted 3-D MRI, diffusion-weighted imaging (DWI), and intrinsic functional connectivity MRI (ifc MRI). For neurodegeneration , neuroimaging will be one major tool to elaborate the concept of computer-based neuroanatomy and pathoneuroanatomy, also for studies on functional reserve and compensation in aging and disease so that advanced neuroimaging (which is descriptive as a technique) has recently moved away from mere qualitative characteristics of the brain's structural and functional organization to quantitative measures and predictive models or treatment monitoring tools in disease , movemenThe goal of this Research Topic was to report and reflect recent applications of multiparametric MRI to patients with various neurodegenerative diseases. Starting from applications at the group level, continuous progress of a transfer to individual diagnostic classification is reviewed and discussed. The Research Topic includes six articles and provides a synopsis of the variety of approaches of computerized MRI-based neuroimaging to neurology with the special focus on neurodegenerative diseases.Liu et al. show changes in global brain lateralization in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to controls by resting-state functional magnetic resonance imaging (rs-fMRI). The abnormal rightward dominance observed in the patients with MCI and AD may indicate that these patients use additional brain resources to compensate for the loss of cognitive function, and the observed disappearance of the leftward laterality in the patients with AD was likely associated with the damage in the left hemisphere. That way, this study is a good example for the deepened insight into neurodegeneration on the one hand and conclusions about potential compensation by addressing differences between MCI and full dementia on the other hand. Also technically, the study shows how multisite data sharing improves the power of this kind of analyses, since the imaging data used were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu/).As an example for dementia syndromes, Lahr et al. studied working memory-related effective connectivity in early Huntington's disease (HD) patients and pre-symptomatic HD mutation carriers by task-based functional magnetic resonance imaging (fMRI) and dynamic causal modeling. They were able to characterize effective connectivity in a WM network of HD mutation carriers by evaluating HD-related changes in the neural network underlying working memory (WM). Given that presymptomatic mutation carriers were investigated in this study, this is a blueprint of how neuroimaging in subjects with mutations for a neurodegenerative disease but without clinical symptoms can improve the understanding of disease progression and its effect on network connections in the central nerve system, with the aim to identify biomarkers and targets for potential disease-modifying interventions as early as possible.In the field of neurodegenerative multisystem disorders, Prell), as well as the structural and functional brain mapping correlates of impaired eye movement control in PD patients . In addition, an overview was given on the disruption of the inferior longitudinal fasciculus microstructure as assessed by diffusion tensor imaging (DTI) and its clinically significant correlation with PD symptoms, most consistently with tremor, depression/negative emotion recognition, color discrimination deficit, and cognitive decline in several domains . These advanced MRI studies address the deepened understanding of the underlying pathophysiological abnormalities in PD by the correlations of the clinical motor and non-motor syndrome with structural and functional brain network alterations (DTI and rs-fMRI).Further studies have reviewed multifaceted aspects of computerized MRI applications to Parkinson's Disease (PD), with a focus on correlates of non-motor clinical symptoms. The structural and functional brain patterns associated with non-motor syndromes in PD were reviewed  disease, In conclusion, this Research Topic offers an overview in the field of advanced MRI-based analyses and their application to neurodegeneration and aging. These MRI-based techniques have the potential for future use in the work-up of individual patients by potentially enlarging the spectrum of non-invasive biological markers as neuroimaging-based candidate read-outs for clinical studies and by providing target information to currently available scores for longitudinal screening, Furthermore, these techniques are also prone to be used for the stratification of patients for future clinical trials in disease-modifying strategies. Further studies will complement this Research Topic, and we are looking forward to the translation of the neuroscientific evidence generated from neuroimaging progress into the clinical context.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "However, this number was significantly decreased following disclosure of a list of hospitals with MERS-CoV cases . Disclosing the list of hospitals exposed to MERS-CoV was critical to the prevention of further infection. It reduced the number of confirmed MERS-CoV cases. Thus, providing accurate and timely information is a key to critical care response.This study examined the effect of disclosing a list of hospitals with Middle East respiratory syndrome coronavirus (MERS-CoV) patients on the number of laboratory-confirmed MERS-CoV cases in South Korea. MERS-CoV data from 20 May 2015 to 5 July 2015 were from the Korean Ministry of Health & Welfare website and analyzed using segmented linear autoregressive error models for interrupted time series. This study showed that the number of laboratory-confirmed cases was increased by 9.632 on 5 June ( The first case of Middle East respiratory syndrome coronavirus (MERS-CoV) was reported in Saudi Arabia in 2012 . The firMERS-CoV crisis not only exerted massive social and economic impact on South Korea, but also revealed drawbacks in South Korean public health and infection control of the healthcare system. Large-scale MERS-CoV infection in South Korea occurred by intra- and inter-hospital transmission . The firThe Ministry of Health and Welfare supervises infectious-disease disaster management in South Korea while the Ministry of Public Safety and Security supports disaster control . After tThe government revised its policy to disclose information in accordance with the public\u2019s opinion that nondisclosure of information would in fact cause MERS-CoV to spread and generate public anxiety. However, the South Korean government restricted and controlled information regarding MERS-CoV during the initial response. It has been claimed that inadequate information disclosure was the main reason for the spread of MERS-CoV. The lack of an appropriate management system and a prevention strategy for infectious disease has been raised as additional reason for the initial failure to contain the outbreak .The purpose of this study was to evaluate the effect of policy to avoid disclosure of information, the most controversial issue regarding the initial response, on the spread of MERS-CoV in South Korea. The study sought to determine whether changing this strategy and releasing a list of hospitals treating infected individuals was associated with containment of the disease .http://mers.go.kr/) managed by the Korean Ministry of Health & Welfare. This website provides information regarding the statistics and management status for MERS-CoV [Data were obtained from the MERS-CoV information website , Time was a continuous variable initiated on 20 May 2015 (daily), disclosure was binary variable representing disclosure of the hospital list , Quarantines was a continuous variable representing the daily number of quarantined individuals, Time_after_disclosure was a continuous variable initiated on 5 June 2015 (daily), and Segmented linear autoregressive error models for interrupted time series were used to assess the effect of disclosure of hospital names and disease-related hospital management on the number of laboratory-confirmed MERS-CoV cases . Segmentp < 0.001). The number of confirmed cases was increased by 9.632 on 5 June (p < 0.001). It showed a significant downward trend following disclosure of hospital list . The spread of the disease ceased because potential MERS-CoV patients were screened. Results of segmented regression for confirmed cases are shown in The study aimed to analyze the effect of disclosing a list of hospitals exposed to MERS-CoV on the spread of the disease. On the day when the list of hospitals that MERS-CoV patients had visited or attended for treatment was disclosed, the number of confirmed cases was increased. However, a downward trend was observed thereafter. This result implies that disclosing the hospital list was very effective in preventing people from further infection of MERS through timely provision of information.The following two mechanisms were presumably involved in the downward trend of infection. First, the information dissemination was likely to lower the possibility of the public\u2019s further contracting MERS-CoV, as it helped members of the public to avoid exposed hospitals with the given information by the health authority . FollowiThis study showed that the Korean health authorities\u2019 decision to disclose information regarding hospitals exposed to MERS-CoV contributed to the prevention of further MERS-CoV infection during the outbreak, despite the criticism that the disclosure occurred too late. In addition, findings of this study indicate that health authorities should disseminate information regarding facilities affected by an outbreak of infectious diseases as soon as possible to ensure that people are able to avoid the risk of infection. This confirms the risk communication principle of timely provision of information in coping with outbreaks is so important. It is inappropriate to withhold information that is crucial to decision making for members of the public not only from a communication perspective, but also from epidemiological and clinical perspectives. Therefore, authorities should pay greater attention to risk communication . FollowiThese results also suggest that Korea health authorities should consult with experts and produce a crisis and risk communication guide to develop communication strategies such as informing the public and providing training for communicators who possess the necessary competence and expertise . OverallThis study had several limitations. First, we did not analyze the effects of other noteworthy variables such as the increased number of health authorities\u2019 staff, medical facilities\u2019 capacity bolstering, the strengthened engagement of media, and other private sectors over time. For example, increases in the number of staff members in the Central MERS Management Task Force played an important role in preventing and controlling the outbreak. Therefore, the size of the MERS Rapid Response Team dispatched to exposed hospitals should be included in further studies. Besides, hospitals regardless of having MERS patients at that time in Korea had been more involved in detecting and controlling outpatients and visitors as time went by. Therefore, this factor could be one of the reasons to help decrease the number of Patients during this outbreak. For instance, some hospitals started to set up the system of screening the ER patients by their disease of communicable and non-communicable type. Plus, private organizations such as media, transportation, many business associations had done their job to raise awareness of the importance of hygiene campaigns like proper and frequent handwashing and coughing on sleeves. These voluntary movements also could be an element of dealing with 2015 MERS-CoV in Korea. Second, some individual- and hospital-level information was not adjusted for in this study because of data limitation. The transmission of MERS-CoV in Korea occurred mainly in hospitals . We assuIn summary, we found that providing timely and accurate information to the public during an outbreak was crucial to both risk communication and the control and prevention of further infection. Therefore, health authorities should bolster their capacity to disclose information in a timely, accurate, and transparent way."}
{"text": "The journal retracts the 6 September 2017 article cited above. Following publication, the publisher was alerted to potential instances of image manipulation. In accordance with our established procedures, an investigation was initiated. The investigation revealed image duplication in Figure 8 and copy-paste marks and image manipulation in western blot gels . The authors and their institution have remained unresponsive to multiple requests for the raw data for this study. Given the authors' unresponsiveness and extant concerns over the validity of the study, the article has been retracted.The retraction of the article was approved by the Chief Editors of Cellular Neuroscience and the Editor-in-Chief of Frontiers."}
{"text": "The authors noticed the erroneous duplication of an image between the 60- and 120-min time points in the top row of Both the HTML and PDF versions of the article have been corrected. These errors appear only in print and PDF versions downloaded on or before August 21, 2018."}
{"text": "Nature Communications 10.1038/s41467-018-07709-6; published online 02 January 2019Correction to: In the original HTML version of this Article, the order of authors within the author list was incorrect. The IMEx Consortium contributing authors were incorrectly listed as the last author and should have been listed as the first author. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."}
{"text": "In the original publication of this article , an authMelissa Ward-Petersen\u2019s name should be corrected to Melissa Ward-Peterson.The correct name has been included in the author list of this Correction article and has already been corrected in the original article."}
{"text": "Post-annealing treatment is a necessary process to create/eliminate/repair defects in self\u2013assembly (SA) metal oxide by providing enough thermal energy to the O atoms to overcome the migration energy barrier in ZnO. The height of migration energy barrier is dependent on the depth from the surface, which is hard to be estimated by theoretical calculations, as well as the optical analyses. SA ZnO nanorods (ZNRs) have high surface-to-volume ratio to provide complete picture between the optical and surface properties obtained by photoluminescence (PL) and ultraviolet/X-ray photoemission spectroscopy (UPS/XPS), which is used to investigate the evolution of structure and chemical states of the surface layers to reveal mutual agreement on all observations in PL, XPS, and UPS. We demonstrate variation of the surface structure of SA-ZNRs by scanning over a range of annealing temperatures and time to regulate the structure variation of SA-ZNRs, and their optical analyses agrees well with PL, XPS and UPS, which indicates the dependence of migration energy barriers on the depth from the surface of ZNR. The results reveal the well ZNRs formed at 570 \u00b0C and the further oxidation process and the formation of hydroperoxide on the Zn-rich surface of ZNRs at 640 \u00b0C. Metal oxides and their nanostructures are popular subjects because of their applications in photoelectric , photo-cbE) of ZnO is a defined quantity between the equilibrium configuration and the saddle point along the migration path, which can be obtained from first-principles calculations  Some of the existence bottlenecks on analyzing ZNRs are to separate the optical response of ZNR surface from whole ZNR and controllable modification on the structural variation of ZNR surface. In order to realize the structural evolution and migration energy barriers of ZNR surface, the methods of multi-optical analyses with distinguishable depth resolution and post-treatment with precisely controlling annealing conditions are provided to overcome the bottlenecks. Additionally, the knowledge about the surface migration energy barriers on ZNRs is helpful for design ZNR sensors  whose seAbove inspections on PL, XPS, and UPS for annealed SA-ZNRs with scanning temperature provide the quantitative analyses on the restructure and annihilation of deficiencies. As the discrepancy on PL and XPS, the structure evolution in depth can be inspected and reveal activation energies with the dependence of depth. The restructure and the elimination of deficiencies of SA-ZNRs occur in the limited depth if the annealing temperature is limited within 470\u2013540 \u00b0C even at longer annealing time. It is obvious that the annealing treatment with specific temperature can only restructure the SA-ZNRs with certain depth which determines the corresponding activation energy. The amplitude of activation energy is certainly correlated to the depth of ZNRs. Moreover, the surface layers of SA-ZNRs were not only restructured but also create another set of deficiencies according to the annealing environment if the annealing process lasts longer time at higher temperature. The further application based on the knowledge about the evolution of the migration energy barriers on ZNR surface would improve the fabrication of ZNR sensors . The sen"}
{"text": "Several states have adopted Medicaid Managed Long-Term Care (MLTC) programs over the last several years. At this point at least 30 states are either administering such models or have plans to in the near future. We do not, however, know much yet about the relative cost-effectiveness of the MLTC model when compared to the traditional non-profit model of Medicaid LTC. Is the for-profit MLTC model actually generating savings in the Medicaid program while improving the quality of care? This symposia is designed to address the question through three presentations on experiences with MLTC programs in the states of Ohio, Texas and Pennsylvania and a fourth presentation offering a national overview and critique of Medicaid MLTC in comparison to the traditional Medicaid LTC program still administered through non-profit Aging Network organizations. The state focused presentations describe the current status and results of MLTC in three states that vary in their specific features, extent of formal accountability for outcomes and the political contexts in which the programs currently function. The presentations also include discussions of the implications of each states experiences for the future of Medicaid LTC policy at the state and federal levels. The fourth presentation is a critical analysis of the main differences between the traditional non-profit model of Medicaid LTC services and the for-profit MLTC programs in terms of commonly accepted criteria of cost-effective LTC services, such as access, quality of care and per-person costs and differences in the roles of advocacy and accountability."}
{"text": "A new joining by forming process that combines lancing and shearing with sheet-bulk compression is utilized to assemble thin-walled crash boxes utilized as energy absorbers. Process design and fabrication of the new crash boxes are analyzed by finite elements and experimentation. Axial crush tests were performed to compare the overall crashworthiness performance of the new crash boxes against that of conventional crash boxes assembled by resistance spot-welding. Results show that the joining process is a good alternative to resistance spot-welding because the new crash boxes can absorb the same crushing energy, and because the new process helps to overcome typical manufacturing problems of welding. An energy absorber is an important element of a vehicle because it protects the lives of passengers by managing the absorption of energy and collapse of its structure during an accident. One of the strategies currently employed by vehicle manufacturers to meet the increasing requirements on safety and the diminishing weight targets is the utilization of energy absorbers made of high-strength materials in lightweight body structures. However, the search for more effective energy absorbers is wider and includes new geometries and materials with the potential to enhance the crashworthiness performance of the structures under different types of loading. These trends are comprehensively discussed in two recently published state-of-the-art reviews on energy absorbers ,2.The search for new processes to manufacture energy absorbers has so far received little attention. Most of the publications in the field make use of energy absorbers produced by conventional extrusion ,4 or by Joining by forming  can alsoThis paper is focused on the assembly of thin-walled crash boxes with double-hat shaped sections made from individual formed panels. The aim and objective is to present a new fabrication process that combines lancing of the tenons, in which specific areas of the panels are sheared and bent in a single press operation a, sheariThe new fabrication process draws from two previous investigations on joining by forming in which \u201cmortise-and-tenon\u201d joints were successfully utilized to fix two sheets longitudinally in position by sheet-bulk compression. The two sheets were joined either perpendicular  or paralThe main challenge of applying the \u201cmortise-and-tenon\u201d joint concept in the assembly of crash boxes e derivesThe crash boxes assembled with the new proposed \u201cmortise-and-tenon\u201d joint concept are subjected to static and dynamic axial crushing and its overall crashworthiness performance is compared against that of resistance spot-welded. Results show that the new crash boxes are a good alternative to those assembled by resistance spot-welding.The new proposed joining by forming process can easily assemble thin-walled crash boxes with individual panels made from dissimilar materials with different thicknesses. However, it was decided to select a single high-strength low alloy steel (HSLA 340) with 1 mm thickness and 7 \u00b5m thickness galvanized coating to ensure a fair comparison of the crashworthiness performance of the new crash boxes against those assembled by resistance spot-welding.The mechanical characterization of the HSLA 340 steel was performed by means of stack compression tests  due to iThe thin-walled crash boxes with double hat-shaped sections were made from two individual formed panels that were assembled by sheet-bulk compression with \u201cmortise-and-tenon\u201d joints placed every 40 mm along their flanges. Conventional thin-walled crash boxes assembled by resistance spot welding were included in the experimental work plan for reference purposes. The welding parameters were selected by finite element modelling refer to  and the The crash boxes were tested for quasi-static and dynamic axial crushing at room temperature. The quasi-static crush tests were performed in the hydraulic testing machine (Instron SATEC 1200 kN) that had been used in the mechanical characterization of the material. A cross-head velocity The dynamic crush tests were performed in a drop weight testing machine that was designed and fabricated by the authors. The machine and its main components are schematically shown in The tool utilized in the quasi-static and dynamic crush tests is shown in The assembly of the individual panels of the thin-walled crash boxes by means of sheet-bulk compression with \u201cmortise-and-tenon\u201d joints was simulated with the finite element computer program I-form. The computer program was developed by the authors and is based on the irreducible finite element formulation,eference .The numerical simulation made use of two-dimensional plane strain deformation models and the cross section of the tenons and mortises were discretized by means of approximately 1000 quadrilateral elements. The tools were modelled as rigid objects and their geometries were discretized by means of linear contact-friction elements.The assembly of the individual panels of the thin-walled crash boxes by means of resistance spot-welding was simulated with the commercial finite element computer program SORPAS , which iThe first term is related to heat conduction through the conductivity eference .The stress-strain curve of the HSLA 340 steel obtained from the stack compression tests is shown in The reference joining process was simulated by the commercial software SORPAS . The simThe assembly of the thin-walled crash boxes by the novel sheet-bulk compression process with \u201cmortise-and-tenon\u201d joints required the tenons to be cut and bent out of the panels by lancing a, and sung punch a and a tbuckling b.Successfully compressed tenons are needed for the second stage of the sheet-bulk compression, during which a flat heading punch assembles the crash boxes by mechanically locking the individual formed panels to each other. As seen in In the above equation, ool part a. The maAs seen, the overall trend of the dynamic force-displacement curves is similar to that of the quasi-static tests a but theThe crashworthiness performance of the new crash boxes with \u201cmortise-and-tenon\u201d joints raises the question of the alignment of the protrusions of the flat-shaped surface heads of the tenons above the adjacent sheet panel, after compression. Should the flat-shaped surface heads be collinear or perpendicular to the longitudinal axis of the crash box?Experiments performed by the authors revealed that the flat-shaped surface heads must be perpendicular to the longitudinal axis of the crash boxes because if they are collinear, they are easily pulled-out during axial crushing, diminishing the overall performance of the crash box .The evolution of the force with displacement for the quasi-static and dynamic axial crush tests performed with the two different types of crash boxes allow concluding that the new proposed \u201cmortise-and-tenon\u201d joints can successfully replace resistance spot-welds. In fact, The energy refer to .The results are shown in The maximum absorbed energy in the dynamic tests, is approximately 30% higher than in the quasi-static tests. This increase of crashworthiness performance with velocity is attributed to the strain-rate sensitivity of the HSLA 340 steel . HoweverAnother result that is relevant from a manufacturing point of view is the total energy required to fabricate a \u201cmortise-and-tenon\u201d joint and a resistance spot-welded joint. From the experimental and numerical evolution of the force with displacement for the first and second stages of the sheet-bulk compression of the tenons it may be concluded that approximately 7 J and 10 J will be needed to accomplish both stages. Thus, by considering these values of energy as well as that required to perform the lancing operation, it is concluded that the total amount of energy to fabricate a \u201cmortise-and-tenon\u201d joint is a very small fraction of that required by a resistance spot-welded joint . This isThe fabrication of crash boxes by sheet-bulk compression with \u201cmortise-and-tenon\u201d joints can successfully replace conventional production processes based on resistance spot-welding. The crash boxes with \u201cmortise-and-tenon\u201d joints can absorb the same amount of energy as those with resistance spot-welding joints in quasi-static and dynamic axial crush tests. They can also avoid the problems caused by residual stresses in the resistance spot-welding of panels made from dissimilar materials with different thicknesses.The greater applicability of the new crash boxes comes with a disadvantage regarding productivity due to the multi-stage characteristics of the proposed joining by forming process. However, this disadvantage can be offset by the environmental friendliness resulting from the total required energy to assemble a crash box by sheet-bulk compression with \u201cmortise-and-tenon\u201d joints being a very small fraction (1.3%) of that required by resistance spot-welding."}
{"text": "In this work, the non-uniform corrosion characteristics of steel bars in stressed reinforced concrete beams after accelerated depassivation and seven-year outdoor natural corrosion is analyzed using fractal theory. 3D laser scanning and 3D reconstruction technology are applied to collect the cross-sectional area along the steel bars and obtain the corrosion curves. The non-uniformity of corrosion is analyzed by fractal dimensions which is calculated by variation method. The results indicate that the initial loading level and loading zone have some influence on non-uniform characteristics of steel bars. For an ordinary concrete beam, the increase of load can cause a reduction of fractal dimension of corrosion curves by 5%, which indicates the non-uniformity of corrosion will increase with the increase of load level. The fractal dimension in the bending zone is lower than that in the tension\u2013shear zone, which indicates that corrosion is more non-uniform in bending zone. However, the loading level and loading zone have a slight influence on corrosion level, and the maximum difference of corrosion level caused by load is merely 0.23%. Furthermore, the corrosion level increases with the decrease of fractal dimension, suggesting that the non-uniformity of corrosion increases with the growth of corrosion level. The incorporation of slag powder can help reduce the non-uniformity of corrosion, but the influence on reduction of the corrosion level is about 0.25%. For concrete structures under marine environment, application of slag powder is a good method to slow down the corrosion and reduce the non-uniformity of corrosion. As corrosion of steel reinforcement causes a remarkable performance deterioration of concrete structures, reliable monitoring and assessment methods of corroded reinforcement have drawn significant attention. For a long time, the steel reinforcement in concrete is assumed to be uniformly corroded, partly for simplicity of analysis ,2. HowevIn order to characterize the non-uniformity of corrosion along the steel bars, lots of efforts have been made. For instances, Wang et al. defined the non-uniform corrosion coefficient R by calculating the ratio of the maximum corrosion rate to the corresponding average corrosion ratio of a corroded steel bar . ConsideFractal theory was developed in the 1970s, which shows its advantages in the study of complex shapes and patterns from a multi-scale perspective , and theIn this study, the fractal theory was utilized to characterize the non-uniformity of corrosion along the steel bars obtained from long-term outdoor naturally-corroded reinforced concrete beams after being dispassivated by wetting\u2013drying cycles under different load levels. Two types of concrete, including slag concrete and ordinary Portland cement concrete, were studied to evaluate the influence of slag incorporation on the corrosion of steel bars. All the concrete beams were placed under ambient conditions for seven years to achieve the natural corrosion of steel bars. The 3D laser scanning technique was applied to obtain the morphology of cross-sections along the steel bars. The corrosion level was also calculated to evaluate the corrosion degree of steel bars. The influence of loading level, stress state, and slag incorporation on the non-uniform corrosion of steel was analyzed through fractal dimension and corrosion level analysis. In the end, the relationship between non-uniformity of corrosion and corrosion level is studied by fractal dimension for this case.2/kg and the corresponding mineral composition is given in 2/kg, according to the Chinese standard ; S is the sum of the area of the shifting windows.A parameter D based on the variation method, all the fractal dimensions of the cross-sectional area curves for the twelve corroded steel bars are calculated and shown in According to the arithmetic of fractal dimension It can be seen from The relationship between fractal dimension and load level is shown in The concrete in the pure bending zone suffers tension stress, resulting in the micro-cracks generating vertically to the steel bars in the concrete beam. Therefore, the chloride ions will transfer to the steel bars from the surface of the beam more quickly through the shortest path. As a result, a higher free chloride ions concentration leads to more severe corrosion of the cross-section. Several typical cross-sections in these two load zones are shown in The fractal dimensions of steel bars in different loading zones are shown in The corrosion level of the full-length steel bars under the same load level also exhibit a difference, as shown in It can be concluded from A quantitative analysis on the corrosion level and the fraction dimension of steel bars is further performed, as demonstrated in The non-uniformity of corrosion along a reinforcement bar can be expressed by the fractal dimension; the smaller the fractal dimension is, the higher the non-uniform corrosion degree will be.The load level has a slight influence on corrosion level and it has some influence on non-uniform corrosion along the reinforcement bar embedded in the ordinary reinforced concrete beam. A larger load level will result in a higher corrosion level for the CO group. Meanwhile, the incorporation of mineral powder helps to reduce the corrosion level and the non-uniformity of corrosion.The loading zone leads to different stress states, which induces non-uniform corrosion along the reinforcement bar. The average loss fraction of cross-sectional area and non-uniform corrosion degree in the pure bending tension zone are generally higher than that in the tension\u2013shear zone.In this case, there is a positive proportion correlation between the average loss fraction of cross-sectional area and the non-uniformity of corrosion along the reinforcement bar.In this paper, the non-uniform corrosion characteristics of reinforced concrete beams after depassivation under different load levels and seven-year outdoor natural corrosion is studied by fractal dimension. The following conclusions can be drawn based on this study:"}
{"text": "The majority of Americans overwhelmingly prefer to age in place and in the communities in which they reside. Age-friendly communities support aging in place by focusing attention on features both inside and outside of the home. The global age-friendly community model provides a framework that requires assessing community-based older adults\u2019 needs and preferences about, and developing subsequent action towards, features of the social, service and built environment including housing and transportation which are considered essential to aging successfully at home. This presentation discusses the intersect between research, policy and practice in an age-friendly community which utilized micro-level findings from older adults  to enact macro-level collaborations across local and statewide government and professional groups to facilitate aging in place across the domains of housing and transportation."}
{"text": "The more preterm they are, the greater the riskPoor neonatal care increases the risk, even in less premature babiesHigh quality neonatal care. If there is not enough equipment to safely deliver and monitor oxygen, this must be strongly advocated forScreening: All babies at risk must be screened before 30 days after birthTreatment: Laser treatment should be given urgently, with confluent spotsFollow-up: All children born preterm are at risk of visual impairment and must be followed up by an ophthalmologist and/or optometristInvolve parents in the day-to-day care of the baby and encourage kangaroo careKeep parents informed of the need for screening and the results of screening, and the need for urgent treatment, if requiredEnsure parents understand the need for follow-up visits"}
{"text": "Outcomes related to person-centered care in nursing homes have been difficult to ascertain. Much of the extant literature has suffered from differing definitions of what it means to be person-centered, variation in the levels of implementation of person-centered care that an organization has achieved, and small sample sizes. The PEAK program provides a unique opportunity to control for these variables across a large sample of nursing homes throughout the state of Kansas. This presentation will discuss the methodological advantages of evaluating the PEAK program and the findings from an evaluation of resident satisfaction in nursing homes at varying levels of implementation of person-centeredness."}
{"text": "The self-assembly of polymers is a powerful tool for producing various functional materials with a high precision from nano- to macroscale. Nowadays, the polymer self-assembly has become extremely attractive for both biological  and non-biological  applications. Besides this, a number of key biological processes in nature are driven by self-assembly of macromolecules.This special issue gives insights into diverse spectrum of peculiar tailor-made self-assembled polymer structures and hybrid materials that have been designed through modern powerful techniques and approaches such as the micellization , hydrogeIn particular, significant attention has been attracted to the layer-by-layer assembly of biopolymers. Thus, Balabushevich et al. have presented the study of mucin-based layer-by-layer assemblies that are mainly composed from the natural component of mammalian mucus and therefore show high potential for mucosal drug delivery . In the Another issue in the field of polymer self-assembled structures that has been reflected in this special issue is the design of stimuli-responsive materials. This includes both, chemical stimuli such as pH and physical stimuli including light. In this special issue, Xu et al. presented an elegant way for fabrication of pH-responsive amphiphilic block copolymer-based assembles ; Yang etBridging the gap between the science of the polymer self-assembly and the industrial application of this technology, Nelson et al. have designed and constructed a new solvent vapour annealing chamber that allowed the potential scaling-up of the production of block copolymer thin films .The next equally interesting aspect that has been deciphered in this issue is organisation of self-assembled polymer-based and hybrid structures in 3D. Herein, microfluidics-assisted assembly of porous calcium carbonate templates and their covering with polymer coatings opened new avenues for the fabrication of tailor-made biocompatible scaffolds for advanced tissue engineering and 3D cell culture as reviewed in  and crysThat is rather interesting to note that while the papers listed above mostly aimed at the invention and investigation of the new types of materials, the paper presented by Jeannot et al. took under the consideration a well-known poly(styrene-sulfonate)/poly polyelectrolyte pair and the authors have shown principally new insights into the classical understanding of the internal structure of multilayer capsules . Their fFinally, it is worth to emphasize the review of Savoca et al. that summarises the up to date knowledge on the biocatalysis by transglutaminases, enzymes that crosslink polymer-bound glutamine and lysine residues and plays a special role in the formation of extracellular polymer matrix . The revWe would like to take the opportunity to thank all the authors for submitting their papers to this special issue. We also want to thank all the reviewers for dedicating their time and helping to improve the quality of the submitted papers."}
{"text": "The cSMSustained TCR/CD3 signaling is required to achieve a proper T cell activation and the endocytosed and degraded TCR during activation should be replenished by TCR molecules recruited to the IS from the endosomal compartment  is poorly understood. Although CAR-T cell stimulation induces an efficient MTOC polarization and lytic granule secretion (even faster than in TCR-IS), actin cytoskeleton is not completely depleted from the center of the IS, microclusters of the CAR and signaling molecules are evenly dispersed through the IS, cSMAC and LFA-1 ring at the pSMAC are not properly organized and activating signals as well as cell-cell interactions are shorter than in conventional TCR-IS  Mukherj. It shouIn spite of the above-mentioned recent contributions, a precise understanding of the spatial and temporal topology of the CCB-IS remains elusive. To what degree is the physiological IS organization maintained in the artificial CCB-IS formed in CAR-T cells or following CD3\u03b5 engagement by a TAA-bound bsAb? This question is particularly relevant as an altered topology of the TCR-IS has been associated with immune pathologies (Schubert et al., The influence of some of these factors in the assembly of the CCB-IS has been studied. For example, in the bsAb-mediated IS membrane proximal TAA-epitopes are necessary for the assembly of the IS with CD45 exclusion and central clustering of the TAA, the signaling molecule ZAP70 and the bsAb (Li et al., PR-N and L\u00c1-V contributed to the conception of the work and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "Docking simulations illustrated how the TnC molecule undergoes significant conformational transition on complex formation, a phenomenon that can be modeled only when protein flexibility is properly accounted for. This way our procedure opens up a new possibility for studying mechanisms of protein complex assembly, which may be a supporting tool for rational drug design.Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool for modeling the structure, dynamics and interactions of protein complexes. The docking protocol employs a coarse-grained representation of proteins, a simplified model of interactions and advanced protocols for conformational sampling. CABS-dock is one of the very few tools that allow unrestrained docking with large conformational freedom of the receptor. In an example application we modeled the process of complex assembly between two proteins: Troponin C (TnC) and the N-terminal helix of Troponin I (TnI N-helix), which occurs The development of new drugs is one of the most challenging tasks in science today. Combined efforts of the pharmaceutical industry, academic researchers and biotech companies have not only improved the process of drug design, but also contributed to advances in science itself. Computational modeling and simulations have become integral procedures in introducing new drugs to the market and it is safe to assume that the role of theoretical computations in this field will increase in the future .Protein activity in organisms involves interactions with other biomolecules, which makes them perfect targets for rationally designed drugs. After the Human Genome Project  was compMolecular docking is a technique for predicting the structure of a molecular complex, given the structures of its individual components. There is a great number of software packages available for protein-ligand docking, including DOCK , AutoDoc vs. the other. The rigid-body assumption is naturally a shortcoming for proteins that exhibit large-scale conformational changes on binding. In some cases even small backbone deformations could be essential  can be defined as follows:K is kernel function and h is the bandwidth (smoothing parameter). The Kernel estimator of an unknown probability density function In our calculation we used the standard Gaussian function with mean zero and variance 1. For more details see the Bioshell  manual.The paper describes the application of the CABS-dock protocol to a difficult problem of protein-peptide complex assembly. Starting from near-native structures of the receptor and completely random structures of the peptide (located at random positions around the receptor structure), we performed REMC simulations of free docking. The docking simulations and the clustering of the manifold of generated conformations led to a well-defined structure of the complex, in good agreement with the available crystallographic structure . ExperimTo investigate the influence of peptide binding on the structure of the whole complex, we also performed CABS-flex simulations, a tool for the computational study of protein domain dynamics. The simulations showed that the binding of the peptide fixed to a large extent the troponin C structure seen in the bound state, while the structures of the receptor without any ligand were closer to the unbound experimental structure of troponin C ,44 and eFinally, let us note that CABS-dock method enables free search (without predefined binding site location) of the peptide docking pathways with properly predefined ranges of the receptor structure fluctuations , which g"}
{"text": "This paper provides a brief review of recent progress in the field of metal coordination polymers assembled from azole-containing carboxylic acids and gives a diagrammatic summary of the diversity of topological structures in the resulting infinite metal-organic coordination networks (MOCNs). Azole-containing carboxylic acids are a favorable kind of multifunctional ligand to construct various metal complexes with isolated complexes and one, two and three dimensional structures, whose isolated complexes are not the focus of this review. An insight into the topology patterns of the infinite coordination polymers is provided. Analyzed topologies are compared with documented topologies and catalogued by the nature of nodes and connectivity pattern. New topologies which are not available from current topology databases are described and demonstrated graphically. The diverse coordination modes of diazole, triazole and tetrazole-containing carboxylic acids and the various topology patterns in the one, two, and three-dimensional metal-organic coordination polymers enrich the fields of research in the coordination and structural chemistry of these compounds, and contribute plentiful novel MOFs materials with better practical value as supporting carriers, in gas sorption and magnetic, optic or electronic applications."}
{"text": "To the Editor: We read with interest the recent article describing involvement of Crithidia-related parasites in visceral leishmaniasis (VL) in Brazil  strains with a patient phenotype is risky because of the selection biases of in vitro isolation and maintenance. Using a recently developed method for direct sequencing of"}
{"text": "Dear Editor,Indian Journal of Hematology and Blood Transfusion profoundly interesting. The article is devoted to the measurement of the concentration of protein Z (PZ) in patients during the stable phase of acute coronary syndrome (ACS). PZ is a glycoprotein synthesized in the liver and in the vascular endothelium. Its main function is to inhibit, with the participation of another glycoprotein\u2014ZPI (protein Z-dependent protease inhibitor), the active factor X [We found the paper penned by Ghozlan et al.  which wafactor X . The metfactor X  proved tThe main observation made by Ghozlan et al.  is findiIn the light of other papers, it would also be interesting to broaden the panel of tests to determine the concentration of ZPI and anti-PZ autoantibodies class IgG and IgM. The presence of circulating antibodies is relatively rare , but it"}
{"text": "In the Primary outcome-functional status subsection of the Results section, there is an error in the sixth sentence. The correct sentence is: In the study by Hensel et al. [29], osteopathic care was found to significantly improve functional status.In the Primary outcome-functional status subsection of the Results section, there is an error in the last sentence. The correct sentence is: In another US study [30], functional status also significantly improved in the osteopathic care group compared to controls .There is an error in"}
{"text": "In the Abstract, there is an error in the eighth sentence. The correct sentence is: The parameters of defect fill were significantly higher at EMD-treated site than at EMD-untreated sites in both diabetic and non-diabetic rats.In the Statistical analysis subsection of the Materials and Methods, there are errors in the second sentence of the first paragraph. The correct sentence is: Fisher\u2019s exact test and binomial test were used to compare the frequency of primary closure in control and diabetic rats.In the Observation of postsurgical healing subsection of the Results, there are errors in the first and second sentences of the first paragraph. The correct sentences are: At 7 days after surgery, wound closure rates were higher in control rats than in DM rats (not significant). Wound closure rates were higher at the EMD-treated sites of both control and diabetic rats than at untreated sites (not significant).In the Discussion section, there is an error in the fourth sentence of the fourth paragraph. The correct sentence is: The reduced bone regeneration observed in diabetic animals, although statistical significance was not observed, is attributed to the fact that primary closure is a crucial factor for tissue regeneration."}
{"text": "There is an error in the penultimate sentence of the Abstract. The correct sentence is: Available evidence from medium-to-high quality observational studies suggests that POD and POCD are indeed correlated with the concentration of peripheral inflammatory markers."}
{"text": "The negative impact of obesity on neurocognitive functioning is an issue of increasing clinical interest. Over the last decade, a number of studies have analyzed the influence of high-fat diets (HFDs) on cognitive performance, particularly in adolescent individuals. Different approaches, including behavioral, neurochemical, electrophysiological and morphological studies, have been developed to address the effect of HFDs on neural processes interfering with learning and memory skills in rodents. Many of the studies have focused on learning and memory related to the hippocampus and the mechanisms underlying these processes. The goal of the current review article is to highlight the relationship between hippocampal learning/memory deficits and nutritional/endocrine inputs derived from HFDs consumption, with a special emphasis on research showing the effect of HFDs intake during the juvenile period. We have also reviewed recent research regarding the effect of HFDs on hippocampal neurotransmission. An overview of research suggesting the involvement of fatty acid (FA) receptor-mediated signaling pathways in memory deficits triggered by HFDs is also provided. Finally, the role of leptin and HFD-evoked hyperleptinemia is discussed. Elevated consumption of so-called western diets (WDs) is one of the main causes of overweight and obesity and a matter of concern for public health institutions. The damaging effect of these diets seems to be not only related to their content in terms of both saturated fat and easily assimilated carbohydrates, but also to the fact that they promote disorganized feeding patterns consisting of frequent energy-dense snacking and/or copious meals before bedtime  and choroid plexus permeability  expression in CA1 pyramidal neurons -induced long-term depression (LTD), but does not affect long-term potentiation  up-take kinetics along with the up-regulation of glial GLU transporters (GLT-1 and GLAST) and a concomitant down-regulation of glutamine synthase. In addition, this treatment led to the down-regulation of the glucose transporter GLUT-1 , characterized by the induction of leptin synthesis and the repression of adiponectin expression, which occur together with a rise in WAT-derived inflammatory cytokines, all of which are able to cross brain barriers  and G protein-coupled receptor 120 (GPR120).PPARs mediate pleiotropic actions in the brain, including neurogenesis and synaptic plasticity  makes it difficult to draw reliable conclusions. Systematic studies carried out with diets of defined composition, which do not merge elevated amounts of saturated fat and sugar and that are preferably enriched in a particular FA, would be necessary to investigate in more depth the influence of fat on brain functions. In this regard, future research based on the use of experimental HFD manufactured with highly saturated or unsaturated oils, enriched in a particular FA, are needed to identify the specific contribution of the various types of dietary fat to memory processes.Otherwise, the translational value of all of these findings remains unclear, as strong epidemiological studies are lacking. Therefore, it is necessary to carry out parallel clinical and basic research devoted to the identification of the molecular mechanism underlying memory deficits evoked by the regular consumption of HFD.NDO and MR-G contributed to the conception and design of the review, as well as the drafting and revision of the manuscript. The authors have approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "The potential interconnectedness of medication adherence, glycemic control, and clinical inertia in resource-constrained settings of the developing world needs further evaluation. Dear Editor,Low- and middle-income countries account for 80% of the global diabetes burden . MoreoveThe study by Rathish et al. from a rural province in Sri Lanka makes an important contribution to the sparse literature on the subject in the country and establishes the benefits of government-funded universal free-health services in enhancing medication coverage and adherence in low-income diabetes patients . HoweverThe researchers applied the Morisky-Green-Levine scale to assess medication adherence in diabetes patients. The scale has low sensitivity and doubtful validity in this patient population that is further lowered by the application of a cutoff score of 2 that indicates moderate adherence only which might be inadequate in the attainment of good glycemic control. The direct comparison of the rates of adherence of this study with other studies that applied a different medication adherence scale and/or a different adherence definition is inappropriate as more sensitive scales and a more stringent definition of non-adherence could yield different adherence rates.A major limitation of the present study is also the lack of reporting of glycemic control status in the patients. This is particularly important for the identification of the phenomenon of clinical or therapeutic inertia indicating the failure to adequately intensify the treatment in patients showing poor glycemic control that increases the risk of incident diabetes-related complications. Previous studies from government tertiary care hospitals in India that provide free medication coverage have observed a high prevalence of poor glycemic control despite good anti-diabetes medication adherence rates in the patients , 5. This"}
{"text": "Noble metal nanostructures are exceptional light absorbing systems, in which electron\u2013hole pairs can be formed and used as \u201chot\u201d charge carriers for catalytic applications. The main goal of the emerging field of plasmon-induced catalysis is to design a novel way of finely tuning the activity and selectivity of heterogeneous catalysts. The designed strategies for the preparation of plasmonic nanomaterials for catalytic systems are highly crucial to achieve improvement in the performance of targeted catalytic reactions and processes. While there is a growing number of composite materials for photochemical processes-mediated by hot charge carriers, the reports on plasmon-enhanced electrochemical catalysis and their investigated reactions are still scarce. This review provides a brief overview of the current understanding of the charge flow within plasmon-enhanced electrochemically active nanostructures and their synthetic methods. It is intended to shed light on the recent progress achieved in the synthesis of multi-component nanostructures, in particular for the plasmon-mediated electrocatalysis of major fuel-forming and fuel cell reactions. T. T2, whi2 nanosheets  [2 [2 hybrids drastically improve the HER, with a three-fold increase of the current under excitation of the Au LSPR bands.Transition-metal disulfides such as MoSs (HERs) . To overHERs) [2 . The autThis short review summarizes the recent developments on nanomaterials for plasmon-enhanced electrochemical reactions with the aim of interesting the communities working in plasmonic and electrochemical processes, providing a common base for jointly progressing in this exciting area of plasmon-mediated electrochemistry. To understand better the design of the nanostructures, the physical fundamental of localized surface plasmon resonance and the various mechanisms for plasmon-enhanced electrochemistry have been provided. Despite the significant advances achieved in the last three years, researchers are facing many challenges in this field. While a large variety of synthetic methods have been developed for the synthesis of these heterostructures, the scale-up of such processes will be an important and imperative aspect for the use of these concepts on a wider scale. The formation of highly reproducible nanostructures with comparable catalytic and plasmonic properties is at the core of the development to envision scale-up, which is an issue that has not been yet resolved. While laser light is often used for the stimulation of the plasmonic effect, developing plasmonic materials that are responsive to sunlight with high catalytic activity represents an important goal in the field of plasmon-mediated chemical/electrochemical reactions. Which guidelines for the future design of plasmonic electrochemical materials can be provided? The formations of bimetallic and metal/semiconductor nanostructures have both shown to be of great promise for plasmon-enhanced electrochemical systems, taking advantage of the catalytic activity and the strong optical effects of these nanostructures. While such simple plasmonic nanostructures have been demonstrated as concentrating light efficiently from the UV to the near-infrared range of the light spectrum and transferring it to adjacent species, thus improving electrochemical transformations, a better understanding of the underlying mechanism of plasmon-enhanced electrochemistry is primordial for optimizing electrochemical-based oxidation and reduction processes. How to separate the generated hot electrons from the holes in an efficient and controlled manner is one of the critical criteria to be investigated, as it is fundamental for enhancing electrochemical reactions. Next to this, the importance of plasmonic heating in plasmon-enhanced electrocatalysis has to be systematically studied. How to distinguish the contribution from the electromagnetic field-enhancement from hot charge carriers-induced enhancement are big experimental and theoretical challenges to be addressed. Further studies focusing on the morphology, composition, heterojunctions, and other nanomaterials-based aspects need to be conducted in order to fully optimize the plasmon-enhanced electrochemical effects. The future of plasmon-mediated electrochemistry might be full of surprises."}
{"text": "Older adults from racial and ethnic minority groups face health inequities in long-term care facilities such as nursing homes and assisted living facilities just as they do in the United States as a whole. In spite of federal policy to support minority health and ensure the well-being of long-term care facility residents, disparities persist in residents\u2019 quality of care and quality of life. This poster presents current federal policy in the United States to reduce racial and ethnic health disparities and to support long-term care facility residents\u2019 health and well-being. It includes legislation enacted by the Patient Protection and Affordable Care Act of 2010 (ACA), regulations of the U.S. Department of Health and Human Services (DHHS) for health care facilities receiving Medicare or Medicare funds, and policies of the Long-term Care Ombudsman Program. Recommendations to address threats to or gaps in these policies include monitoring congressional efforts to revise portions of the ACA, revising DHHS requirements for long-term care facilities staff training and oversight, and amending requirements for the Long-term Care Ombudsman Program to mandate collection, analysis, and reporting of resident complaint data by race and ethnicity."}
{"text": "Bioproduction is the process of producing added-value chemicals on large-scale using cells as biological factories. Cellular burden represents a significant problem in the scaling of fermentation processes from proof-of-concept to long-term cultures, as the load of heterologous gene expression and depletion of the cell intracellular resources cause unpredictable cellular physiological changes that can lead to decreased growth and lower production yields (Borkowski et al., E. coli engineered to produce mevalonic acid in long-term cultivations (Figure In a recent paper in PNAS, Rugbjerg et al.  developes Figure .product addiction, the authors selected the chromosomal genes glmM and folP for a positive feedback control associated with the product. Both of these genes are known to supply essential intermediates for cell growth. In initial screening, the folP-glmM operon was placed under the control of the PBAD arabinose-inducible promoter and integrated into the genome. To avoid imposing extra-burden to cells, different library variants were designed where promoter and RBS strength were tuned. By analyzing the growth profiles in the presence and absence of the arabinose inducer, the authors identified a good genetic design that matches the requirements for both responsive-growth regulation and low burden. In order to make product addiction specific to mevalonic acid, the inducible promoter guiding the expression of the operon was then replaced by the AraCmev promoter, known to be responsive to the mevalonic acid product.To achieve E. coli cells, in presence of a mevalonic acid-producing construct. During long-term growth in bioreactor conditions, the addicted population grew slower than the non-addicted one, but was able to maintain constant and robust mevalonic acid production over time, thus yielding higher titers overall. The addicted population also did not display any outbreak of non-producing subpopulations, as seen with non-addicted cells. These populations were also examined using deep-sequencing techniques, allowing the authors to investigate the presence of genetic heterogeneity in both addicted and non-addicted cells. Interestingly, the sequencing results for the mevalonic acid-producing pathway identified mobile insertion elements from the native host genome as the main cause for the disruption of the genetic program in non-producing cells. This confirmed work released in parallel by the same group investigating the mutation and failure modes of constructs in E. coli (Rugbjerg et al., The authors then went on to compare growth profiles and product yields of mevalonic acid in both addicted and normal This elegant piece of research by Rugbjerg et al. advances metabolic engineering of bacterial cells, by building on previous achievements in synthetic biology and engineered feedback control. In the last decade, bacterial synthetic biology has witnessed the development of a plethora of synthetic systems and tools for the rational control of gene expression (Bradley et al., The approach of Rugbjerg et al. makes use of insights from the synthetic biology field relating to circuit engineering and burden analysis, and combines them for a metabolic engineering application. Previous approaches exploited well-controlled bio-reactor conditions or adaptive evolution to improve synthesis of growth-associated products, leveraging natural selection for reducing metabolic burden (Wu et al., folP-glmM operon variant for the sustained growth of addicted-cells while conferring tunable response to variant product concentrations.By contrast, Rugbjerg et al. smartly exploit non-conditional dependency of growth on the fermentation product so as to render production independent from external inputs. They take a rational approach in circuit design to identify the optimal The general strategy also proves effective as a way to reward producing cells at the expense of non-producing ones limiting the detrimental effects of burden on the population homogeneity. The emergence of escape mutants as a consequence of cellular burden was previously shown by Sleight et al. (Sleight and Sauro, Product addiction is achieved by exploiting a specific promoter responsive to mevalonic acid. If another product were being made instead, a different sensor promoter would need to be identified and the build-and-test cycle of the system repeated ad hoc. Ideally, in the future, variant but related strategies will be developed that are also universal and portable. Overall, the work by Rugbjerg et al. proves the power of the synthetic biology approach toward the optimization of bacterial metabolic engineering.This paper from Rugbjerg et al. represents a fine example of how advances in burden characterization and genetic system design can be exploited to significantly improve yields in bioproduction processes. The strategy they develop is autonomous from external stimuli and allows maximization of product recovery as a consequence of more robust gene expression over time. A potential drawback of the approach presented is its non-universality: All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
{"text": "To the Editor,We thank Diaz and co-authors for their recent review of Global Critical Care . We agreUnfortunately, the review misrepresents a finding from our Vital Signs Directed Therapy (VSDT) study . We did Improved recognition of critical illness and the delivery of basic care for critically ill patients throughout the hospital should be a central aspect of a global critical care roadmap. We have recently proposed the concept of Essential Emergency and Critical Care (EECC) \u2013 the care that all critically ill patients should receive in all hospitals in the world . If the When assessing the global burden of critical illness, we agree that there are major limitations of extrapolating data from ICU admissions and incomplete diagnosis-based registries and that novel methodologies are needed. Further examples to those mentioned in the review include our ongoing multi-national Critical Illness Prevalence and Outcome Study (CRISPOS), which uses point-prevalence estimations, whereby all in-patients are assessed for critical illness. Similarly, as electronic health information systems start to proliferate in low- and middle-income countries, routinely collected hospital-wide data could be exploited .for all is the foundation of critical care systems.We agree with the authors about the importance of cost-effectiveness. To maximise this, innovative tools that aim at getting the most out of the basics should be paramount in the roadmap for the future. Funders and researchers could reduce the risk that their investments in critical care end up benefitting just a few individuals by acknowledging that the quality of essential services"}
{"text": "Implementation of culture change in nursing homes shifts the care model from a traditional, more medically focused approach to person-directed care. Person-directed care promotes resident autonomy and decision making and the empowerment of direct care staff. In this paper, we examine how different stakeholders in nursing homes  conceptualize and experience a selection of person-centered care concepts . We describe the commonalities and differences in the ways different groups of stakeholders operationalize these core person centered care practices and describe areas of potential conflict of views. Lastly, we consider how the well-being and quality of life for residents is affected by the use of these practices."}
{"text": "The cognitive health needs of LGBT older adults have not been adequately addressed in mainstream clinical trials. Aging with Pride: IDEA (Innovations in Dementia Empowerment and Action), is an intervention designed to improve physical functioning and quality of life of LGBT adults with dementia and caregivers. We evaluate the processes and effectiveness of culturally-responsive recruitment approaches implemented in this study. A strong research-community partnership was necessary for the development and implementation of the intervention. LGBT participants with dementia made the first contact to research team as often as caregivers did and showed a higher rate of living alone and having a friend-based care network. The most common reason for ineligibility was not having a caregiver. Participants learned about the study via multiple venues including community events, newsletters, and social media. This study illustrates important new ways to sustain collaborations with disadvantaged communities and conduct a clinical trial with hard-to-reach participants."}
{"text": "A 30-year-old man presented to the emergency department (ED) complaining of right-hand pain after punching a wall in anger approximately one hour prior to arrival. On examination, there was obvious deformity of the dorsal aspect of the hand with a palpable bony step-off extending across the distal aspect of the wrist. Neurovascular examination of the hand and digits was normal. We obtained standard posterior-anterior  and lateCarpometacarpal (CMC) dislocations not involving the thumb are rare, accounting for <1% of all hand trauma.4On radiographs, the usual 1\u20132 millimeter CMC joint space seen on the posterior-anterior view is obliterated by bony overlap, and displacement of the proximal ends of the metacarpals is seen on the lateral view. Closed reduction by applying longitudinal traction to the involved digits with direct pressure over the bases of the dislocated metacarpals should be performed in the ED since delayed reduction is less likely to be successful.What do we already know about this clinical entity?Carpometacarpal dislocations not involving the thumb are rare. The diagnosis is frequently missed on initial examination, resulting in significant morbidity.What is the major impact of the image(s)?It identifies the characteristic obscurement of the carpometacarpal joints on the posterior-anterior view and displacement of the proximal ends of the metacarpals on the lateral view radiographs.How might this improve emergency medicine practice?Identification of this rare, though commonly missed, injury in the emergency department will prevent long-term hand morbidity."}
{"text": "This paper deals with the experimental studies conducted on the effects of using sea sand on the properties of polymer concrete modified using epoxy resin. The physical properties including workability, mechanical properties, and durability properties were evaluated as a function of sea-sand substitution. The results obtained behave as strong evidence for the feasibility of using sea sand as fine aggregate to solve the problem associated with the exhaustion of natural aggregates when used in combination with epoxy polymer. A clear understanding of the behavior of polymer concrete with sea sand as aggregate was obtained through some preliminary investigations. The test results showed a significant improvement in the compressive and flexural strength due to the sea-sand substitution in polymer concrete. Resistance to the water intrusion was also improved for the concrete mixes due to the inclusion of epoxy resin. The quality and the integrity of the concrete were also improved, as evident from the SEM analysis and infrared (IR) spectroscopy, and the results function as solid basis for the use of sea-sand polymer-modified concrete for practical applications. Results also show that 15% replacement of fine aggregate by sea sand in air-cured polymer concrete exhibited enhanced strength and durability properties; thus, the produced concrete can be an effective material for unreinforced concrete applications. Polymer concrete is in no way new to civil engineering, and several attractive properties were achieved due to its superior performance . SeveralHence, the present research work aimed at investigating the properties of epoxy-modified sea-sand concrete, as well as the internal microstructure of the produced concrete. Polymer concrete shows significant resistance to chloride penetration, and this study aimed at utilizing the lower chloride penetration capacity of epoxy concrete to mitigate the drawback of sea-sand concrete. Thus, the present work not only focuses on studying the strength variations, but also serves as an initiative to propose the widespread usage of epoxy-modified sea-sand polymer concrete to ensure sustainability in the building construction industry.3 of the concrete is presented in Type Iordinary Portland cement (OPC)  was the cement used in the present study. The concrete mixes were produced using natural river sand and sea sand for fine aggregates, and coarse aggregate. The natural river sand conforms to Zone III as per BIS 383-1970 . The finThe workability of the polymer concrete was assessed by measuring the slump values at constant water-binder ratios (IS 1199-1959) . The comThe workability of the epoxy-modified concrete containing different proportions of sea sand is shown in 3 to 2222 kg/m3 with increasing sea-sand substitution ratio and epoxy substitution in the concrete.The bulk densities of the concrete mixes are shown in The compressive strength of the concrete specimens at various ages after being subjected to different curing conditions is shown in 2, which is a major hydration product of cement. This helps in the formation of C3A , which enhances the durability and strength of concrete. Due to the pore-occupying nature of the polymers, they occupy the capillary pores, contributing to an increase in strength.The compressive strength of sea-sand-substituted polymer concretes showed a strength improvement in normal curing and water curing. Generally, the reaction of hydrated pastes of cement with dissolved chlorides and sulfate present in the sea sand leads to the formation of calcium bicarbonates and gypsum, leading to leaching and weakening of the insoluble aggregates. Cement reacts with dissolved salts, leading to the formation of gypsum and complex compounds like ettringite and brucite, which lead to brittleness of the cement matrix, causing strength loss and disruptive expansion. The addition of polymer retards the formation of these complex compounds by controlling the formation of Ca(OH)Thus, it can be concluded that the addition of epoxy polymer played an important role in the improvement of compressive strength at all ages. The higher strength of air-cured specimens may be due to the minimal quantity of epoxy used. An excess quantity of epoxy resins may disturb the hydration mechanism, thereby reducing the compressive strength of concrete. Sea sands have the ability to increase the compressive strength of concrete at early ages, and epoxy resin increases the strength at later ages. Previous works also saw improved compressive strength of the sea-sand concrete at early ages when compared to the strength of ordinary concrete .As per the flexural strength results shown in The bond strength of the concrete mixes is shown in The water absorption of the polymer concrete mixes is shown in \u22121 to 4000 cm\u22121 is due to the presence of \u2013OH bonds in the concrete, which corresponds to the chemically combined water of the hydration product Ca(OH)2. The presence of \u2013OH bonds in all the concrete mixes indicates the formation of well-reacted hydration products. The water crystal lattice of CSH gel may also be indicated by the \u2013OH band. The CSH gel formation is indicated by the band formed around 1000 cm\u22121. The spectra clearly show a strong CSH band with relatively higher intensity in all the epoxy-modified sea-sand concrete mixes when compared to the normal concrete mix. The epoxy-modified concrete showed out-of-plane bending of the phenyl ring around 300\u2013700 cm\u22121. The band around 1200cm\u22121 corresponds to the H\u2013O\u2013H deformation which is different in the epoxy concrete, signifying the presence of stretching vibrations of C=C of epoxy polymer. This further confirms that the epoxy resin reacted well with the H\u2013O\u2013H deformations to form highly stable complexes.FTIR spectra of the polymer concrete mixes are shown in The morphology of the polymer concrete mixes and the plain concrete as obtained from the SEM imaging is shown in Generally, sea sand should be subjected to pre-treatments or de-salting procedures to remove the excess chloride content for use in concrete applications due to itsadverse effect on concrete properties by promoting corrosion of reinforcement. The present study utilized sea sand without appropriate de-salting procedures and, hence, cannot be used for reinforced structural applications, which is the limitation of the present study. The high cost associated with the de-salting procedure and lack of appropriate technologies prompted the direct use of sea sand in concrete. With this background, future studies will try to determine the possibility of using sea sand in epoxy-modified concrete for reinforced concrete applications by conducting corrosion studies, thereby ensuring the safety and durability of the proposed methodology.In the current investigation, the properties of concrete utilizing epoxy resin as a cement substitute and sea sand as a substitute for river sand were investigated to their suitability for unreinforced concrete applications. Both epoxy substitution and sea-sand substitution affect the workability of concrete, but the effect of the latter is minimal. The compressive strength development was accelerated at the early ages due to sea sand, whereas the polymer cement concrete produced stronger concrete when compared to the conventional concrete at the latter ages. About 30% improvement in the compressive strength and 35% improvement in the flexural strength were achieved in the 20% sea-sand-substituted air-cured polymer concrete at 180 days when compared to the conventional concrete. The flexural strength of the epoxy concrete was further enhanced by the incorporation of sea sand that acted as a micro filler. Bond strength was markedly superior with improved pull-out strength of the polymer concrete in the presence of sea sand as fine aggregate. Other parameters such as water absorption and pore spaces were reduced showing the superior performance of epoxy-modified sea-sand concrete. Compared to ordinary concrete, the initial and secondary rate of water absorption was also reduced, showing the greater resistance to water permeability. The microstructure of polymer sea-sand concrete showed significant morphological improvement at the inside of the concrete, indicating the bonding between sea sand and the cement matrix. Thus, a limited supply of fine aggregates may be compensated for by the utilization of sea sand as fine aggregate without disturbing the ecosystem and sustainability of the concrete structures when used in combination with epoxy resins."}
{"text": "The effect of different abiotic stresses (extreme temperatures and osmotic stress) on the synthesis of glutathione and hydroxymethylglutathione, on the ratio of the reduced to oxidised forms of these thiols , and on the glutathione reductase (GR) activity was studied in maize and wheat genotypes having different sensitivity to low temperature stress. Cold treatment induced a greater increase in total glutathione (TG) content and in GR activity in tolerant genotypes of both species than in sensitive ones. The GSH/GSSG and hmGSH/hmGSSG ratios were increased by this treatment only in the frost-tolerant wheat variety. High-temperature stress increased the TG content and the GSH/GSSG ratio only in the chilling-sensitive maize genotype, but GR activity was greater after this treatment in both maize genotypes. Osmotic stress resulted in a great increase in the TG content in wheat and the GR activity in maize. The amount of total hydroxymethylglutathione increased following all stress treatments. These results indicate the involvement of these antioxidants in the stress responses of wheat and maize."}
{"text": "The study, funded by the Pennsylvania Council on the Arts and the Pennsylvania Department of Aging, measured the effect that an artist in residence program  had on self-reported loneliness in older adult. All participants were aged sixty years or older and participated in programming in state-funded adult community centers located in fourteen sites throughout the Commonwealth of Pennsylvania. Artists offered 10 sessions in creating and critiquing art to older citizens in the artists\u2019 respective art forms including performing arts, visual arts and multidisciplinary/interdisciplinary arts. Through pre and post-tests, changes in loneliness were measured using the Revised UCLA Loneliness Scale. The data revealed that there was a significant correlation between a self-reported decrease in feelings of loneliness and participation in a program conducted by professional artists. . It was proposed that findings from the study could influence the quality of programs provided by state-funded adult community centers in Pennsylvania and increase funding levels to adult community centers throughout the Commonwealth of Pennsylvania."}
{"text": "The data in the present article are related to the previous article entitled \u201cCoxsackievirus and adenovirus receptor-positive cells compose the putative stem/progenitor cell niches in the marginal cell layer and parenchyma of the rat anterior pituitary\u201d . The data describe the characteristic localization in the immature cells of the prenatal and adult tissues beyond the germ layer. Germ cells and the reproductive tissues of both sexes showed distinct intracellular polarities of CAR: apical, basolateral, and pericellular in the immature cells of the embryo and adult tissues. In addition, the\u00a0data describe on localization of CAR in the methimazole-induced damage of olfactory epithelium tissue. The data show that the CAR-_immuno-positive cells at the apical side of the olfactory epithelium disappeared following methimazole treatment and reappeared in the regenerating stem/progenitor cells (positive for KI67 and E-cadherin) of the basal layer with basolateral expression. Breeding of rats and sampling of brains are described in the previous papers Lesions in the olfactory epithelium were induced according to a previously published method 2.2Procedures of an antigen retrieval, fixation, and immunostaining were performed as described previously"}
{"text": "The gold standard for ensuring satisfactory delivery of an intervention remains fidelity monitoring. In-person observations for fidelity monitoring has received less attention in the literature compared to evaluating sessions via video and audio-recordings. This presentation focuses on a qualitative analysis of field notes from 15 scheduled fidelity visits of a home-based intervention involving persons with dementia and their caregivers . The findings of advantages , disadvantages , and ethical considerations  with be discussed. Future research recommendation is to explore participant perspectives on having an in-person fidelity monitor in the home."}
{"text": "This presentation is a reflective piece on developing and staging of the inaugural Gerontology Student Workforce Day at the Georgia Capitol held in January 2016 through coordination with the state-level Council on Aging (GCOA: Georgia-Council-on-Aging). The aims of this initiative focused on bridging students\u2019 gerontology education and career aims with current legislative concerns for older adults at the state level through networking and advocacy efforts. We also sought out to highlight to state legislators the necessity to support gerontology education. Results of this networking engagement included educating state legislators on both the role of gerontology education to support the needs of older residents at the community-level and highlighting to both parties the impact of gerontology professionals on the state\u2019s workforce. As a result, we engaged gerontology students and early career aging professionals in high-impact networking opportunities focused on service and policy efforts with state legislators and local AAAs (area-agencies-on-aging)."}
{"text": "Assessment of skeletal status and bone mineral density (BMD) in the pediatric population requires knowledge of the child\u2019s overall health, clinical history of chronic illness and/or risk factors for osteoporosis, and atraumatic fractures. Dual-energy X-ray absorptiometry (DXA) is the gold standard for the assessment of bone health, in children and adolescents. The interpreting physician needs to acknowledge that diagnosis of low BMD in growing subjects should include in addition to densitometric measurements, the synchronous assessment of the DXA-generated image for collateral findings that may cause erroneous evaluation of bone mass and improper management. Osteonecrosis refers to the in situ death of bone  and usua2Herein we report the case of a young child with osteonecrosis of both hips who underwent dual energy X-ray absorptiometry (DXA) to evaluate bone mass. Although it allowed evaluation of evolution of osteonecrosis over time, this case clearly indicates that osteonecrosis can be another source of diagnostic error causing artifactual elevation of the BMD measurements. The teaching point of this pediatric case is that visual inspection of DXA images should always precede interpretation of the densitometric data.An 8-year-old boy with a history of 5 years of acute lymphoblastic leukemia was referred for radiographic evaluation of the pelvis because of left hip pain and a limp. The patient had undergone radiation therapy of the total body and bone marrow transplantation at age 6. Since the onset of the disease he had been receiving intravenous and oral corticosteroids. Three months post-transplantation, the patient developed lung disease secondary to graft- versus-host disease and received high doses of intravenous and oral steroids. Subsequently, the patient developed autoimmune hemolytic anemia and was treated again with high doses of intravenous and oral steroids.rd and 9th centile and his weight was 54.3 lb, which lies between the 24th and 50th centile. Radiographic evaluation of the spine and hips revealed compression fractures in thoracic spine  and mild deformity of the femoral epiphyses , or at risk for a secondary bone disease  and an elevated risk of fracture . Skeleta6676778In this complex pediatric clinical case, BMD as measured by DXA was found to spuriously increase on the follow-up scans. Osteonecrosis of the femoral head was the cause of false elevation of the BMD, in our patient. If this pitfall was not recognized, this patient with low BMD would be misdiagnosed as responding to treatment over time. Our case highlights the importance of analysis of DXA images in addition to numeric data for identification of the variable sources of diagnostic error, including osteonecrosis of the femoral head.The authors declare that they have no competing interests."}
{"text": "The CFSIE experiments are designed to reduce weather noise and using a few ten-year long forecasts this study shows that reduction in weather noise leads to lower SST forecast skill. To understand the pathways that cause the reduced SST prediction skill, two twenty-year long forecasts produced with CFS and CFSIE for 1980-2000 are analyzed for the ocean subsurface characteristics that influence SST due to the reduction in weather noise in the North Pacific. The heat budget analysis in the oceanic mixed layer across the North Pacific reveals that weather noise significantly impacts the heat transport in the oceanic mixed layer. In the CFSIE forecasts, the reduced weather noise leads to increased variations in heat content due to shallower mixed layer, diminished heat storage and enhanced horizontal heat advection. The enhancement of the heat advection spans from the active Kuroshio regions of the east coast of Japan to the west coast of continental United States and significantly diffuses the basin-wide SST anomaly (SSTA) contrasts and leads to reduction in the SST prediction skill in decadal forecasts.The sensitivity of the sea-surface temperature (SST) prediction skill to the atmospheric internal variability (weather noise) in the North Pacific (20 The view of the first category is that due to the higher heat capacity of oceans in the earth-climate system, stochastic forcing by weather noise acts to redden the low-frequency Ocean SST variability spectra  on North Pacific SST. The primary goal is to understand the pathways that influence the variability in the North Pacific SST in the absence of weather noise at the ocean-atmosphere interface in a CGCM. To achieve this a CGCM simulation should be compared against the exact same CGCM counterpart that has no weather noise. In this study, the impact of weather noise on the North Pacific SST variability is analyzed by comparing a twenty-year long forecast produced by state-of-the-art Climate Forecasting System version 2  againstInteractive Ensemble method . A brieIn the Interactive Ensemble configuration, the momentum, heat and fresh water fluxes that atmospheric component exchanges with ocean component are controlled in a way that the higher frequencies in these fluxes are reduced at the ocean-atmosphere interface. This is achieved by concurrently coupling the mean of the fluxes simulated by several atmospheric components with a single ocean component that in turn forces each atmospheric component with the same SST. This setup leads to a reduction in the atmospheric internal variability in the coupled system. For a more detailed discussion on how the Interactive Ensemble approach reduces the weather noise in a CGCM, refer to Kirtman et al. .http://cfs.ncep.noaa.gov/cfsr/). The initial conditions needed for the six copies of the atmospheric components in CFSIE integration are obtained from the CFS reanalysis data separated by 6 hours starting from 00Z of 1 November 1980.The twenty-year long CFS and CFSIE forecasts are produced from 1 November 1980 to 31 October 2000. The atmosphere and the ocean initial conditions for the forecasts are derived from CFS reanalysis products (available online at http://pcmdi3.llnl.gov/esgcet/), and are run in the 20th century historical external forcing. The CFSf are initialized with NEMOVAR-COMBINE ocean reanalysis data  are produced in this study to understand the SST prediction skill in the NPR. The CFSf are a set of monthly forecasts that follow the guidelines set forth by Coupled Model Intercomparison Project phase 5 . However, in the CFSIE the contribution from the KAA index on PAA index is larger  in each month is estimated by interpolating the ocean depths, between which, the ocean temperature differs from the SST by 0.5\u2218C  on standard deviation of HT (SD_HT) shows that in the CFSIE, HT contributes more to the variance of PAA index (not shown). The strong spatial contrast of the regression parameter in the NPR indicates that HT acts to diffuse the variance of PAA index. The higher HT in conjunction with the lower MXLD in the CFSIE forecast prompts to diffuse stronger SST contrasts that are specific to decadal SST forecasts in the North Pacific region that were found in the CFS forecasts. The depth cross-section of averaged SST along the transect that connects the locations 20ons Fig.\u00a0.Fig. 10\u2218-60\u2218N and 120\u2218E-80\u2218W, referred as NPR) SSTA forecasts as produced by CMIP5-style decadal forecasts with state-of-the-art global climate forecasting system model (CFS) in an Interactive Ensemble set-up (CFSIE), which reduces atmospheric internal variability. The main goal of this study is to examine and understand the pathways that prompted the reduced prediction skill in the CFSIE forecasts in comparison with the regular CFS forecasts. Two 20-year long forecasts produced with CFS and CFSIE for 1980-2000 are compared for the subsurface characteristics that influence SST in the North Pacific Region. The detailed heat budget analysis in the oceanic mixed layer of the CFS and CFSIE experiments reveals that the heat transport in the oceanic mixed layer is driven significantly by the atmospheric internal variability (weather noise). In the CFSIE, the reduction in the weather noise leads to shallower mixed layer depths and the increase in the heat content variations associated with lower heat flux result in diminished heat content storage and enhanced horizontal heat advection throughout the basin. Due to the deeper mixed layer in CFS, the available heat flux channels to raise the temperature in the the mixed layer and this diminishes the heat available for the basin-wide horizontal transport.The motivation for this study stems from the reduced prediction skill in North Pacific region (20The enhanced HT in the CFSIE is basin-wide in the spatial extent and spans from the active Kuroshio regions of east coast of Japan to the west coast of continental United States. This enhanced horizontal advection of heat in the oceanic mixed layer acts in a way to diffuse the SSTA contrasts and leads to reduced skills in decadal forecasts."}
{"text": "The skin of vertebrates acts as a biological barrier defending the organism against many harmful environmental factors. It is well established that the main stress hormone cortisol, together with antioxidants such as melatonin (Mel) and its biologically active metabolites set up a local stress response system in the mammalian skin. Recently, our research group has shown that in fish there are basic conditions for the functioning of a cutaneous stress response system (CSRS) similar to that in mammals, where Mel with its biologically active metabolite AFMK (N1-acetyl-N2-formyl-5-methoxykynuramine) and cortisol act together to protect organism against unfavorable environment. Since aquaculture is making an increasing contribution to the global economy and new laws are demanding people to respect the welfare requirements of animals there has been increasing interest in indicators of fish well-being in aquaculture. This article addresses the problem of on-farm assessment of fish welfare and proposes the CSRS as a new source of information on the welfare status of farmed fish. There has been growing public concern for the well-being of farmed fish since aquaculture is making an increasing contribution to the global economy and, at the same time, new laws are demanding people to respect the welfare requirements of animals to ensure their right treatment  (Gasterosteus aculeatus) (cutaneous synthesis of Mel would seem to be confirmed by studies in various fish species where higher Mel concentrations were found in their skin than in plasma or muscles (Ciconia ciconia) living near a copper smelter, toxic compounds in the diet can stimulate Mel synthesis on-the-spot in the gut, to serve as a first-line defensive step in the protective mechanism of the organism   and the uleatus) . Moreove muscles . A stimu muscles . For insorganism . Variousorganism , but notCertainly, one might expect to find some dissimilarity between the stress response systems in fish skin and in terrestrial vertebrates\u2019 skin. The aquatic environment and the specific structure/function of fish skin make a difference! The skin in fish is covered by mucus and this outermost layer has been considered a first line of defense against a wide range of detrimental environmental conditions  and pathThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}