The aim of this survey was to evaluate attitudes and preferences for the clinical management of hypertension and hypertension-related cerebrovascular diseases (CVD) in Italy.A predefined 16-item survey questionnaire was anonymously administered to a large community sample of general practitioners (GPs), trained by specialized physicians (SPs), who have been included in an educational program between January and November 2015. A total of 591 physicians, among whom 48 (8%) training SPs and 543 (92%) trained GPs, provided 12,258 valid answers to the survey questionnaire. Left ventricular hypertrophy was considered the most frequent marker of hypertension-related organ damage, whereas atrial fibrillation and carotid atherosclerosis were considered relatively not frequent (10–20%). The most appropriate blood pressure (BP) targets to be achieved in hypertensive patients with CVD were <140/90 mmHg for SPs and <135/85 mmHg for GPs. To achieve these goals, ACE inhibitors were considered the most effective strategies by GPs, whereas SPs expressed a preference for ARBs, both in monotherapies and in combination therapies with beta-blockers.This survey demonstrates that Italian physicians considered left ventricular hypertrophy frequently associated to CVD and that drugs inhibiting the renin-angiotensin system the most appropriate therapy to manage hypertension and hypertension-related CVD.The online version of this article (doi:10.1186/s40885-017-0066-0) contains supplementary material, which is available to authorized users. Effective control of high blood pressure (BP) reduces incidence of major cardiovascular complications, and improves event-free survival from cerebrovascular diseases (CVD), mostly stroke . DespiteIn order to improve BP control, several interventions have been proposed and applied in various countries, including Italy. Among these, a closer attention to global cardiovascular risk stratification and a proper selection of antihypertensive drug therapies on the basis of individual global CV risk profile have emerged as the best way to ameliorate hypertension management and control –6. HowevMore recently, an extensive use of epidemiological surveys and observational studies has emerged as a valuable option to evaluate physicians’ workflow, particularly when managing hypertensive outpatients at different CV risk –15. In tIn the present survey, we evaluated the clinical attitudes and preferences for the management of patients with hypertension and hypertension-related CVD, expressed by a large sample of physicians in Italy.The primary aim of this survey was to evaluate the clinical attitudes and preferences of both general practitioners (GPs) and specialized physicians (SPs), who were included in an educational program performed in Italy in 2015.Secondary aims of the survey were to analyse pharmacological preferences  in patients with hypertension and CVD.The methodology of the study has been previously described . BrieflyThe study conformed to the Declaration of Helsinki and its subsequent modifications. Confidentiality on demographic and personal data of each physician included in the present survey was carefully preserved and strictly protected during each phase of the study. No access was made to individual data of neither physicians’ own patients nor their medical databases. Written consent to participate to the educational program was obtained by all involved physicians.The survey questionnaire included a total of 16 questions addressing the following items: 1) estimated concomitant prevalence of hypertension and CVD and prevalence of hypertension-related markers of organ damage and comorbidities in patients with hypertension and CVD (questions num. 01–06); 2) diagnostic options to assess the presence of CVD in hypertensive patients (questions num. 07–08); 3) BP targets and the most appropriate therapeutic targets to be achieved in a setting of clinical practice, when managing hypertensive patients with CVD (question num. 09–10 and 13–14); 4) preferences for antihypertensive drug classes in hypertensive patients with CVD to be used as first line therapy (monotherapy) or combination therapy (questions num. 11–12 and 15–16). The full survey questionnaire is reported in Additional file Physicians’ engagement was carried out during the first 6 months of 2015. As per study protocol , particiPhysicians were invited to participate to an educational program, aimed at improving knowledge on hypertension-related cardiovascular diseases and implementing strategies for achieving better BP control in their practice. Educational program was structured into two distinct sections: one start-up meeting, held in January 2015 and pointed to SPs, and local meetings, distributed throughout the whole Italian territory, during which SPs involved in the start-up meeting trained GPs. Before starting each educational meeting, involved physicians were asked to fill the survey questionnaire anonymously. The entire survey questionnaire was completed by participants on-site and then delivered to the data collection centre. Physicians who completed the survey did not receive any compensation for their participation.All data derived from the survey questionnaires were reported into a computerised sheet . Then, analyses were made to generate proportions of individual answers to each question of the survey questionnaire. A separate sheet, containing graphs, was produced for the 16 questions of the survey questionnaire. Data were presented as a percentage of the total answers to each question.Overall, 591 physicians  were included in the survey. Among these, 48 (8.1%) were training SPs and 543 (91.9%) were trained GPs. Involved physicians provided 12,599 answers to the survey questionnaire, among which 312 (2.5%) were considered inappropriate or incorrect and 29 (0.2%) were missing or not reported. Thus, a total of 12,258 valid answers were included in the present analysis, which represents the 97.3% of the overall results generated by the survey questionnaire.As shown in Table Renal organ damage was considered to be frequent by 54% of SPs and 45% of GPs, although about one third of both groups of physicians considered this marker relatively not frequent in their clinical practice. At the same time, vascular organ damage  was considered relatively not frequent in hypertensive outpatients by the vast majority of involved physicians. Of note, estimated prevalence of CVD, including transient ischemic attack and stroke, was reported to be relatively low mostly in those hypertensive outpatients followed by SPs compared to those followed by GPs.As shown in Table On the other hand, the majority of GPs considered the carotid vascular ultrasound the most appropriate diagnostic tool to be used in patients with hypertension for excluding the presence of CVD in their clinical practice, whereas, the majority of SPs expressed a clear preference for brain imaging techniques, including CT or MR.As shown in Table Also in the clinical management of hypertensive outpatients with stroke, the achievement of the recommended BP targets was considered the most important therapeutic target by 47% of GPs, followed by absolute BP reductions (38.4%) and protection from hypertension-related organ damage (10.9%), whereas SPs gave similar clinical relevance to protection from organ damage (40.4%) and achievement of the recommended BP targets (38.3%). Also in this case, adherence to prescribed medications was relatively partially considered by SPs (10.6%) and GPs (3.5%). Of note, reduction of drug-related side effects and adverse reactions was basically not considered of clinical relevance by both groups of physicians.Differences between two groups of physicians were observed with regard to BP goals in hypertensive outpatients with TIA Fig. . Indeed,In hypertensive outpatients with TIA Fig. , angioteIn hypertensive outpatients with stroke Fig. , about 6Combination therapies based on ACE inhibitors with beta-blockers, diuretics or calcium-channel blockers represented the preferred options for treating patients with hypertension and TIA by GPs Fig. . On the Similar proportions were observed for physicians’ preferences with regard to different combination therapies used for treating hypertensive patients with stroke Fig. . In partIt is well known that hypertension management and control have been not achieved for many years, and that this relative failure has largely contributed to a persistently high burden of hypertension-related CVD, mostly including TIA and stroke, worldwide. It has been also shown that many factors can be advocated to try to explain the reported poor rates of BP control observed in various Western Countries, including Italy. Among these factors, patients’ clinical characteristics and behaviours , as well as poor effectiveness of antihypertensive drug strategies  have been acknowledged.As a matter of fact, all these items are mostly focused on hypertensive outpatients rather than on treating physicians. Indeed, minor data are available to evaluate physicians’ preferences and behaviours in the clinical management of hypertension in real practice. In this view, we recently analysed the preferred options for the clinical management of outpatients with hypertension and hypertension-related diseases expressed by Italian physicians with different medical skills –19. ThesFirst of all, concomitant presence of hypertension and CVD was considered to be relatively not frequent in a setting of clinical practice. The vast majority of both groups of Italian physicians reported an estimated prevalence of hypertension and CVD between 10 and 20%. On the other hand, physicians reported a relatively high prevalence of cardiac organ damage, namely left ventricular hypertrophy, which has demonstrated high predictive value on the risk of hypertension-related CVD. This highlights the need for having specific diagnostic and therapeutic indications, in order to improve the clinical management of patients with hypertension and cardiac organ damage and reduce the potential risk of CVD.In addition, Italian physicians considered the presence of cardiac organ damage, namely left ventricular hypertrophy, as the most common marker of organ damage. Also, the estimated prevalence of left ventricular hypertrophy was considered to be substantially higher than those reported for other hypertension-related markers of organ damage, including renal abnormalities and carotid atherosclerosis, thus highlighting the clinical relevance given by both groups of physicians to hypertension-related cardiac organ damage. However, the existence of left ventricular hypertrophy can be easily detected by simple ECG, whereas tests for other markers of organ damage except for cardiac one, may result in additional costs. Given this consideration, lower prevalence of some types of organ damage may be due to incomplete evaluation in a setting of real clinical practice.Preferred options expressed by involved physicians for BP targets to be achieved in treated hypertensive patients with CVD resulted of particularly relevance, because of Italian GPs aimed to achieve more ambitious targets than those expressed by specialized physicians and recommended by current guidelines. In the most recent guidelines , 20, it As applied for previous analyses , 17, somAlthough limited by the descriptive nature of the survey, this study provides some relevant information on attitudes and preferences, as well as on different diagnostic and therapeutic approaches applied by physicians when managing hypertensive outpatients with CVD in Italy. The main findings of our analysis, in fact, demonstrated that the concomitant presence of hypertension and cardiac markers of organ damage is reported to be high, whereas that of hypertension and CVD is considered to be relatively low in a setting of clinical practice by both groups of involved physicians. Even in the absence of specific indications from international guidelines, GPs tended to attain more ambitious BP targets in hypertensive outpatients with CVD. To achieve these BP targets, pharmacological therapies based on ACE inhibitors, either in monotherapy or combination therapy (mostly with beta-blockers), represented the preferred options.


Primary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma.A 12 year old Sri Lankan girl presented with progressive difficulty in walking since 1 year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790 pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of −3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned.PHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes. Primary hyperparathyroidism (PHPT) is a common condition among adults. However it’s an uncommon disorder in children and adolescents associated invariably with delay in diagnosis. This is mainly attributed to incidental detection of hypercalcemia in routine blood investigations done in adults thus allowing diagnosis at an asymptomatic stage. In contrast diagnosis in children is often when they are symptomatic with target organ involvement. It is postulated that puberty may result in unmasking of certain skeletal manifestations which result due to PHPT.We present a case of an adolescent with PHPT who presented with rare skeletal manifestations of genu valgum, bilateral SUFE and bilateral epiphyseal displacement of humeri.A 12 year old Sri Lankan girl presented with crooked legs and progressive difficulty in walking for 1 year duration. She did not complain of any leg pain, joint pain or proximal muscle weakness. There was no history of trauma, fractures, abdominal pain, vomiting constipation, neck swelling or renal calculi. She had been relatively healthy up to now taking part in athletic events in school until the development of these symptoms. Her menses were regular following attaining menarche at the age of 11 years. She was a product of a non consanguineous marriage and both her siblings were healthy. Family history was nil of note for any renal disease or multiple endocrine neoplasia (MEN). Her diet was deficient in milk and meat products. Bilateral stapling of knees done 6 months back did not lead to any symptomatic resolution. On examination she had bilateral valgus deformities of the knees without any other clinical features of Rickets or dysmorphism. No other joint deformities were noted. Height and weight were age appropriate and she was in Tanner 2 in pubertal development. The rest of the systemic examination was normal.X ray imaging of the lower limbs revealed bilateral slipped upper femoral epiphysis (SUFE) and bilateral genu valgus deformity of the knees. As SUFE is associated with a wide range of endocrine and metabolic disorders she was screened for these diseases. Ionized calcium levels were 1.5 mmol/l (1–1.3 mmol/l) which was repeated and confirmed. Serum phosphate levels were low at 2.3 mg/dl (2.5–4.5 mg/dl). Serum Alkaline phosphate levels (ALP) were elevated at 3210 U/L (age matched reference range 182–587 U/L). Serum intact Parathyroid Hormone (PTH) levels were 796 pg/ml (8–76 pg/ml) indicating hyperparathyroidism. Calcium creatinine ratio was 0.06 (>0.02 suggestive if primary hyperparathyroidism). Vitamin D levels were 25 nmol/l (<30 nmol/l suggestive of deficiency). Anterior pituitary hormones inclusive of Thyroid function tests, 9 am Cortisol, Follicular Stimulating Hormone, Luteinizing Hormone, Prolactin and baseline hematological indices, serum electrolytes, renal and liver profile were all normal. A skeletal survey revealed evidence of epiphyseal displacement of bilateral humeral heads, rugger jersey spine and subperiosteal bone resorptions involving lateral aspects of 2nd and 3rd phalanges. There were no radiological features of rickets such as widening, cupping or fraying of the metaphysis. An ultrasound scan performed to detect a possible parathyroid adenoma failed to detect any masses. Ultrasound scan of abdomen did not show any evidence of nephrocalcinosis or renal calculi. Bone densitometry of spine revealed low bone mineral density with a Z score of −3.4. At this stage a differential diagnosis of Primary hyperparathyroidism (PHPT) with vitamin D deficiency or Tertiary hyperparathyroidism due to vitamin D deficiency was considered. It was decided to reassess her following adequate supplementation with vitamin D. She was treated with 50,000 IU of vitamin D2 weekly for 8 weeks followed by maintenance therapy of vitamin D3 1000 IU daily Table As adequate vitamin D supplementation failed to reduce the PTH levels a diagnosis of primary hyperparathyroidism was made. A Tc99 Sestamibi parathyroid scan revealed focal abnormal and persistent tracer retention in right inferior thyroid pole. As the diagnosis of PHPT was most likely due to parathyroid adenoma she underwent surgery where a large 2 × 3 cm parathyroid gland was removed from the right inferior pole of the thyroid gland. Ipsilateral parathyroid gland was atrophied. Histology favoured a parathyroid adenoma. Post operatively she developed perioral numbness and paresthesia in fingers. Serum ionized calcium levels were 0.8 mmol/l, serum intake PTH levels were 61 pg/ml with normal levels of magnesium 0.82 mmol/l (0.75–0.95 mmol/l) and phosphate 1.0 mmol/l (0.8–1.5 mmol/l). A probable diagnosis of hungry bone disease was made and she was treated with a single dose of intravenous calcium followed by oral calcium carbonate 3 g/day and calcitriol 2 μg/day with monitoring of serum calcium levels. She required calcium supplementation for 3 months following surgery. Bilateral osteotomy was performed for SUFE even prior to completion of metabolic evaluation as delay in treatment can have detrimental effects such as progression of the slippage and avascular necrosis. Series of surgeries for correction of limb deformities were planned following the improvement of quality of bone after treatment of PHPT Figs. , 5 and 6PHPT is common disease among adults. However it’s occurrence is very rare among children and adolescents with about 200 cases reported worldwide up to now . It’s inThe characteristic feature in older children is delayed presentation. Almost 80% of children are symptomatic and have end organ damage at the time of presentation , 4. ThisPHPT in our 12 year old patient was unmasked due to these skeletal deformities as she progressed through puberty. Apart from these she did not have any other clinical features suggestive of PHPT. Following excision of the parathyroid adenoma she developed biochemical resolution. However further surgeries will be required to correct the limb deformities.PHPT is a rare disease in children which is often diagnosed late once target organ involvement had developed. In contrast, adults with PHPT are incidentally detected in the asymptomatic phase during routine blood investigations. Apart from the well known skeletal manifestations, PHPT can affect the bone and epiphysis resulting in rare skeletal deformities such as genu valgum, SUFE and epiphyseal displacement especially during the pubertal growth spurt in adolescents. Having a high degree of suspicion when children and especially adolescents present with skeletal symptoms may aid in speedy diagnosis and prevention of detrimental long standing deformities.


LC8, a highly conserved 10-kDa light chain, and IC74, a 74-kDa intermediate chain, are presumed to promote the assembly of the cytoplasmic dynein motor protein complex and to be engaged in the controlled binding and release of cargo. The interactions of LC8 from Drosophila melanogaster with constructs of IC74 were characterized in vitro by affinity methods, limited proteolysis, and circular dichroism spectroscopy. Previously, we have performed limited proteolysis on the N-terminal domain of IC74, IC(1-289), when free and when bound to dynein light chains LC8 and Tctex-1[1]. We have also shown that upon addition of LC8, IC(1-289) undergoes a significant conformational change from a largely unfolded to a more ordered structure. The purpose of the work presented here is to determine whether residues 1-30 in IC74, predicted to be in a coiled coil, are involved in the stabilization of the protein upon binding to LC8. Constructs of IC74, IC(1-143), and IC(30-143) that include the LC8 binding site but with and without the first 30 residues were prepared, and their binding and protection patterns were compared to our previous results for IC(1-289). The results suggest that coiled coil residues 1-30 are not responsible for the increase in structure we observe when IC(1-289) binds to LC8.


Remarkably, when B-γ-CsSnI3 perovskite is deposited from a dimethylformamide solution onto a 180–190 nm thick CuSCN film supported on an indium-tin oxide (ITO) electrode, the CuSCN layer is completely displaced leaving a perovskite layer with high uniformity and coverage of the underlying ITO electrode. This finding is confirmed by detailed analysis of the thickness and composition of the film that remains after perovskite deposition, together with photovoltaic device studies. The results of this study show that, whilst CuSCN has proved to be an excellent hole-extraction layer for high performance lead-perovskite and organic photovoltaics, it is unsuitable as a hole-transport layer in inverted B-γ-CsSnI3 perovskite photovoltaics processed from solution.We report the findings of a study into the suitability of copper (I) thiocyanate (CuSCN) as a hole-transport layer in inverted photovoltaic (PV) devices based on the black gamma phase (B-γ) of CsSnI However, the possibility of lead contamination of the environment due to failure of the device encapsulants or improper disposal at the end of life is a serious concern for commercial exploitation6. The latter is because lead is a highly toxic element that accumulates in the food chain7 and lead perovskites decompose upon exposure to moisture and water to form lead compounds with significant solubility in water9. Consequently, there is a need for lead-free alternative matched to the needs of photovoltaic (PV) applications. Recent research has shown that tin (Sn) is a potential replacement for Pb in halide perovskites, an element with much lower toxicity than Pb10. PPVs based on wholly inorganic tin perovskite PVs are however at a very early stage of development and so to date the highest reported power conversion efficiency is only 6.4%11. Much of the dramatic improvement in the power conversion efficiency of lead PPVs has resulted from identification and optimisation of the electron transport layer (ETL) and hole transport layer (HTL)12 which interface the light harvesting perovskite layer with the electrodes. These interfacial layers are critically important because they: (i) enable the optimization of the light distribution in the device; (ii) facilitate efficient and selective charge extraction, by minimizing the barrier to the extraction of one carrier type, whilst presenting a large barrier to extraction of the charge carriers with opposite polarity carrier; (iii) physically separate the metal electrode form the perovskite layer, blocking the adverse reactions between them.Perovskite photovoltaic (PPV) devices using lead (Pb) halides as the light harvesting semiconductor have shown an unprecedented evolution over the span of less than a decade, with the power conversion efficiency increasing from 3.8% in 200913. It is however recognized that the high cost and instability of this material will negatively impact the prospects of commercialization and so there is a need to identify lower cost alternative HTLs. In addition to offering long term stability, the charge transport layer at the transparent electrode must also offer high optical transparency, and so there is interest in using wide band gap wholly inorganic HTLs14 including NiO15, CuI16, Cs2SnI617 and copper (I) thiocyanate (CuSCN)22. Among these CuSCN has proved to be a particularly effective HTL for high performance Pb-PPVs with both a conventional12 and inverted device architecture18, and also for high performance organic PVs22. The success of this material as a HTL is due to its wide band gap (≥3.50 eV), excellent solution processability at room temperature and high hole-mobility combined with an ionization potential suitable for the efficient extraction of holes22. Herein, we report the findings of an investigation into the suitably of CuSCN as a HTL in inverted PV devices based on B-γ-CsSnI3, a semiconductor that is attracting considerable attention because it offers near ideal optoelectronic properties for a single junction PV devices and can be processed at room temperature from dimethylformamide (DMF) solutions of CsI and SnI223.In the context of Pb-PPVs the doped organic semiconductor spiro-OMeTAD  has proved to be the best HTL to date in terms of the device power conversion efficiency22. A solution concentration of 50 mg/ml deposited at room temperature yielded a film thickness of 180–190 nm as measured by step height analysis using atomic force microscopy (AFM): Supporting Information Figure 3 + SnCl2 (10 mol% excess) |phenyl-C60-butyric acid methyl ester (PC61BM)|bathocuproine (BCP)|Al. The B-γ-CsSnI3 layer was deposited from DMF solutions at room temperature, with 10 mol% excess SnCl2 added as a source of excess Sn, according to our previously reported optimized procedure23. In a dry nitrogen-filled glovebox CsI, SnI2 and SnCl2 were mixed together in 1:1:0.1 molar ratio. To this mixture DMF was added to make an 8 wt% solution , which was stirred overnight before use. To deposit films, two drops of solution were cast onto a substrate spinning at 4,000 rpm for 60 s. To confirm that DMF is an orthogonal solvent for CuSCN a 180–190 nm thick film of CuSCN was washed with DMF using the same spin-coating procedure as used for perovskite film deposition. The AFM images in Fig. q), measured over an area of 10 μm × 10 μm is reduced from ∼30 nm before spin casting DMF to ∼10 nm after washing with DMF by spin casting. This reduction in surface roughness is consistent with partial dissolution of the CuSCN layer during DMF washing and its possible  removal. However, it is clear from Fig. 19.In this study diethylsulfide was the solvent of choice for CuSCN deposition because it has been shown to be an excellent solvent for the formation of CuSCN films for electronic applications3 perovskite films deposited from 8 wt% DMF solutions by spin coating directly onto CuSCN supported on ITO glass have a high surface coverage with improved uniformity as compared to perovskite films deposited directly onto ITO glass , open-circuit voltage (Voc), fill factor (FF) or shape of the external quantum efficiency (EQE) spectrum for PV devices with and without a CuSCN HTL. Given that the CuSCN layer increases the total semiconductor thickness in the device by up to a factor of 5, it is surprising that the Jsc remains unchanged (8.1 mA cm−2vs 8.2 mA cm−2) and the shape of the EQE spectrum remains unchanged, since the light distribution in the device would be significantly changed by the inclusion of such a thick additional layer24. It is also unexpected that Voc for the devices with and without CuSCN; 0.31 V and 0.30 V respectively, is essentially unchanged since the CuSCN layer would be expected to reduce the reverse saturation current by blocking the unwanted extraction of electrons by the ITO electrode, giving rise to an increase in Voc23.It is evident from Fig. 3 based PV devices without a HTL23, and so it is unexpected that PV devices incorporating a CuSCN HTL should exhibit the same evolution in performance with storage.Additionally, devices with and without a CuSCN layer improve significantly with storage under nitrogen: Fig. 2, and the result was the same  analysis  of the films of CuSCN and B-γ-CsSnIs Figure  which pr7 Figure  confirmi7 Figure  is consi7 Figure  and all 3 perovskite does not form directly from DMSO solutions at room temperature, but there is rapid crystallization to form a solvated intermediate29 which must be annealed for conversion to the perovskite. Figure 30 environment  as the solvent for perovskite film deposition. Notably, unlike for DMF, B-γ-CsSnIt Figure  shows tht Figure . Taken t3 perovskite or a solvated intermediate29. Tin perovskites are known to crystallize much more rapidly than their lead analogues due to the high Lewis acidity of Sn2+ 30, and the enthalpy of formation of the B-γ-CsSnI3 perovskite is very low as compared to that of CuSCN (∼0.06 eV31vs 1.14 eV32), so the process of complete ejection of the CuSCN under layer is evidently a strongly kinetically driven process.The complete displacement of the 180–190 nm thick CuSCN film by the perovskite film  is remarkable, not least because of the high speed of film formation during spin-casting. This finding is attributed to a combination of the increased solvation power of DMF and DMSO for CuSCN, due to the high ionic strength associated with halide and metal ions, together with the tendency for very rapid crystallization either directly to the B-γ-CsSnI3 based PPV with an inverted device architecture. Unencapsulated PPV based on B-γ-CsSnI3 with an inverted architecture have been shown to exhibit promising device stability23, although the power conversion efficiency has remained stubbornly low primarily due to a low Voc. The ionization potential of B-γ-CsSnI3 is particularly small amongst tin and lead halide perovskites33 and so in order to achieve a significantly increased Voc, energetic losses that occur during hole-extraction must be minimized. The identification of a suitable HTL layer, which has hitherto proved elusive31, is therefore essential to improve the efficiency of B-γ-CsSnI3 based PPVs, and so represents a fertile area of research.In conclusion, whilst CsSCN has proved to be a low cost HTL for Pb-PPV and high performance organic PVs, here we have shown that is unsuitable as a HTL in solution processed B-γ-CsSnIA solution concentration of 50 mg/ml CuSCN in diethyl sulfide was drop cast onto a freshly cleaned ITO glass substrate spinning at 3000 rpm for 60 seconds.2 and tin(II) halide were mixed together in 1:1:0.1 molar ratio. To this mixture N,N-dimethylformamide (DMF) was added to make an 8 wt% solution , which was stirred overnight before use. To deposit films, two drops of solution were cast onto the substrate (sufficient to cover the whole substrate), followed by spinning at 4,000 r.p.m. for 60 s. The B-γ-CsSnI3 phase forms immediately upon solvent evaporation.In a dry nitrogen-filled glovebox CsI, SnI−1.) were held in vertical slide holders and ultrasonically agitated in an acetone bath, followed by a high purity water bath with a few drops of surfactant, followed by high purity deionized water only bath, acetone and finally an isopropanol bath. Slides were then UV/O3 treated for 15 minutes. Immediately after UV/O3 treatment the slides were transferred into a dry nitrogen filled glovebox for CuSCN film deposition followed by deposition of the perovskite and finally the PC61BM layer from 13 mg ml−1 chlorobenzene solution using a spin speed of 1500 rpm. This was followed by thermal evaporation of 6 nm bathocuproine (BCP) deposited at 0.5 Å s−1 and then 60 nm of Al deposited at 1 Å s−1. Thermal evaporation was performed at a pressure of 1 × 10−5 mbar with substrate rotation. The Al electrode was deposited through a shadow mask to make six devices per slide, each with an area of 6 mm2.Indium tin oxide (ITO) coated glass slides (Thin Films Devices Inc. 15 ± 3 Ω sqJ–V) curves were measured using a Keithley 2400 source-meter under AM1.5 G solar illumination at 100 mW cm2 (1 sun), scanned from 1 V to + 1 V at 0.1 Vs-1. External quantum efficiency (EQE) measurements were carried out using a Sciencetech SF150 xenon arc lamp and a PTI monochromator, with the monochromatic light intensity calibrated using a Si photodiode (Newport 818-UV). The incoming monochromatic light was chopped at 180 Hz. For signal measurement a Stanford Research Systems SR 830 lock-in amplifier was used. J–V and EQE measurements were made using custom LabVIEW programs.Device testing was performed in the same glove box as used for device fabrication using a solar simulator inside the glove box. Current density–voltage , with the photoelectrons being detected at a 90° take-off angle. The sputtering was carried out at room temperature using a Minibeam I ion gun . A beam of 4 keV Ar+ ions was incidenton a 3 × 3 mm area of the sample surface. Curve fitting was performed using the CasaXPS package, incorporating Voigt (mixed Gaussian Lorentzian) line shapes and a Shirley background.XPS analysis was performed using a Kratos AXIS Ultra DLD. Samples were unavoidably exposed to air for approximately 1 min during transfer from an air-tight box to the vacuum chamber of the instrument. XPS measurements were carried out in an ultrahigh vacuum system with a base pressure of 5 × 103 prepared from 8 wt%  DMF solution deposited onto a glass substrate (13 × 13 mm2) spinning at 4000 rpm for 60 seconds. Measurements were made on a Panalytical X’Pert Pro MRD equipped with an Anton Paar DHS 1100 domed stage under a flow of N2. Simulated diffraction patterns were calculated using the program Mercury 3.122 using CIFs from the Inorganic Crystal Structure Database (ICSD).XRD was performed on thin films of CuSCN prepared from diethyl sulphide solution and a bilayer of CuSCN and B-γ-CsSnISupporting Information


Effects on Fatty Acid Metabolism of a New Powdered Human Milk Fortifier Containing Medium-Chain Triacylglycerols and Docosahexaenoic Acid in Preterm Infants [We thank Bernard and colleagues for their careful reading and interest in our article  Infants . Bernard Infants , our rep Infants ,4,5,6,7. Infants , the levA second point raised by Bernard et al.  is that Finally, we agree with the remaining two points raised by Bernard and colleagues . First, We fully share the perspective of Bernard and colleagues that improving preterm infants’ lipid nutrition is an urgent task, and we are appreciative of the opportunity to provide a corrected


Designing, changing and adapting organizations to secure viability is challenging for manufacturing companies. Researchers often fail to holistically design or transform production systems. Reasons are often the conflict of interests between production and maintenance, the temporal divergence of their activities and their organizational structure. Thus, the aim of this study is to propose a holistic approach of how production and maintenance can be designed, changed or managed. Hereby, the Viable System Model was applied. This structure can be applied to any kind of structured organization and for its management with goals to be achieved in modern society; however, focus of the research is the coordination of production and maintenance management. The goal of the developed model is to be able to react to some potential production environments by taking coordinated decisions correctly and in the right moment based on the needed information. To ensure this, standardized communication channels were defined. In conclusion, this proposed approach enables production systems to have internal mechanisms to secure viability depending on all potential environment scenarios. The global logistics flows have increased dramatically in recent years due to a globalized economy that introduces inherent challenges to the establishment of international business  (p. 10).The success of the actors involved in a cooperative supply chain depends in an essential way on the extent to which they are able to deal with the dynamic market requirements  (p. 101)Information in real time and its processing for production planning and control can give the correct answer how to face increasing dynamic requirements. However, the current planning and control logics do not provide the necessary support for this, which causes unexpected deviations in planning which cannot be compensated in the short term  (p. 160)According to a survey carried out by the VDMA  organization of 240 European companies of all sizes and of different industries, in 2006, 78.5% of managers claimed that the importance of maintenance has increased significantly in recent years and 67.1% that it will continue to increase in the future  (p. 38).Many approaches have been considered to make production and maintenance planning as efficient and flexible as possible. All pursue and many theoretically achieve the partial or total optimization of global production systems by making them efficient. However, when applying these theoretical internal logistics management models to practice, information systems should be used as a vehicle to communicate the necessary information to be managed within the organization. The reasons why the majority of applications of such concepts in information systems, as in ERP (Enterprise Resource Planning) systems, have failed are: the delay or lack of information, the misuse of production planning tools and maintenance, lack of coordination or conflict of interest between the production and maintenance departments, the non-consideration of the environment and the requirements of the final customer in a dynamic process of continuous improvement, leading all of them to take strategic, tactical or operational decisions at an optimal time or in an optimal way.Research focus is the design and simulation of a coordination model for production and maintenance management using as a basis the current state of the art and pursuing high adaptability to environment changes. To achieve this, the Viable System Model (VSM) is used as a methodological structured approach and system dynamics is used to describe interrelationships between parameters and control loops in production and maintenance. The goal of the research is to generate an approach of how to design and develop production systems to be successful in all potential future environment scenarios considering developments in other areas of the company and in external fields of a company such as customer and supplier needs and conditions, politics, economy, technology, environment and energy regulations and society. In this context, simulation serves as tool to prove the approach in some potential future scenarios for production and maintenance coordination.The initial hypothesis is that a production system built using the structure of the VSM will be able to react faster to environment changes and therefore to improve short-, medium- and long-term goals of every producing company.This chapter contains a literature review of the viable system model, system dynamics as well as a description of the simulation technique and software employed.The Viable System Model (VSM), a cybernetic management model, was developed by Stafford Beer throughout his life  (p. 57).To validate the research methodology, research and practical applications using the VSM were searched. Many authors have used the VSM as basis to describe and develop models how to deal with complex challenges in social and industry fields. Some of the topics worked and that give an indication of the scientific value of the approach are: organizational models for companies  .System dynamics is a computer-guided approach for studying, managing and solving complex feedback problems with focus on policy analysis and design  (p. 342)SD has been applied to a great set of systems from corporate strategy to the dynamics of diabetes as well as for the cold war arms race between the USA and USSR. System dynamics can be applied to any dynamic system, with any time and spatial scale  .This chapter provides the basic terminology needed to successfully perform this work.Production is the foundation of human activity. Natural resources are transformed into useful products through production processes to meet the needs of society  p. 319)931]  model, which is a reference model for its analysis, evaluation and design, is used  (p. 29).All tasks are distinguished vertically in Industrial maintenance is defined according to DIN (German Institute for Standardization) 31051 as the “combination of all technical, administrative and management measures during the life cycle of an observation unit in order to maintain the functional status or restoring it so that it can fulfill the required function”  (p. 26).The “ideal maintenance organization” does not exist  (p. 65) According to experts, German companies spend around 140,000 million euros annually on maintenance of machines and installations. This, together with the fact that between 75% and 80% of the execution time of a maintenance order are activities without added value, defines a great potential for savings in production companies. Many of the time losses are in the interfaces between the different areas. The management of maintenance processes must ensure the change from a functional orientation to an orientation towards processes  (p. 60).Maintenance management of production units affects not only the maintenance personnel but also all the employees of the whole company  (p. 104)Total Productive Maintenance (TPM),Lean Maintenance,Total Lifecycle Cost Strategy (TLC),Reliability Centered Maintenance (RCM),Knowledge Based Maintenance.Logistics can be described as an interdisciplinary strategy to optimize production. Availability is, therefore, a key factor for logistics and is also the link between logistics and industrial maintenance  .This chapter describes the components of an integrated planning model for production and maintenance management. In a first step, the planning tasks are presented according to its planning level . Later, the recursion levels of the VSM are described. Then, the planning tasks are associated with the different recursion levels and the information flows are defined between recursion levels and systems of the VSM.Production systems are considered important in relation to aspects of quality, time and costs  (p. 1). The highest level, company (n − 1),○The recursion level of plant or production workshop, for example production management activities in an automotive production or assembly shop (n + 1),○The level of machine group, machine or installation with the associated activities for the different production activities such as preparation of the machine, change of tools, operation, control of production, etc. (n + 2),The recursion level of production (n). In the same recursion level it can be found finance, human resources, IT, research and development, etc.○The recursion level of plant or production workshop—for example, maintenance management activities in an automotive production or assembly shop (n + 1),○The recursion level of installation or machine with the associated activities for the different maintenance activities: preventive, planned repairs, corrective, etc. (n + 2).The recursion level of maintenance (n). In the same recursion level can be found finance, human resources, production, etc.A company is assumed as a viable system that is the first level of recursion in which the five systems neededto ensure viability are found. Therefore, in this research work, four levels of recursion can be differentiated as it is shown in The activities in the recursion level n + 2 are no longer viable systems in contrast to the higher recursion levels because they do not contain a structure like that of the VSM, since they are the elements of production or maintenance execution.Within this first level of recursion, company, the different functions of a company can be found, such as production, maintenance, commercial, finance, research and development, information systems, etc. In this research project, production and maintenance tasks will be analyzed in detail, recursion level n, but also considering the function of system 2 at the company level, n − 1, whose function is to coordinate the different functional areas of a company.System 5 establishes the production and maintenance objectives and communicates them to the other management systems, systems 3 and 4.System 4 observes and collects essential information from the external environment of maintenance and production. Production environment is mainly represented by the demands of customers, but also by other factors such as information systems offered by the market for the management, planning and control of production, new manufacturing technologies and, in general, all factors affecting the production system such us market standards, delivery times, production strategies, delays, production costs in external companies for example to help in making decisions about outsourcing or to not manufacture certain parts or about the assembly of certain sets, etc. Maintenance environment could be described by the costs in the market for maintenance activities, average reaction times in the market as well as service level standards, information systems for maintenance, technology development, environmental and work safety regulations and customer delays. With these and other information from the external environment and information from system 5, system 4 creates a vision of what the production and maintenance areas have to be, and which should be the measures to be followed to reach that state. This vision is validated internally with system 3 so that system 4 makes the decision and system 3 makes the changes internally.System 3 is responsible for maintaining the internal stability of the model by optimizing the use of internal resources using the information received by system 4 about the clients as well as the information on the different divisions of system 1 through system 2. It would be related to functions such as operative production and maintenance management and control, information management, quality management, operative logistics planning and control, etc. Moreover, system 3* allows a quick response to possible emergencies in the manufacturing process or in the production control and monitoring by acting before information flows through system 2. It is capable of performing actions in real time if something happens outside of normal limits such as making changes in sequencing and production scheduling to avoid stopping production flow.System 2 is represented by the functions of coordination between the different production locations in daily activities. This system receives all the information of the different production plants and acts as a filter so that only the necessary information reaches system 3. The difference between both is in the time horizons of action. While system 2 performs functions in daily activities, the tactical system optimizes the performance of the internal system over a longer time horizon.System 1: each plant or workshop within the production system is an operational unit that includes the management of the unit and the division that performs the operational activities. An example could be an assembly workshop that contains the planning and production control departments responsible for the components of the workshop with their team leaders together with the operators that finally perform the production tasks.Environment: represents all the external factors that influence the production and maintenance management in a company. System 2 at company level plays the role of coordinator between the functional areas of the company trying to solve conflicts between them. Moreover, systems 1 at company level are all functional areas of every company such as production or maintenance. At the recursion level of production and maintenance (n), it is assumed that the different production plants or workshops will be the respective system 1, which also contains a viable system in each of these locations. The VSM of production and maintenance management within a company is described in the next paragraphs by the tasks performed by its five necessary systems:Production and maintenance management tasks were assigned to the VSM systems at recursion levels n and n + 1 defined before. In Between the company environment and system 4 at the production/maintenance recursion level,Between systems 5 of company and production/maintenance,Between systems 4 of company and production/maintenance,Between systems 3 of company and production/maintenance,Between systems 2 of company and production/maintenance,Between the operating units, systems 1, of company and production / maintenance,Between the alarm/monitoring filter (System 3*) of the company’s recursion level and system 4 of production/maintenance.Current technical literature agrees that the connection interfaces between recursion levels is extremely important  (p. 59).Between the two normative systems of company and production/maintenance, there is a flow of information that defines the degree of freedom of decision-making in which production/maintenance recursion level can act. Specifically, it means that the decisions taken by the management of the company are communicated to production and maintenance management defining its guidelines for autonomous decision-making within the respective areas. These guidelines can be financial, on personnel, on affectation to other areas, etc. In the same way, the objective levels such as production in term, production quality and production costs and adaptation capacity are influenced by decisions from the management, defining the priorities and the limits for the coordination among production areas. An example could be: the direction of the company in its strategic plan establishes the target production volume for the following years as well as the required flexibility in percentage on the production as well as the decrease in target costs. Of course, these decisions would influence the decision-making framework for production and maintenance that should adapt their methods and tools to be able to optimize costs, times and quality based on that flexibility also securing the required availability and adapting its maintenance strategy.As explained during the research work, basic communication flows were defined. In total, 88 information connections were defined for the production recursion level specifying if the communication goes from company’s recursion level to production recursion level or between systems in production recursion level. Moreover, for the recursion level of maintenance, a total number of 77 information connections were defined specifying if the communication goes from company’s recursion level to maintenance recursion level or between systems in production recursion level. An extract is shown in Press shopBodywork shopPaint shopEngines shopAssembly shopsFinal assembly shopsThe automotive supply chain is composed of suppliers at three levels (Tier 1–3), OEM (car manufacturers), distributors. For the work, we are going to focus on the production process of an OEM   are growing. The complexity of customized models and variants is on the rise, especially as regards the way individual vehicles are equipped. The key trend in automotive production is the standardization of construction modules in common platforms. The modules refer to groups of components and related systems. The diversity of models is an important sales argument and delivery time is the key factor for the automotive market and in the manufacturing process. These requirements involve a change in assembly operations that need to be more flexible and agile  In this step, the conceptual model for a manufacturing process is specified. To do this, the interrelations between indicators are defined by Causal Loop Diagrams (CLD). Later, the concepts are modeled in the VENSIM commercial simulation program. The simulation models present a simplified depiction of a real production and maintenance process to quantify the effect of decisions in a production system. Moreover, it contains the validation of the models and the presentation of the results obtained. Finally, the main conclusions are summarizedas well as a critical reflection of the work including a perspective for future research activities.The possibility of developing simulation models for production and maintenance management starts from the knowledge of the interrelations between its elements. Using casual loop diagrams (CLD), the effects of the changes of certain factors in their dependent parameters are shown. Five CLDs are developed from production management to maintenance planning. Definition of the objective, hypothesis and methodologyNumber of simulation modelsSimplification of the complexity of the conceptual model through assumptionsCriteria that make possible a comparison between modelsDefinition of quantitative parameters to obtain results and compare modelsDefinition of the production flowCreation of the model based on the CLD Validation of the behavior of the simulation modelsDetermination of scenarios, simulation and extraction of resultsEvaluation of the results and derivation of conclusionsThe aim of the simulation is to observe the impact of the delay in decision-making in a chain of manufacturing processes from the steel stamping process to the end of assembly in the automotive industry. The hypothesis is that a simulation model applying the VSM will present better results in terms of study parameters compared to the one that does not apply the VSM or that has delays in internal decision-making. The methodology for the simulation design is:Production times for car models are not variableTimes for material transport and employee movements are not variableDistribution of finished products as givenProcurement of raw material as givenDemand does not change if customer service is better or worseEach order has a production unitBill of materials are not consideredFirst, assumptions are defined to simplify the model with focus on the simulation goal:Same demand, same patterns of demand, demand replicationSame production capacities per production stepSame breakdowns per production stepSame reaction times depending on the locationSame task execution timesSame workforce capacityThe same maintenance capacity is considered for the same class of workerSome elements are equal in all models to make possible a comparison between the models under the same conditions:Production on time (% per week)Total production (# thous. cars)Total downtime Availability of final assembly workshop (%)Capacity utilization of final assembly workshop (%)Cumulated stocks (# Mill. cars)MAD (Mean Absolute Deviation) (# thous. cars)Cumulated demand (# thous. cars)The objectives can be qualitative or quantitative. The research goal is to study the behavior of the different models in different situations of demand and configuration of maintenance and production areas. The results are quantified to evaluate the response according to the following key performance indicators:The production process consists of a process from steel stamping to the final revision shop. The plants in the process are shown in Press shopBodywork shopPaint shopPre-assembly shop—assembly 1Mechanical assembly shop—assembly 2Final assembly shop—assembly 3Final inspection shopAll of them are in different shops and have production and maintenance units associated to each one of them.Time restrictions: first, the modeler must define a time horizon and units of time. It is easy to fulfill that step by asking to what extent the simulation should be considered. In the case of the study, it has been decided to simulate four working years to evaluate influences in the medium and long term.Production strategy: the model offers the possibility to manufacture according to the push or pull principle. A mixed strategy can also be chosen. It assumes the existence of a single product or model in the production flow.Maintenance strategy: the simulation allows defining a preventive maintenance ratio so that it reduces the corrective according to a factor that is assumed.Capacity and production methods: in the model there are two methods: CONWIP (CONstant Work in Progress) in which the quantity of products in production process is always the same and BOA (Workload-dependent order release) that initiates production of an order based on the current and expected workload for the plants.Organizational structure and tasks distribution between production and maintenance: the simulation allows personnel changes in the areas of maintenance and production as well as between them. In addition, assumptions about the influence of the changes are made, for example, if there are more maintenance personnel, it will take less time to perform preventive maintenance tasks.Demand characteristics and forecast: the model makes different forecasts using two different methods: moving average and linear regression.As shown in For a lower number of employees, production on time (%) must be lower and the total stock should be higher because the production facility provides more products than employees can process. Moreover, utilization of shop capacities should be lower and therefore also the production output.The validation of the simulation models can be done using different methods. In this process, some simulation variables will be used to observe their behavior and to evaluate if the models will be validated. Sterman defined 12 possible methods to validate system dynamics models  (p. 6). As shown in For higher initial stocks in WIP (work in progress) at initial time, production on time (%) must be higher and total stock should be higher in the first weeks because the production facility has more products within production process at the beginning. Moreover, utilization of shop capacities should be higher and therefore also the production output in the first weeks. Afterwards, due to the CONWIP method, the production WIP converges to a CONWIP goal that is equal to one week of demand and therefore all other indicators also converge.In For a make-to-order production, it is expected to have less stock during the production process, less capacity utilization and production output as well as less production on time than with a make-to-stock production.As shown in The model is validated because logical expected values are obtained for three different input parameters influencing multiple key performance indicators of the simulation.Case study 1—reorganization of production and maintenance employees: the production area transfers workers to the maintenance area when there is a low customer demand. With this scenario, how the utilization of production workforce for maintenance activities could increase global production performance, if the decision is made in an early moment when demand starts to be lower than production capacities, is studied.Case study 2—reorganization of production and maintenance employees: the maintenance area transfers workers to production when there is a high customer demand. With this scenario, how the utilization of maintenance employees in production activities could increase global production performance, if the decision is made in an early moment when demand starts to be almost at the maximum level of production capacities, is analyzed.Case study 3—comparison between the CONWIP and BOA methods: for the same customer demand, the order initiation method varies. CONWIP (CONstant Work in Progress) initiates production of new orders maintaining the same WIP cars while BOA initiates production of new orders depending on current and future equipment workload. BOA tries to optimize utilization and CONWIP in the model tries to maintain a week of production demand always as WIP.Case study 4—comparison between preventive and corrective maintenance: for the same demand, a low level of preventive maintenance activities and a high level of maintenance activities is simulated. With this scenario, the effect of the preventive level of maintenance activities can be simulated. In the models, a parametrization is done considering that preventive activities require a certain employee capacity but reduced the unexpected downtimes of the production shops.Four case studies are proposed in which two different model configurations are simulated, trying to reflect the importance of decision-making. The VSM model takes earlier these decisions and therefore can benefit earlier from the new production system configuration:Case study 1—reorganization of production and maintenance employees with a low demand:Case study 2—reorganization of production & maintenance employees with a high demand:Case study 3—comparison between the CONWIP and BOA methods:Case study 4—comparison between preventive and corrective maintenance:For the four scenarios, the following results are obtained:Case study 1: the production area transfers workers to the maintenance area when there is a low demand for production. This decision is only taken in the VSM simulation model and moves three employees of a total of 20 employees from each production area to its respective maintenance area. The logic reason for this change is, since production employees cannot be fully utilized, they can help the maintenance units to perform maintenance activities in order to improve the production system performance. As it can be seen in Case study 2: the maintenance area transfers workers to production when there is a high production demand. In this case, the Non-VSM model presents in one case 20 maintenance and production workers per plant or workshop while the VSM model changes to 23 workers for production and 17 for maintenance. Therefore, maintenance activities have less capacity while production capacity is increased. As it can be seen in Case study 3: it can be observed in Case study 4: in the simulation model, there is a parameter that indicates the level of intensity of preventive maintenance. As it can be seen in Based on the results presented, it can be said that the VSM simulation model improves relevant KPIs when making the decision to move employees and can help production systems when deciding which production methods should be used as well as deciding the optimal percentage of preventive maintenance to be performed.Identification of the objectives, key performance indicators and functions of production and maintenance management as well as basic methods and toolsClear evidence of the need for new approaches in the coordination of production and maintenance management after reviewing the state of the artConfirmation of the need for new communication and coordination systems as well as integral management of internal logistics as one of the biggest potentials to deal with current and future challenges in the manufacturing sectorThe application of the structure of the Viable System Model (VSM) for the design of the conceptual model for production and maintenance management provided a structure that has allowed the definition of information flows, planning levels as well as mechanisms of autonomy and escalation between levels within a company and within the areas of production and maintenance.System Dynamics has provided the notation and functions necessary for the design of simulation models using VENSIM as commercial software.The comparison of the different models for the four cases presented has shown the relevance of the organizational structure decisions and methods for production and maintenance management. In addition, it was proved how production and maintenance performance can be optimized by making decisions at the right moment. Key performance indicators such as total production, service level, downtime, etc. improved significantly when moving employees, changing production method or the maintenance strategy.After completion of the research work, the importance of the design and management of a productive system that integrates the planning tasks of production and maintenance of a company has been proved. In addition, the following points can be successfully concluded:According to the results of the comparison, it has been demonstrated that correct and early decision-making through the application of the VSM gives a better response of all the key performance indicators. A similar response of the models without application of the VSM can occur when there are no external or internal changes that affect the productive system, that is, if the production system would be in a static situation. As environments and companies are always dynamic, the usefulness of the VSM as a principle for the definition of responsibilities, interfaces, escalation methods and decision-making are confirmed.Improve the conceptual model with all the different methods and tools by level of recursion and task as well as its inclusion in the simulation modelExtend the study for all internal logistics processes to generate a tool to help management, since, as we have seen, the markets require flexibility and right now the companies do not have mechanisms to make the right decisions in most of the cases. Many of them centralize maintenance units and a few years later they decentralize it again, which suggests that there is no strategic or tactical direction.Apply the simulation model based on the VSM for a real productive systemIn conclusion, this proposed approach can increase the efficiency of internal logistics models such as the productive system in its interaction with industrial maintenance. Finally, it is important to point out new ways of research or new ways to continue improving the project carried out:


Plasma IL-18 levels were significantly decreased in patients with AN compared with controls. Plasma IL-18 levels correlated to BMI in controls, but not in patients with AN. These results suggest that a decline in plasma IL-18 levels in patients with AN is not only due to malnourishment, but other pathophysiologic changes as well. IL-18 has a role in the brain’s reaction to sadness and chronic stress. Therefore, decreased levels of IL-18 may commonly occur in patients with chronic AN.Multiple studies on the dynamics of inflammatory cytokines in patients with anorexia nervosa (AN) have been published, although results are not consistent among reports. Thus the pathophysiologic roles of these cytokines are not clear. We performed an exploratory analysis that included (1) comparisons of plasma interleukin-18 (IL-18) concentrations between patients with AN ( Anorexia nervosa (AN) is sometimes fatal due to severe malnutrition. Leukocytopenia frequently accompanies AN , althougInterleukin-18 (IL-18) is an inflammatory cytokine first identified by Okamura et al. in 1995. It was formerly referred to as an interferon gamma-inducing factor and is known to activate natural killer cells in the spleen ,11. IL-1In this exploratory analysis, we compared (1) plasma concentrations of IL-18 between patients with AN and healthy controls, and (2) correlations between body mass index (BMI) and IL-18 concentrations in both groups to examine the relationship between malnourishment and IL-18 levels.The ethics review committees at Nagoya University Graduate School of Medicine and Nagoya University Hospital approved the study protocol, and written informed consent was obtained from all participants.2) based on the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) [2 to 14.54 kg/m2. Patients’ medical records were reviewed retrospectively for psychiatric comorbidities; two cases had bipolar I disorder, one had bipolar II disorder, one had major depressive disorder, and one had a history of sedative, hypnotic, or anxiolytic use. No other psychiatric comorbidities were identified. Patients were treated in the psychiatric ward of Nagoya University Hospital and received medical nutritional therapy aimed to increase weight by 1 kg per week along with supportive psychotherapy by psychiatrists. They also received psychotropics or plasma electrolyte replenishers, as needed. The control group consisted of 39 healthy participants recruited from medical and co-medical students and hospital staff. A structured interview confirmed the absence of any psychiatric history in the control group. BMI in the control group ranged from 17.12 kg/m2 to 33.23 kg/m2. Patients included 21 Japanese women living in Japan who met the criteria of extremely severe AN (BMI < 15 kg/m (DSM-5) , includiBlood samples from patients were drawn around 8 a.m., before breakfast. Body height and weight were measured under surveillance in the early morning, before the blood was drawn, every Monday and Thursday, and the data obtained closest to the date of blood draw within the same week were used for analysis. In the control group, blood samples, body height, and weight were acquired during a visit to our institute, so the time of day for sampling was not fixed.Plasma IL-18 concentrations of all subjects were measured by enzyme-linked immunosorbent assay (ELISA) using a human bioactive IL-18 ELISA kit from Medical Biological Laboratories .p-values were calculated between plasma IL-18 concentrations and BMI in each group. P values < 0.05 were considered statistically significant.All data were analyzed with Excel 2013  and JMP pro 13 . The Wilcoxon rank sum test was used to compare plasma IL-18 concentrations between groups. The coefficients (Pearson’s r) and p = 0.014) lower concentrations  than controls .p = 0.01). However, no such correlations were observed in patients   .The lack of correlation between plasma IL-18 levels and BMI in patients with AN suggests that plasma IL-18 concentrations are affected not only by nutritional status but by an unknown pathophysiologic factor in these patients. Increased levels of IL-18 in plasma have been observed in patients with schizophrenia and moderate to severe depression , so a psWhen exposing mice to chronic stress, IL-18 expression is increased in the basolateral amygdala (BLA). IL-18 knock-out mice show tolerance to chronic stress, through a decline of vasopressin and oxytocin levels in the BLA, caused by suppression of phosphorylated nuclear factor-κB induced from IL-18 ,16. PlasPatients with AN often show chronic depression ,21; howeOur research had a small sample size, so a replication study and subtype-sensitive research, with larger samples, are needed. Pharmacologic and nutritional effects on plasma IL-18 levels cannot be excluded. The time of day for blood sampling from control participants was not fixed, so diurnal effects of plasma IL-18 cannot be disregarded. Because the linear association of IL-18 levels in plasma and in cerebrospinal fluid (CSF) has not been proven, levels of IL-18 in CSF should be measured. However, lumbar punctures may be unsafe in patients with AN, who tend to have hemorrhagic issues. Thus we did not determine CSF levels. It is unclear why plasma IL-18 levels in patients with AN did not correlate with BMI levels. Pathophysiologic factors in patients with AN other than low body weight or malnutrition should be examined. Moreover, future prospective and longitudinal studies focused on disease duration, measuring IL-18 at different stages of AN including recovered patients, psychosocial factors and determining IL-18 and endogenous opioid levels in CSF may be needed. Our current results lead us to hypothesize that the decline of plasma IL-18 levels in patients with AN may affect disease chronicity.


Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids—cysteine, glycine, and glutamate—enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed. Glutathione (GSH) is a low molecular weight, water-soluble thiol that is present in all eukaryotic cells . It is sDue to the strong cytoprotective effects of GSH, it could be a therapeutic option to maintain cellular integrity and slow tissue degeneration in various diseases. Researchers have tested the impact of administering GSH through several routes, including intravenously , intranaThis review presents the effect of oral supplementation of individual amino acids on GSH homeostasis in mammals with emphasis on clinical studies. Then, we highlight particular micronutrient supplements that have been found to improve GSH status by generally enhancing cellular antioxidant systems. Lastly, since specific dietary patterns are commonly being prescribed as first-line therapeutics for certain chronic diseases, this review will also briefly assess the impact of these overall diets on GSH homeostasis.L-Glutamine is the most abundant free amino acid in the body . ThroughWhen healthy human volunteers were supplemented with oral glutamine at 0.3 g/kg/day for 10 days, both glutamine and glutamate concentrations increased in plasma, but blood GSH concentrations unexpectedly decreased . This ef+ patients were supplemented with glutamine (20 g/day) for 7 days, plasma GSH, glutamine, and glycine levels were normalized [It has been proposed that glutamine most effectively increases GSH levels during times of GSH depletion . Thereformalized . Howeverrmalized . Glutamine supplementation may not be as effective in patients in the intensive care unit (ICU) ,40 or wiRodent studies support the notion that GSH levels increase with glutamine supplementation ,43,44,45+ individuals, but not in ICU patients or those with sickle-cell disease. It is crucial that future research efforts expand beyond RBC, as RBC lack mitochondria, producing a unique biochemical milieu that may not fully represent other cell types [It must be noted that long-term glutamine supplementation should not exceed >40 g/day due to its negative effects on biochemical pathways . Glutamill types .Glycine is one of three amino acids used to form GSH , so it hGlycine seems to improve GSH concentrations in animals with higher levels of oxidative stress. When supplemented in the diet, glycine may exert a beneficial effect via promotion of GSH biosynthesis and attenuation of oxidation, which in turn protects against endothelial and vascular dysfunction. There is evidence that glycine supplementation could be even more effective when orally supplemented with cysteine in older HIV-infected individuals . The rolL-cysteine is the rate limiting amino acid in de novo synthesis of GSH [s of GSH , so natus of GSH , signifis of GSH ,60,61,62s of GSH ,64. BecaN-acetylcysteine (NAC), S-Adenosyl-L-methionine (AdoMet), and L-2-oxothiazolidine-4-carboxylate (OTC) supplementation on GSH levels are evaluated in the next sections. Methionine is also a cysteine prodrug that increases RBC GSH levels when supplemented orally [The efficacy of cysteine precursors d orally , but supd orally ,67, so iNAC is a cysteine precursor that, when administered orally, increases GSH concentrations in individuals with GSH deficiency caused by infections, genetic defects, or metabolic disorders . Orally + patients were orally supplemented with NAC (1 g/day), plasma GSH, cysteine, homocysteine, taurine, methionine, and glutamine concentrations increased significantly [In a study by De Rosa et al., HIV-infected individuals were orally supplemented with 8000 mg NAC daily for 8 months, and whole blood GSH levels significantly increased with no major adverse effects . An addificantly . In a seficantly . In addificantly , and mayficantly .Overall, orally administered NAC is an effective way to replenish GSH in HIV-infected patients, but more research is needed to better understand the effect of NAC supplementation on GSH levels in healthy individuals. Despite its potential benefits, NAC is limited by potentially harmful side effects, such as nausea or gastric distress, but investigators hypothesize that the intestinal side effects found in the trial may have been due to the ingestion of the excipient, which contained lactose .AdoMet is a precursor to the transsulfuration pathway, the metabolic pathway responsible for condensing homocysteine to form cystathionine, which is then converted to cysteine . AdoMet In baboons, supplementation of oral AdoMet resulted in significant hepatic uptake of the molecule, and eventually, restored GSH levels . These rAdoMet supplementation does not appear to have a significant effect on homocysteine concentrations in healthy individuals , so suppOTC is converted to cysteine through 5-oxoprolinase in cells  and has Studies suggest that OTC may be a safe and viable option for elevating GSH concentrations, but some limitations remain unaddressed. A study by Nishina, Ohta, and Obuka (1987) found that intraperitoneal delivery of OTC increased hepatic GSH concentrations in guinea pigs, but decreased renal GSH levels . It was 6, condenses homocysteine and serine to ultimately form cysteine [The transsulfuration pathway is a major source of sulfur for GSH formation . In the cysteine . PresentSirt1 [In mice fed a HFD, supplementation of serine in drinking water significantly decreased hepatic ROS compared to the control group . Serine Sirt1 .Sirt1 and other age-related pathways.In experimental models of oxidative stress, serine appears to conserve tissue GSH levels and attenuate oxidative damage. But more research is needed to better define mechanisms by which serine protects GSH pools and acts on Cysteine is a necessary metabolic precursor for taurine synthesis, so it has been postulated that taurine supplementation would spare cysteine for eventual incorporation into GSH . In reseEffects of taurine on the enzymes GPx and GR have been evaluated in both rodent and human studies. Taurine supplementation recovered hepatic GR activity in diabetic rats , whereasOverall, these results point to a limited impact of taurine on GSH, implying that other amino acid or micronutrient supplements may be a more effective option at targeting and raising GSH concentrations.Fat-soluble vitamins  have been evaluated for their potential effects on GSH homeostasis. These vitamins exhibit antioxidant properties, and there is evidence that status of vitamin A ,117, vitVitamin E is a lipid-soluble antioxidant that protects the cell membrane against oxidation and supports other antioxidant reactions, including those involving GSH . Studies1c levels decreased [The beneficial impact of vitamin E on GSH translates to clinical studies as well ,127,128.ecreased ; the resecreased . In addiecreased  and suppecreased .Based on these rodent and clinical studies, it appears that vitamin E, when taken in safe doses, has the potential to increase RBC and brain GSH concentrations.6, is a coenzyme in the conversion of homocysteine to cysteine, which supports GSH biosynthesis [Pyridoxal 5′-phosphate (PLP), the biologically active form of vitamin Bynthesis . PLP is ynthesis ,135.6 is especially critical for maintaining GSH pools [6 supplementation increased renal and hepatic GSH levels in rats with chromium-induced toxicity [6 supplementation had no effect on hepatic GSH levels in control rats, with or without supplementation [6 supplementation increased blood GPx levels of control rats, indicating that the vitamin may directly stimulate the GSH redox system under normal conditions [Homocysteinemia and chromium toxicity are high stress environments wherein vitamin BSH pools ,136,137.toxicity . Conversentation , nor didentation . Unexpecnditions .6 also affects GSH status of human patients. Hepatocellular carcinoma (HCC) patients exhibit high levels of oxidative stress, and when 33 HCC patients—who had recently undergone a tumor resection—were supplemented with vitamin B6 (50 mg/day) for 3 months, plasma GSH/GSSG ratios and GR activity unexpectedly decreased while GSSG and GPx levels did not change [Vitamin Bt change . The autt change .6 supplementation with other vitamins has been also evaluated [6 (200 mg/day) and folic acid (15 mg/day) supplementation for 1 month increased RBC and whole blood GSH levels in both hemodialysis patients and healthy patients [12 and B6 had improved GSH status [The impact of vitamin Bvaluated ,141. ComH status .6 supplementation cannot be made due to the limited clinical research and conflicting results on the effect of vitamin B6 supplementation on GSH concentrations. Future research on vitamin B6 supplementation is warranted given the possibility of beneficial effects on GSH status.At this time, recommendations on BAscorbate, a potent free radical scavenger, and GSH are biochemically intertwined ,143. GSHRodent models have clarified the role of ascorbate in GSH metabolism. Ascorbate normalized hepatic GSH levels in homocysteinemic rats, despite the fact that serum homocysteine levels remained high . When agHealthy adults were supplemented with ascorbate to better understand the vitamin’s effects on GSH homeostasis. Subjects were supplemented with a placebo for 1 week, 500 mg/kg/day for 2 weeks, 2000 mg/day for 2 weeks, then placed on a placebo-controlled withdraw week . RBC GSHAscorbate has also been combined with vitamin E since the two vitamins have an additive effect against oxidative stress . When asBased on this evidence, ascorbate, if used in safe and tolerable doses, appears to attenuate GSH depletion under stress conditions and promote an increased antioxidant status.In the enzymatic reduction of hydrogen peroxide to water, GSH is utilized by GPx, a selenoprotein that requires Se for proper functioning ,154. ResFurther research is needed to better define the impact of Se on GSH concentrations, given its proven ability to increase GPx protein levels. Although Se could be a viable option to increase GPx activity in individuals with high oxidative stress, Se supplementation may be most effective in combination with another therapeutic known to directly increase GSH. After all, without GSH, an increase in GPx may not induce significant health effects.Mg is an important mineral whose status has been linked to oxidative damage . When diBased on these clinical trials, it is possible that Mg supplementation may provide antioxidant protection. Importantly, more research is needed to identify the optimal dose of Mg supplementation to boost GSH metabolism.The Mediterranean diet (MedDiet) emphasizes high intakes of extra virgin olive oil, vegetables, fruits, cereals, nuts, pulses and legumes, and moderate intakes of fish, dairy, and red wine, while limiting intakes of eggs and sweet foods . There iEfforts to understand the relationship between the MedDiet and GSH levels should now be expanded. For instance, new efforts may be conducted in pediatric populations to identify any protective antioxidant mechanisms that may be enhanced when beginning the diet early in life.The DASH diet was developed in the 1990s and rose in popularity once the National Institutes of Health began supporting research efforts to identify dietary interventions that were efficacious against hypertension . The DASChronic disease patients often have impaired GSH statuses and heightened GSSG levels . It has Naturally, vegetarian diets exclude meat, a significant source of amino acids needed for GSH biosynthesis . Yet veg6 [A Western-type diet is characterized by high amounts of meats, saturated fat, refined grains, and sugar, with low amounts of fruits and vegetables . The Wes6 , methion6 , and cys6  status, 6 , suggest6 , so an aWhey protein is a rich source of cysteine, so research is being conducted on its relationship with GSH status. Evidence suggests that the consumption of whey protein can raise intracellular GSH levels in healthy individuals . In addiOral GSH supplementation is not the most effective means of increasing GSH status, so researchers anticipate that alternate forms of oral GSH may be more promising. Notably, food-grade sublingual and liposomal GSH supplements have been designed. Sublingual forms of GSH have received significant attention because sublingual compounds are able to by-pass hepatic first-pass metabolism and degradation, maintaining supplement bioavailability . A 3-weeTo supplement with lipoceutical GSH, GSH is first packaged into liposomes, small droplets that fuse with cellular membranes, directly releasing their contents into target cells. Recent studies have underscored the beneficial effects of liposomal GSH on intracellular GSH concentrations ,205. ForTo date, a limited number of animal and clinical interventions have evaluated the efficacy of liposomal GSH ,205,206.GSH is an exciting and promising therapeutic target against oxidative stress. Given the low bioavailability of oral GSH, researchers have supplemented with compounds that directly or indirectly affect the GSH system. The list of supplements discussed in this review is not exhaustive, and other amino acids and micronutrients, or their combinations, may have significant effects on GSH homeostasis in specific populations. It is important to ensure that interventions are tested in various age groups, in particular because pediatric populations have been consistently understudied. And it is important to consider the health status of each population under investigation, as dysfunction of the liver and other essential organs can impede the body’s ability to synthesize GSH and thus, nutraceutical supplementation may not be as effective as it would be in healthy individuals. Investigators must also consider the analytical method used to quantify GSH and GSSG in each study. GSH and GSSG are often quantified via colorimetric assays , high pe