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In professional soccer clubs in the UK, nutrition support is often polarised towards senior players or those in the senior academy age groups seeking first team selection/involvement. Accordingly, there is an increased reliance on parents and caregivers to provide support regarding nutritional intake. Therefore, the aim of this study was to evaluate the quality of nutrition knowledge of parents and caregivers of male youth soccer players within developmental academies in the UK. Across a single competitive season, 360 registered parents and caregivers of male soccer players from English Premier League under 9–11 (Foundation Phase) and under 12–16 (Youth Development Phase) age group academies completed an online version of the 88-item validated Nutrition for Sport Knowledge Questionnaire. Nutrition knowledge scores were classified as “poor” (43 ± 23%). Nutrition knowledge scores were significantly greater in respondents with dependents representing Category 1 (45 ± 13%) vs. Category 2 (39 ± 15%) academies and in Foundation Phase (44 ± 13%) vs. Youth Development Phase (41 ± 15%). These results demonstrate that there is room for improvement in the nutrition knowledge levels of parents and caregivers of male soccer academy players. We recommend that club academies provide appropriate resources towards nutritional education for parents and caregivers.

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS:Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of pa

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

[Background] In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., [Objective] This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., [Methods] We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., [Results] Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., [Conclusion] : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

BackgroundThe Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood.MethodsThis multicenter observational cohort study will enroll at least 600 patients <21 years old who meet the Centers for Disease Control and Prevention case definition of MIS-C across multiple North American centers over 2 years. The study will collect detailed hospital and follow-up data for up to 5 years, and optional genetic testing. Cardiac imaging at specific time points includes standardized echocardiographic assessment (all participants) and cardiac magnetic resonance imaging (CMR) in those with left ventricular ejection fraction (LVEF) <45% during the acute illness. The primary outcomes are the worst LVEF and the highest coronary artery z-score of the left anterior descending or right coronary artery. Other outcomes include occurrence and course of non-cardiac organ dysfunction, inflammation, and major medical events. Independent adjudication of cases will classify participants as definite, possible, or not MIS-C. Analysis of the outcomes will include descriptive statistics and regression analysis with stratification by definite or possible MIS-C. The MUSIC study will provide phenotypic data to support basic and translational research studies.ConclusionThe MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Objective: Soccer match-play is typically contested over 90 min; however, in some cup and tournament scenarios, when matches are tied, they proceed to an additional 30 min, which is termed “extra-time” (ET). This systematic review sought to appraise the literature available on 120-min of soccer-specific exercise, with a view to identifying practical recommendations and future research opportunities. Methods: The review was conducted according to the PRISMA guidelines. Independent researchers performed a systematic search of PubMed, CINAHL, and PsycINFO in May 2019, with the following keywords entered in various combinations: “soccer”, “football”, “extra-time”, “extra time”, “extratime”, “120 minutes”, “120 min”, “additional 30 minutes”, and “additional 30 min”. Results: The search yielded an initial 73 articles. Following the screening process, 11 articles were accepted for analyses. Articles were subsequently organized into the following 5 categories: movement demands of ET, performance responses to ET, physiological and neuromuscular response during ET, nutritional interventions, and recovery and ET. The results highlighted that during competitive match-play, players cover 5%–12% less distance relative to match duration (i.e., meters per minute) during ET compared to the preceding 90 min. Reductions in technical performance (i.e., shot speed, number of passes and dribbles) were also observed during ET. Additionally, carbohydrate provision may attenuate and improve dribbling performance during ET. Moreover, objective and subjective measures of recovery may be further compromised following ET when compared to 90 min. Conclusion: Additional investigations are warranted to further substantiate these findings and identify interventions to improve performance during ET.

The 20 h responses of International female netball players to training days requiring two sessions (netball and strength, separated by two hours) ordered alternatively were examined. Eleven players completed strength followed by netball training two hours later (STR-NET), with the order reversed (NET-STR) on a separate day. Well-being, neuromuscular performance (jump height [JH], peak power output [PPO], peak velocity [PV]) and endocrine function (testosterone, cortisol concentrations) were measured before sessions one (PreS1) and two (PreS2), immediately after sessions one (IPS1) and two (IPS2), and 20 h post session one (20P). Session and differential ratings of perceived exertion (upper-body, cognitive/technical [RPE-T], lower-body, breathlessness) were collected, and accelerometry and heart rate measured netball load. Identification of clear between-order differences was based on the nonoverlap of the 95% confidence interval (95%CI) for mean differences relative to baseline. Compared to PreS1, greater increases in JH (percentage difference between trials; 95%CI: 9%; 4–14%), PPO (5%; 2–8%), PV (3%; 1–5%) and cortisol concentration (45%; 1–88%), and a greater decrease for testosterone/cortisol ratio (−35%; −72 to −2%) occurred at PreS2 in NET-STR. At 20P, greater decreases in JH (10%; 5–15%), PPO (4%; 1–8%) and PV (4%; 2–6%) were observed following STR-NET. No differences existed for well-being, whilst RPE-T was greater (15 AU; 3–26 AU) for strength training during NET-STR. Session order influenced neuromuscular and endocrine responses in International female netball players, highlighting session ordering as a key consideration when planning training.

The 20 h responses of International female netball players to training days requiring two sessions (netball and strength, separated by two hours) ordered alternatively were examined. Eleven players completed strength followed by netball training two hours later (STR-NET), with the order reversed (NET-STR) on a separate day. Well-being, neuromuscular performance (jump height [JH], peak power output [PPO], peak velocity [PV]) and endocrine function (testosterone, cortisol concentrations) were measured before sessions one (PreS1) and two (PreS2), immediately after sessions one (IPS1) and two (IPS2), and 20 h post session one (20P). Session and differential ratings of perceived exertion (upper-body, cognitive/technical [RPE-T], lower-body, breathlessness) were collected, and accelerometry and heart rate measured netball load. Identification of clear between-order differences was based on the nonoverlap of the 95% confidence interval (95%CI) for mean differences relative to baseline. Compared to PreS1, greater increases in JH (percentage difference between trials; 95%CI: 9%; 4–14%), PPO (5%; 2–8%), PV (3%; 1–5%) and cortisol concentration (45%; 1–88%), and a greater decrease for testosterone/cortisol ratio (−35%; −72 to −2%) occurred at PreS2 in NET-STR. At 20P, greater decreases in JH (10%; 5–15%), PPO (4%; 1–8%) and PV (4%; 2–6%) were observed following STR-NET. No differences existed for well-being, whilst RPE-T was greater (15 AU; 3–26 AU) for strength training during NET-STR. Session order influenced neuromuscular and endocrine responses in International female netball players, highlighting session ordering as a key consideration when planning training.

Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years (NCT01912534). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

Soccer match-play is typically contested over 90-min, however, in some cup and tournament scenarios when matches are tied, matches proceed to an additional 30-min termed extra-time (ET). This systematic review sought to appraise the literature available on 120-min of soccer-specific exercise, with a view to identifying practical recommendations and future research opportunities. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Independent researchers performed a systematic search of PubMed, CINAHL and Psych Info in May 2019 with keywords entered in various combinations: soccer, football, extra-time, extra time, 120 minutes, 120 min, additional 30 minutes and ‘additional 30 min. The search yielded an initial 73 articles and following the screening process, 11 articles were accepted for analyses. Articles were subsequently organised into five categories: ‘movement demands of extra-time’, ‘performance responses to extra-time’, ‘physiological and neuromuscular response during extra-time’, ‘nutritional inventions’, and, ‘recovery and extra-time’. The results highlighted that during competitive match-play, players cover 5–12% less distance relative to match duration (i.e., m.min-1), during ET compared to the preceding 90-min. Reductions in technical performance (i.e., shot speed, number of passes and dribbles) were also observed during ET. Additionally, carbohydrate provision may attenuate and improve dribbling performance during ET. Moreover, objective and subjective measures of recovery may be further compromised following ET when compared to 90-min. Additional investigations are warranted to further substantiate these findings and identify interventions to improve performance during ET.

We report on studies of hyperconductivity in which electric charge moves in a solid in the absence of an applied electric field. This is indicative of a non-Ohmic mechanism. Our results are consistent with charge being carried ballistically by mobile nonlinear lattice excitations called quodons moving along close-packed atomic chains in the cation layers of some silicates. The finding that quodons can trap and carry a charge was first found by the authors in muscovite (Russell F. M. et al., EPL, 120 (2017) 46001), which previously was not possible. In this paper we have also found hyperconductivity in lepidolite, phlogopite and synthetic fluorphlogopite but not in biotite or quartz. We have found that a current continues to flow for many seconds after the creation of quodons is stopped, indicating they have long flight-paths. This shows that quodons are decoupled from phonons, must experience elastic reflection at boundaries and are not stopped by inevitable dislocations or other minor defects. We have also found that quodons can anneal defects caused by mechanical working of crystal faces. The current carried by quodons is unaffected by a magnetic field of 1.1 T.

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) >= 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean +/- SD, 12.5 +/- 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 +/- 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 +/- 4.1). The overall mean IVST was 20.5 +/- 9.6 mm and the overall mean PWT was 11.0 +/- 8.4 mm. The mean IVST in the obese patients was 21.6 +/- 10.0 mm and mean PWT was 13.3 +/- 14.7 mm. The mean IVST in the non-obese patients was 20.1 +/- 9.5 mm and mean PWT was 10.4 +/- 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied.

BACKGROUND Predictors of risk of lethal arrhythmic events (LAE) is poorly understood and may differ from adults in children with hypertrophic cardiomyopathy (HCM). OBJECTIVE The purpose of this study was to determine predictors of LAE in children with HCM. METHODS A retrospective data collection was performed on 446 children and teenagers 20 years and younger (290 [65%] male; mean age 10.1 +/- 5.7 years) with idiopathic HCM from 35 centers. Patients were classified as group 1 (HCM with LAE) if having a secondary prevention implantable cardioverter-defibrillator (ICD) or primary prevention ICD with appropriate interventions or group 2 (HCM without LAE) if having a primary prevention ICD without appropriate interventions. RESULTS There were 152 children (34%) in group 1 and 294 (66%) in group 2. Risk factors for group 1 by univariate analysis were septal thickness, posterior left ventricular (LV) wall thickness, lower LV outflow gradient, and Q wave > 3 mm in inferior electrocardiographic leads. Factors not associated with LAE were family history of SCD, abnormal blood pressure response to exercise, and ventricular tachycardia on ambulatory electrocardiographic monitoring. Risk factors for SCD by multivariate analysis were age at ICD placement (hazard ratio [HR] 0.9; P = .0025), LV posterior wall thickness z score (HR 1.02; P < .005), and LV outflow gradient < 30 mm Hg (HR 2.0; P < .006). LV posterior wall thickness z score >= 5 was associated with LAE. CONCLUSION Risk factors for LAE appear different in children compared to adults. Conventional adult risk factors were not significant in children. Further prospective studies are needed to improve risk stratification for LAE in children with HCM.

Background: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. Methods: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. Results: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. Conclusions: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912

Background In this Position Statement, the International Society of Sports Nutrition (ISSN) provides an objective and critical review of the literature pertinent to nutritional considerations for training and racing in single-stage ultra-marathon. Recommendations for Training. i) Ultra-marathon runners should aim to meet the caloric demands of training by following an individualized and periodized strategy, comprising a varied, food-first approach; ii) Athletes should plan and implement their nutrition strategy with sufficient time to permit adaptations that enhance fat oxidative capacity; iii) The evidence overwhelmingly supports the inclusion of a moderate-to-high carbohydrate diet (i.e., ~ 60% of energy intake, 5-8 g·kg- 1·d- 1) to mitigate the negative effects of chronic, training-induced glycogen depletion; iv) Limiting carbohydrate intake before selected low-intensity sessions, and/or moderating daily carbohydrate intake, may enhance mitochondrial function and fat oxidative capacity. Nevertheless, this approach may compromise performance during high-intensity efforts; v) Protein intakes of ~ 1.6 g·kg- 1·d- 1 are necessary to maintain lean mass and support recovery from training, but amounts up to 2.5 g.kg- 1·d- 1 may be warranted during demanding training when calorie requirements are greater; Recommendations for Racing. vi) To attenuate caloric deficits, runners should aim to consume 150-400 Kcal·h- 1 (carbohydrate, 30-50 g·h- 1; protein, 5-10 g·h- 1) from a variety of calorie-dense foods. Consideration must be given to food palatability, individual tolerance, and the increased preference for savory foods in longer races; vii) Fluid volumes of 450-750 mL·h- 1 (~ 150-250 mL every 20 min) are recommended during racing. To minimize the likelihood of hyponatraemia, electrolytes (mainly sodium) may be needed in concentrations greater than that provided by most commercial products (i.e., > 575 mg·L- 1 sodium). Fluid and electrolyte requirements will be elevat

Aims/hypothesis: Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. Methods: We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. Results: We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. Conclusions/interpretation: These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent

Aims/hypothesis: The Coxsackie and adenovirus receptor (CAR) is a transmembrane cell-adhesion protein that serves as an entry receptor for enteroviruses and may be essential for their ability to infect cells. Since enteroviral infection of beta cells has been implicated as a factor that could contribute to the development of type 1 diabetes, it is often assumed that CAR is displayed on the surface of human beta cells. However, CAR exists as multiple isoforms and it is not known whether all isoforms subserve similar physiological functions. In the present study, we have determined the profile of CAR isoforms present in human beta cells and monitored the subcellular localisation of the principal isoform within the cells. Methods: Formalin-fixed, paraffin-embedded pancreatic sections from non-diabetic individuals and those with type 1 diabetes were studied. Immunohistochemistry, confocal immunofluorescence, electron microscopy and western blotting with isoform-specific antisera were employed to examine the expression and cellular localisation of the five known CAR isoforms. Isoform-specific qRT-PCR and RNA sequencing (RNAseq) were performed on RNA extracted from isolated human islets. Results: An isoform of CAR with a terminal SIV motif and a unique PDZ-binding domain was expressed at high levels in human beta cells at the protein level. A second isoform, CAR-TVV, was also present. Both forms were readily detected by qRT-PCR and RNAseq analysis in isolated human islets. Immunocytochemical studies indicated that CAR-SIV was the principal isoform in islets and was localised mainly within the cytoplasm of beta cells, rather than at the plasma membrane. Within the cells it displayed a punctate pattern of immunolabelling, consistent with its retention within a specific membrane-bound compartment. Co-immunofluorescence analysis revealed significant co-localisation of CAR-SIV with zinc transporter protein 8 (ZnT8), prohormone convertase 1/3 (PC1/3) and insulin, but not proins, SCOPUS: ar.j, info:eu-repo/semantics/published

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3(K392R,) on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3(K392R) and healthy-control cells, but in later stages, NEUROG3 expressionwas upregulated prematurely in STAT3(K392R) cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3(K392R) -activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3(K392R). Collectively, our results demonstrate that the STAT3(K392R) mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression.

The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

In the face of increasing population, development pressures, and climate change, many regions around the world face freshwater shortages. Planned potable water reuse can improve sustainability and reliability of water supplies by providing drinking water from wastewater. Most potable reuse research has focused on large coastal communities with relatively high mean household incomes. However, the US Department of Interior predicts that “hot spots” of conflict over water in the arid West are “highly likely” in numerous small-to-medium-sized inland communities with low-to-moderate household income levels. Potable reuse options may be different for larger, wealthier coastal communities as compared to small-to-medium-sized inland ones, not only in terms of the technologies used, but also in the communities’ knowledge of, attitudes toward, and ability to pay for the required technologies. Significant knowledge gaps exist regarding these issues for the arid, inland context, making it difficult for inland water managers to understand the feasibility of potable reuse for their communities. This research aims to inform decision-making about planned potable reuse in small-to-medium-sized, arid inland communities by estimating the total present worth of several indirect and direct potable reuse treatment scenarios that are appropriate for the inland context. The Albuquerque Bernalillo County Water Utility Authority in Albuquerque, NM, was used as a case study. Each of the indirect and direct potable reuse scenarios was examined with two different options for advanced treatment: reverse osmosis and ozone/biological activated carbon, both of which were preceded by microfiltration and followed by ultraviolet disinfection. The results showed that the present worth for indirect potable reuse was substantially higher than that for direct potable reuse primarily because of additional pumping and piping requirements. The type of advanced treatment included in an indirect or direct p

Nidhi Sofat,1 Abiola Harrison,1 Mark D Russell,1 Salma Ayis,2 Patrick D Kiely,3 Emma H Baker,1 Thomas Richard Barrick,4 Franklyn A Howe4 1Institute for Infection and Immunity, St George’s University of London, 2Division of Health & Social Care Research, King’s Clinical Trials Unit, King’s College London, 3Department of Rheumatology, St George’s University Hospitals NHS Foundation Trust, 4Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK Abstract: Osteoarthritis (OA) is the most prevalent arthritis worldwide and is characterized by chronic pain and impaired physical function. We hypothesized that heightened pain in hand OA could be reduced with duloxetine or pregabalin. In this prospective, randomized clinical study, we recruited 65 participants, aged 40–75 years, with a Numerical Rating Scale (NRS) for pain of at least 5. Participants were randomized to one of the following three groups: duloxetine, pregabalin, and placebo. The primary endpoint was the NRS pain score, and the secondary endpoints included the Australian and Canadian Hand Osteoarthritis Index (AUSCAN) pain, stiffness, and function scores and quantitative sensory testing by pain pressure algometry. After 13 weeks, compared to placebo, ANOVA found significant differences between the three groups (P=0.0078). In the intention-to-treat analysis, the pregabalin group showed improvement for NRS pain (P=0.023), AUSCAN pain (P=0.008), and AUSCAN function (P=0.009), but no difference between duloxetine and placebo (P>0.05) was observed. In the per protocol analysis, NRS pain was reduced for pregabalin (P<0.0001) and duloxetine (P=0.029) compared to placebo. We conclude that centrally acting analgesics improve pain outcomes in people with hand arthritis, offering new treatment paradigms for OA pain. Keywords: pain, hand osteoarthritis, sensitization, duloxetine, pregabalinCorr

Sofat N, Harrison A, Russell MD, et al. J Pain Res. 2017;10:2437–2449.On page 2443, Table 3, Placebo column, NRS section, the difference was reported as: –0.9 (–0.2 to 0.2). This is incorrect, and it should read as follows: –0.9 (–2.0 to 0.2).Read the original article

Determination of the chemical clearance rate from human blood is a critical component of toxicokinetic exposure assessment. Analysis of temporal biomonitoring data without consideration of ongoing exposure results in calculation of apparent elimination half-life values that are longer than the intrinsic value. The intrinsic elimination half-life is solely a function of the rate of elimination while the apparent elimination half-life reflects the processes of both elimination and ongoing exposure. Confusion between intrinsic and apparent half-life values can lead to misinterpretation of biomonitoring data and can result in exaggerated predictions in subsequent modeling efforts. This work provides a review of the first-order equations that have been developed to calculate intrinsic and apparent half-life values and the potential bias that can result from confusing these two values. Published human biomonitoring data for perfluorooctanoic acid (PFOA) are analyzed using these equations to provide examples of low, medium and high bias in determination of the intrinsic elimination half-life from plasma or serum, the components of blood typically analyzed for PFOA. An approach is also provided to estimate the extent of exposure reduction that is indicated by declining longitudinal or cross-sectional biomonitoring data. Based on the evaluation methodology presented in this work, the intrinsic elimination half-life of PFOA in humans is 2.4 years, representing the average of independent estimates of 2.5 years (95% Cl, 2.4-2.7) and 2.3 years (95% Cl, 2.1-2.4). The declining concentration of PFOA in blood of the general USA adult population represents an estimated exposure reduction of 20-30% over the period 1999-2008.

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

This paper presents selected findings from a recently completed research project, aimed at the investigation of CO2 sequestration in cement-based materials during the early stages of hydration when the cement paste is being mixed. Portland cement pastes were carbonated during the mixing process, using both carbonated water and gaseous CO2, and their properties were compared to the control non-carbonated mix. All mixes were prepared in a purpose-designed chamber that permitted carbonated water and gaseous CO2 to be mixed with the cementbased materials during the mixing process, without losses of CO2 to the external environment. Temperature measurements taken of the samples during mixing were used to evaluate the influence of carbonation on the properties of fresh pastes and their early hydration. Changes in the composition of the hardened pastes, due to the above- mentioned processes, were studied using thermogravimetric (TG) analysis, X ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) in conjunction with energy-dispersive X-ray spectroscopy (EDXS) were used to investigate physical (morphological) and chemical differences between non-carbonated and carbonated samples. It was found that, when compared to the non-carbonated mixes, the rate of the initial hydration of carbonated pastes increased, but the later hydration rate was decreased dramatically. TG, XRD, and FTIR spectroscopy revealed a substantial increase in the CaCO3 content and decrease in the Ca(OH)2 content in carbonated pastes. SEM showed substantial differences in the microstructure of the carbonated mixes when compared to the noncarbonated ones; needle- and lichen-like hydrates, with a high content of CO2, covered the surface of the fractured carbonated samples.

Aims/hypothesis Enteroviral infection has been implicated in the development of islet autoimmunity in type 1 diabetes and enteroviral antigen expression has been detected by immunohistochemistry in the pancreatic beta cells of patients with recent-onset type 1 diabetes. However, the immunohistochemical evidence relies heavily on the use of a monoclonal antibody, clone 5D8/1, raised against an enteroviral capsid protein, VP1. Recent data suggest that the clone 5D8/1 may also recognise non-viral antigens; in particular, a component of the mitochondrial ATP synthase (ATP5B) and an isoform of creatine kinase (CKB). Therefore, we evaluated the fidelity of immunolabelling by clone 5D8/1 in the islets of patients with type 1 diabetes. Methods Enteroviral VP1, CKB and ATP5B expression were analysed by western blotting, RT-PCR and immunocytochemistry in a range of cultured cell lines, isolated human islets and human tissue. Results Clone 5D8/1 labelled CKB, but not ATP5B, on western blots performed under denaturing conditions. In cultured human cell lines, isolated human islets and pancreas sections from patients with type 1 diabetes, the immunolabelling of ATP5B, CKB and VP1 by 5D8/1 was readily distinguishable. Moreover, in a human tissue microarray displaying more than 80 different cells and tissues, only two (stomach and colon; both of which are potential sites of enterovirus infection) were immunopositive when stained with clone 5D8/1. Conclusions/interpretation When used under carefully optimised conditions, the immunolabelling pattern detected in sections of human pancreas with clone 5D8/1 did not reflect cross-reactivity with either ATP5B or CKB. Rather, 5D8/1 is likely to be representative of enteroviral antigen expression.

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

The global economy experienced continuous growth from 2002 to 2007 until the U.S. subprime mortgage crisis caused instability in worldwide stock markets. Simultaneously, global CEO turnover continued to fall to 13.8 percent in 2007. In contrast, the CEO turnover rate in Australia increased to 18 percent in 2007. The purpose of this paper is to determine under what conditions a change in a CEO is associated with firm performance. Succinctly, does the firm’s decision to replace the CEO depend on the CEO’s human capital or firm performance? The empirical study of Australian listed firms (2005 – 2008) shows that firm performance is not a determinant of CEO turnover, rather a CEO with less valuable human capital is more likely to be replaced. The study also finds that merely changing the CEO is not associated firm performance. Rather, there is a positive association between firm performance and the successor’s general human capital for firms that replace the CEO. Specifically, it is the internal successor’s general human capital that is an important determinant of increasing firm performance. These results are important because they imply that CEO turnover is a result of a more active market for CEOs and contributes to explaining why firms retain CEOs despite poor firm performance.

Major fluorinated chemical manufacturers have developed new short-chain per- and polyfluorinated substances with more favorable environmental, health and safety profiles. This study provides the first evaluation of the elimination half-life of perfluorohexanoic acid (PFH)(A) from the blood of humans. PFHxA biomonitoring data were obtained from a recently published study of professional ski wax technicians. These data were analyzed to provide estimates of the apparent half-life of PFHxA from humans, and comparisons were made with kinetic studies of PFHxA elimination from mice, rats and monkeys. The apparent elimination half-life of PFHxA in highly exposed humans ranged between 14 and 49 d with a geomean of 32 d. The half-lives of PFHxA in mice, rats, monkeys and humans were proportional to body weight with no differences observed between genders, indicating similar volumes of distribution and similar elimination mechanisms among mammalian species. Compared to long-chain perfluoroalkyl acid analogs, PFHxA is rapidly cleared from biota. The consistent weight-normalized elimination half-lives for PFHxA in mammalian species indicates that results obtained from animal models are suitable for establishment of PFHxA benchmark dose and reference dose hazard endpoints for use in human risk assessments.

The interference effect attenuates strength and hypertrophic responses when strength and endurance training are conducted concurrently; however, the influence of training frequency on these responses remain unclear when varying ratios of concurrent strength and endurance training are performed. Therefore, the purpose of the study was to examine the strength, limb girth, and neuromuscular adaptations to varying ratios of concurrent strength and endurance training. Twenty-four men with .2 years resistance training experience completed 6 weeks of 3 days per week of (a) strength training (ST), (b) concurrent strength and endurance training ratio 3:1 (CT3), (c) concurrent strength and endurance training ratio 1:1 (CT1), or (d) no training (CON) in an isolated limb model. Assessments of maximal voluntary contraction by means of isokinetic dynamometry leg extensions (maximum voluntary suppression [MVC]), limb girth, and neuromuscular responses through electromyography (EMG) were conducted at baseline, mid-intervention, and postintervention. After training, ST and CT3 conditions elicited greater MVC increases than CT1 and CON conditions (p # 0.05). Strength training resulted in significantly greater increases in limb girth than both CT1 and CON conditions (p = 0.05 and 0.004, respectively). The CT3 induced significantly greater limb girth adaptations than CON condition (p = 0.04). No effect of time or intervention was observed for EMG (p . 0.05). In conclusion, greater frequencies of endurance training performed increased the magnitude of the interference response on strength and limb girth responses after 6 weeks of 3 days a week of training. Therefore, the frequency of endurance training should remain low if the primary focus of the training intervention is strength and hypertrophy.

The Vehicular Integration for C4ISR/EW Interoperability (VICTORY) Systems Integration Lab (SIL) is established and developed at the U.S. Army Tank-Automotive Research, Development, and Engineering Command (TARDEC). The VICTORY SIL will be utilized for the development and integration of the extensive set of C4ISR/EW technologies that are to be systematically down selected to provide the comprehensive VICTORY services & infrastructure required in the development of mission capabilities of the Army's tactical and combat vehicles. A fully functioning VICTORY SIL will be utilized for validation and independent verification of the Army's and the vendor provided C4ISR/EW sub-systems. The lab will emphasize the importance of testing the data, power & physical interface strategy of the sub-systems in a low-cost laboratory environment before integration onto a vehicle. This paper describes how the VICTORY SIL will advance the RDECOM's vision for a standardized electronic architecture for ground vehicles as well as the strategy and process for the design, development and testing of the infrastructure and the VICTORY core services., Submitted to 2012 NDIA GROUND VEHICLE SYSTEMS ENGINEERING AND TECHNOLOGY SYMPOSIUM August 14-16, Michigan.

* Executing multiple VICTORY data services, and reading multiple VICTORY-compliant sensors at the same time resulted in the following performance measurements for the system - 0.64 Amps / 3.15 Watts Power Consumption at run-time. - Roughly 0.77% System Memory Utilization per Service - 1.05%, 0.433%, 0.531% average CPU utilization for Position, Direction of Travel, and Orientation Services, respectively. - Less than 1.7 milliseconds processing time (Building and Publishing Full Featured VICTORY XML Messages). - A delta of 68.97 Watts between workstation and BeagleBoard, which is 95.6% more efficient. * Therefore, boards based on this type of architecture are an excellent candidate for running VICTORY services while providing significant reductions in SWAP-C for the VICTORY 1.0 project., Submitted to 2012 NDIA Ground Vehicle Systems Engineering and Technology Symposium, August 14-16, Troy, Michigan.

The Vehicular Integration for C4ISR/EW Interoperability (VICTORY) Standard adopts many protocols that are traditionally used for developing enterprise application software deployed on general-purpose or server/workstation based computing platforms. This has led to discussions regarding the suitability of the VICTORY Standard for deployment to embedded and resource-constrained platforms. An independent software implementation of VICTORY core services was developed within the U.S Army Tank and Automotive Research, Development and Engineering Center (TARDEC) VICTORY System Integration Lab (SIL). These services were ported from a general-purpose computing platform to an embedded environment. Test procedures were developed and extensive performance tests were conducted to determine the feasibility of operating in this resource-constrained environment. This paper discusses the development procedures, implementation, test procedures, and performance results., Submitted to the 2012 NDIA Ground Vehicle Systems Engineering and Technology Symposium, Vehicle Electronics and Architecture (VEA) Mini-symposium, held on August 14-16, 2012, in Troy, MI. Prepared in cooperation with UBT Technologies, Troy, MI.

Multimedia mass balance models of chemical fate in the environment have been used for over 3 decades in a regulatory context to assist decision making. As these models become more comprehensive, reliable, and accepted, there is a need to recognize and adopt principles of Good Modeling Practice (GMP) to ensure that multimedia models are applied with transparency and adherence to accepted scientific principles. We propose and discuss 6 principles of GMP for applying existing multimedia models in a decision-making context, namely 1) specification of the goals of the model assessment, 2) specification of the model used, 3) specification of the input data, 4) specification of the output data, 5) conduct of a sensitivity and possibly also uncertainty analysis, and finally 6) specification of the limitations and limits of applicability of the analysis. These principles are justified and discussed with a view to enhancing the transparency and quality of model-based assessments.

Laboratory-based research aimed at understanding processes regulating insulin secretion and mechanisms underlying beta-cell dysfunction and loss in diabetes often makes use of rodents, as these processes are in many respects similar between rats/mice and humans. Indeed, a rough calculation suggests that islets have been isolated from as many as 150,000 rodents to generate the data contained within papers published in 2009 and the first four months of 2010. Rodent use for islet isolation has been mitigated, to a certain extent, by the availability of a variety of insulin-secreting cell lines that are used by researchers world-wide. However, when maintained as monolayers the cell lines do not replicate the robust, sustained secretory responses of primary islets which limits their usefulness as islet surrogates. On the other hand, there have been several reports that configuration of MIN6 beta-cells, derived from a mouse insulinoma, as three-dimensional cell clusters termed 'pseudoislets' largely recapitulates the function of primary islet beta-cells. The Diabetes Research Group at King's College London has been using the MIN6 pseudoislet model for over a decade and they hosted a symposium on "Pseudoislets as primary islet replacements for research", which was funded by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), in London on 15(th) and 16(th) April 2010. This small, focused meeting was conceived as an opportunity to consolidate information on experiences of working with pseudoislets between different UK labs, and to introduce the theory and practice of pseudoislet culture to laboratories working with islets and/or beta-cell lines but who do not currently use pseudoislets. This short review summarizes the background to the development of the cell line-derived pseudoislet model, the key messages arising from the symposium and emerging themes for future pseudoislet research.