Update of variants identified in the pancreatic β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.P30 DK020595/NH/NIH HHS/United States K23 DK094866/NH/NIH HHS/United States R03 DK103096/NH/NIH HHS/United States 1-11-CT-41/American Diabetes Association/International R01 DK104942/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom WT098395/Z/12/Z/WT_/Wellcome Trust/United Kingdom UL1 TR000430/NH/NIH HHS/United States P30 DK020595/DK/NIDDK NIH HHS/United States UL1 TR000430/TR/NCATS NIH HHS/United States 1-17-JDF-008/American Diabetes Association/International 105636/Z/14/Z/WT_/Wellcome Trust/United Kingdom 110675/European Association for the Study of Diabetes-Novo Nordisk/International 16/0005407/DUK_/Diabetes UK/United Kingdom R01 DK104942/NH/NIH HHS/United States R03 DK103096/DK/NIDDK NIH HHS/United States K23 DK094866/DK/NIDDK NIH HHS/United Statespublished version, accepted version (12 month embargo), submitted versio

Crystal sedimentation and stone formation

Mechanisms of crystal collision being the first step of aggregation (AGN) were analyzed for calcium oxalate monohydrate (COM) directly produced in urine. COM was produced by oxalate titration in urine of seven healthy men, in solutions of urinary macromolecules and in buffered distilled water (control). Crystal formation and sedimentation were followed by a spectrophotometer and analyzed by scanning electron microscopy. Viscosity of urine was measured at 37°C. From results, sedimentation rate (vS), particle diffusion (D) and incidences of collision of particles in suspension by sedimentation (IS) and by diffusion (ID) were calculated. Calculations were related to average volume and urinary transit time of renal collecting ducts (CD) and of renal pelvis. vS was in urine 0.026 ± 0.012, in UMS 0.022 ± 0.01 and in control 0.091 ± 0.02 cm min−1 (mean ± SD). For urine, a D of 9.53 ± 0.97 μm within 1 min can be calculated. At maximal crystal concentration, IS was only 0.12 and ID was 0.48 min−1 cm−3 which, even at an unrealistic permanent and maximal crystalluria, would only correspond to less than one crystal collision/week/CD, whereas to the same tubular wall being in horizontal position 1.3 crystals/min and to a renal stone 624 crystals/cm2 min could drop by sedimentation. Sedimentation to renal tubular or pelvic wall, where crystals can accumulate and meet with a tissue calcification or a stone, is probably essential for stone formation. Since vS mainly depends on particle size, reducing urinary supersaturation and crystal growth by dietary oxalate restriction seems to be an important measure to prevent aggregation

Pharmacists in general practice: a qualitative interview case study of stakeholders’ experiences in a West London GP Federation

Background Increased patient demand for healthcare services coupled with a shortage of general practitioners necessitates changes in professional roles and service delivery. In 2016, NHS England began a three year pilot study of pharmacists in general practice, however, this is not an entirely new initiative. There is limited, current, evidence-based, UK research to inform the pilot so studies of pre-existing services must suffice until findings from a formal national evaluation are available. Methods The aim of this exploratory, descriptive interview study was to explore the experiences of stakeholders in eight general practices in the Ealing GP Federation, West London, where pharmacy services have been provided for several years. Forty-seven participants, including pharmacy team members (pre-registration and clinical pharmacists, independent prescribers and pharmacy technicians), general practitioners, patients, practice managers, practice nurses and receptionists took part in semi-structured, audio-recorded qualitative interviews which were transcribed verbatim, coded and analysed thematically to extract the issues raised by participants and the practicalities of providing pharmacy services in general practice. Results Findings are reported under the themes of Complementarity (incorporating roles, skills, education and workloads); Integration (incorporating relationships, trust and communication) and Practicalities (incorporating location and space, access, and costs). Participants reported the need for time to develop and understand the various roles, develop communication processes and build inter-professional trust. Once these were established, however, experiences were positive and included decreased workloads, increased patient safety, improved job satisfaction, improved patient relationships, and enhanced cost savings. Areas for improvement included patients’ awareness of services; pharmacists’ training; and regular, onsite access for practice staff to the pharmacy team. Conclusions Recommendations are made for the development of clear role definitions, identification of training needs, dedication of time for team building, production of educational materials for practice staff members and patients, and provision of on-site, full-time pharmacy services. Future work should focus on evaluation of various models of employing pharmacy teams in general practice; integration of pharmacists and pharmacy technicians into multidisciplinary general practice teams; relationships between local community pharmacy and general practice personnel and patients’ service and information needs. A formal national evaluation of the pilot scheme is overdue

Monitoring of post-match fatigue in professional soccer: Welcome to the real world

Participation in soccer match-play leads to acute and transient subjective, biochemical, metabolic and physical disturbances in players over subsequent hours and days. Inadequate time for rest and regeneration between matches can expose players to the risk of training and competing whilst not entirely recovered. In professional soccer, contemporary competitive schedules can require teams to compete in-excess of 60 matches over the course of the season while periods of fixture congestion occur prompting much attention from researchers and practitioners to the monitoring of fatigue and readiness to play. A comprehensive body of research has investigated post-match acute and residual fatigue responses. Yet the relevance of the research for professional soccer contexts is debatable notably in relation to the study populations and designs employed. Monitoring can indeed be invasive, expensive, time-inefficient and difficult to perform routinely and simultaneously in a large squad of regularly competing players. Uncertainty also exists regarding the meaningfulness and interpretation of changes in fatigue response values and their functional relevance, and practical applicability in the field. The real-world need and cost-benefit of monitoring must be carefully weighed up. In relation to professional soccer contexts, this opinion paper intends to: 1) debate the need for PMF monitoring, 2) critique the real-world relevance of the current research literature, 3) discuss the practical burden relating to measurement tools and protocols and the collection, interpretation and application of data in the field, and, 4) propose future research perspectives

The determinants of stroke phenotypes were different from the predictors (CHADS2 and CHA2DS2-VASc) of stroke in patients with atrial fibrillation: a comprehensive approach

<p>Abstract</p> <p>Background</p> <p>Atrial fibrillation (AF) is a leading cause of fatal ischemic stroke. It was recently reported that international normalized ratio (INR) levels were associated with infarct volumes. However, factors other than INR levels that affect stroke phenotypes are largely unknown. Therefore, we evaluated the determinants of stroke phenotypes (pattern and volume) among patients with AF who were not adequately anticoagulated.</p> <p>Methods</p> <p>We analyzed data pertaining to consecutive AF patients admitted over a 6-year period with acute MCA territory infarcts. We divided the patients according to DWI (diffusion-weighted imaging) lesion volumes and patterns, and the relationship between stroke predictors (the CHADS₂and CHA₂DS₂-VASc score), systemic, and local factors and each stroke phenotype were then evaluated.</p> <p>Results</p> <p>The stroke phenotypes varied among 231 patients (admission INR median 1.06, interquartile range (IQR) 1.00-1.14). Specifically, (1) the DWI lesion volumes ranged from 0.04-338.62 ml (median 11.86 ml; IQR, 3.07-44.20 ml) and (2) 46 patients had a territorial infarct pattern, 118 had a lobar/deep pattern and 67 had a small scattered pattern. Multivariate testing revealed that the CHADS₂and CHA₂DS₂-VASc score were not related to either stroke phenotype. Additionally, the prior use of antiplatelet agents was not related to the stroke phenotypes. Congestive heart failure and diastolic dysfunction were not associated with stroke phenotypes.</p> <p>Conclusions</p> <p>The results of this study indicated that the determinants of stroke phenotypes were different from the predictors (i.e., CHADS2 and CHA₂DS₂-VASc score) of stroke in patients with AF.</p

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Background: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. Methods and Findings: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-$\alpha$ and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs. Conclusions: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes

Autoregulation in resistance training : addressing the inconsistencies

Autoregulation is a process that is used to manipulate training based primarily on the measurement of an individual's performance or their perceived capability to perform. Despite being established as a training framework since the 1940s, there has been limited systematic research investigating its broad utility. Instead, researchers have focused on disparate practices that can be considered specific examples of the broader autoregulation training framework. A primary limitation of previous research includes inconsistent use of key terminology (e.g., adaptation, readiness, fatigue, and response) and associated ambiguity of how to implement different autoregulation strategies. Crucially, this ambiguity in terminology and failure to provide a holistic overview of autoregulation limits the synthesis of existing research findings and their dissemination to practitioners working in both performance and health contexts. Therefore, the purpose of the current review was threefold: first, we provide a broad overview of various autoregulation strategies and their development in both research and practice whilst highlighting the inconsistencies in definitions and terminology that currently exist. Second, we present an overarching conceptual framework that can be used to generate operational definitions and contextualise autoregulation within broader training theory. Finally, we show how previous definitions of autoregulation fit within the proposed framework and provide specific examples of how common practices may be viewed, highlighting their individual subtleties