Koenigdaniels4273

Recent advances in Next-Generation Sequencing (NGS) technologies have revolutionized the field of human genetics. Alongside a broad panel of bio-informatics tools and databases, NGS technologies have unprecedentedly improved the molecular diagnosis rate and the identification of new genes associated with rare disorders. However, about 50% of patients remain without a final diagnosis. Here, we highlight the utility of NGS applications in developmental anomalies and intellectual disability, illustrating their main advantages and pitfalls. Through specific examples, we suggest novel strategies and tools for identifying the molecular bases in the remaining patients, and we outline future challenges. This article is protected by copyright. All rights reserved. check details This article is protected by copyright. All rights reserved.Oxysterols are oxygenated forms of cholesterol generated via autooxidation by free radicals and reactive oxygen species, or formed enzymatically by a variety of enzymes such as those involved in the synthesis of bile acids. Although found at very low concentrations in vivo, these metabolites play key roles in health and disease, particularly in development and regulating immune cell responses, by binding to effector proteins such as LXRα, RORγ and Insig and directly or indirectly regulating transcriptional programs that affect cell metabolism and function. In this review we summarise the routes by which oxysterols can be generated and subsequently modified to other oxysterol metabolites, and highlight their diverse and profound biological functions and opportunities to alter their levels using pharmacological approaches. This article is protected by copyright. All rights reserved.Despite new strategies, such as evaluating deep intronic variants and new genes in whole-genome-sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease-causing gene for this phenotype, but the relevance and clinical implication of copy-number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth-of-coverage strategy by next-generation sequencing (NGS) in 5493 HCM probands and 2973 disease-controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease. © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.in English, Spanish ANTECEDENTES Para completar la formación en cirugía general, se requiere que los aspirantes demuestren solvencia en la práctica de los procedimientos comunes efectuados por laparotomía de urgencia. El objetivo de este estudio fue describir los esquemas de formación de los aspirantes en laparotomía de urgencia y su asociación con los resultados postoperatorios. MÉTODOS Todos los pacientes a los que se realizó una laparotomía de urgencia entre diciembre del 2013 y noviembre del 2017 se obtuvieron a partir de la base de datos de la Auditoría Nacional de Laparotomía de Urgencia (National Emergency Laparotomy Audit, NELA). Los pacientes se agruparon según la experiencia del cirujano; cirujanos en periodo de formación (residentes, speciality registrar) o consultores (incluyendo los que habían completado la especialidad). Se investigaron las tendencias entre los residentes por universidad, tamaño del hospital y hora del día de la cirugía. Se realizaron análisis de regresión univariable y ajustadoiben los residentes en laparotomía de urgencia según el área geográfica, el tamaño del hospital y la hora del día. Sin embargo, estas diferencias no parecen afectar a la mortalidad ni a la tasa de reoperaciones.in English, Spanish ANTECEDENTES Los datos existentes sobre la seguridad de la colecistectomía fuera del horario laboral son discordantes. El objetivo de este estudio fue investigar si la colecistectomía para el tratamiento de la colecistitis aguda realizada fuera del horario laboral se asocia con un mayor riesgo de complicaciones en comparación con la cirugía efectuada durante el horario laboral. MÉTODOS Se trata de un estudio de cohortes de base poblacional. Se utilizó el registro Swedish Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography Register (GallRiks) para examinar la asociación entre la colecistectomía por colecistitis aguda realizada fuera del horario laboral y las complicaciones a los 30 días. Se recogieron los datos de los pacientes en los que se realizó una colecistectomía entre 2006 y 2017. Se definió como cirugía fuera del horario laboral aquella realizada entre las 1900 y las 0700 de lunes a viernes y en cualquier momento durante los fines de semana (de viernes 1900 a lunes a factores relacionados con el paciente que con la hora del día en que se practica la cirugía. Debe tenerse en cuenta que las intervenciones realizadas por vía abierta fuera del horario laboral tienen una mayor morbilidad.BACKGROUND AND PURPOSE Cardiovascular (CV) safety is one of the most frequent causes of safety related attrition both pre-clinically and clinically. Preclinical cardiovascular safety, routinely assessed using dog telemetry as part of the safety pharmacology package, monitors key cardiac and hemodynamic functions. The objective of this effort was to develop a semi-mechanistic modeling platform to simultaneously assess changes in contractility (dPdtmax ), heart rate (HR) and mean arterial pressure (MAP) in preclinical studies. METHODS Data from dPdtmax , HR, preload (left ventricular end-diastolic pressure; LVEDP) and MAP were available from dog telemetry studies after dosing with atenolol (n=27), albuterol (n=5), L-NG-Nitroarginine Methyl Ester (L-NAME; n=4), milrinone (n=4), verapamil (n=12), dofetilide (n=8), flecainide (n=4) and AZ001 (n=14). Literature models for rat CV function was used as a starting point for the structural population pharmacodynamic model development. LVEDP was evaluated as covariate to account for the effect of preload on dPdtmax .