Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits.

Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits.

Effect of polygenic risk for schizophrenia on cardiac structure and function: a UK Biobank observational study.

Background: Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases.

A quantitative analysis of MDMA seized at New South Wales music festivals over the 2019/2020 season: Form, purity, dose and adulterants.

Introduction: This research aims to understand the content and nature, and to explore the harm potential, of suspected 3,4-methylenedioxymethamphetamine (MDMA) substances circulating at music festivals in New South Wales.

Methods: Across 19 music festivals held between October 2019 and March 2020, 302 substances detected and suspected by police to contain MDMA were selected for quantitative analysis.

Results: Five percent of substances contained a drug other than MDMA (n = 13) or no drug (n = 2).

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.

Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits.

A population-based phenome-wide association study of cardiac and aortic structure and function.

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors.

Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection.

Background: Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.

CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.

Purpose: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.

Three-dimensional cardiovascular imaging-genetics: a mass univariate framework.

Motivation: Left ventricular (LV) hypertrophy is a strong predictor of cardiovascular outcomes, but its genetic regulation remains largely unexplained. Conventional phenotyping relies on manual calculation of LV mass and wall thickness, but advanced cardiac image analysis presents an opportunity for high-throughput mapping of genotype-phenotype associations in three dimensions (3D).

Results: High-resolution cardiac magnetic resonance images were automatically segmented in 1124 healthy volunteers to create a 3D shape model of the heart.

Coarctation of the aorta: are genes relevant?

In a busy clinic, it is easy to overlook genetic aspects of congenital heart disease. The complexity of genetic influence on disease makes it difficult to provide clear, accurate advice about recurrence risks and genetics to individual patients. This is particularly true of coarctation of the aorta, which appears sporadic in the majority of cases.

Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources.

Endothelial cells form a highly specialised lining of all blood vessels where they provide an anti-thrombotic surface on the luminal side and protect the underlying vascular smooth muscle on the abluminal side. Specialised functions of endothelial cells include their unique ability to release vasoactive hormones and to morphologically adapt to complex shear stress. Stem cell derived-endothelial cells have a growing number of applications and will be critical in any organ regeneration programme.

Real time assays for quantifying cytotoxicity with single cell resolution.

A new live cell-based assay platform has been developed for the determination of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), and overall cytotoxicity in human whole blood. In these assays, the targeted tumor cell populations are first labeled with fluorescent Cell Tracker dyes and immobilized using a DNA-based adhesion technique. This allows the facile generation of live cell arrays that are arranged arbitrarily or in ordered rectilinear patterns.

Contemporary analysis of descending thoracic and thoracoabdominal aneurysm repair: a comparison of endovascular and open techniques.

Background: Endovascular repair of thoracic aneurysm has demonstrated low risks of mortality and spinal cord ischemia (SCI), but few large series have been published on endovascular thoracoabdominal aneurysm repair, and reports suffer from a lack of accurate comparison with similar open surgical procedures.

Methods And Results: A consecutive cohort of patients with thoracic and thoracoabdominal aneurysms treated electively with endovascular repair (ER) or surgical repair (SR) techniques between 2001 and 2006 were analyzed. The association between repair technique and SCI was evaluated with univariable analysis.

Endovascular treatment of thoracoabdominal aortic aneurysms.

Objective: To establish the safety and efficacy of endovascular repair of thoracoabdominal aortic aneurysms.

Methods: Between May 2004 and February 2006, patients with thoracoabdominal aneurysms considered high risk for conventional surgery were enrolled in a prospective trial to evaluate a novel endovascular grafting system. Devices were custom designed for each patient using high-resolution computed tomography.

On-screen portrayals of mental illness: extent, nature, and impacts.

This article reviews the published literature on the extent, nature, and impacts of portrayal of mental illness in fictional films and television programs. The literature suggests that on-screen portrayals are frequent and generally negative, and have a cumulative effect on the public's perception of people with mental illness and on the likelihood of people with mental illness seeking appropriate help. The article concludes that there is a need for the mental health sector and the film and television industries to collaborate to counter negative portrayals of mental illness, and to explore the potential for positive portrayals to educate and inform, as well as to entertain.