A clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment.

Purpose: To develop an algorithm using routine clinical laboratory measurements to identify people at risk for systematic underestimation of glycated hemoglobin (HbA1c) due to p.Val68Met glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Methods: We analyzed 122,307 participants of self-identified Black race across four large cohorts with blood glucose, HbA1c, and red cell distribution width measurements from a single blood draw.

Effectiveness of shared decision making strategies for stroke prevention among patients with atrial fibrillation: cluster randomized controlled trial.

Objective: To evaluate the effectiveness of multiple decision aid strategies in promoting high quality shared decision making for prevention of stroke in patients with non-valvular atrial fibrillation.

Design: Cluster randomized controlled trial.

Setting: Six academic medical centers in the United States.

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

EFP Analyzer: A fast, accurate, and easy-to-teach program for analyzing Extracellular Field Potentials from iPSC-derived cardiomyocytes.

Rationale: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an emerging model for determining drug effects and modeling disease. Specialized devices can generate Extracellular Field Potential (EFP) measurements from these cells, analogous to the ventricular complex of the electrocardiogram.

Objective: The objective of this study was to develop an easy-to-use, easy-to-teach, reproducible software tool to measure EFPs.

Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD.

ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.

Interpreting the clinical significance of putative splice-altering variants outside canonical splice sites remains difficult without time-intensive experimental studies. To address this, we introduce Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed assay to quantify variant effects on RNA splicing. We first apply this technique to study hundreds of variants in the arrhythmia-associated gene SCN5A.

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Nodular Fasciitis of the Buccal Mucosa with a Novel USP6 Gene Rearrangement: A Case Report and Review of the Literature.

Nodular fasciitis is a rare but benign fibroblastic proliferation that typically presents as a solitary lesion with rapid growth and variable mitotic activity. The lesions usually occur on the extremities and occasionally in the head/neck region. Involvement of the buccal mucosa is extremely rare with only few reports in the literature; in this case report, we describe a 41 year old female who presented with a 6-month history of a stable intraoral lump at the junction of the upper and lower lip.

Heparin-Induced Thrombocytopenia in Patients Suffering Cardiogenic Shock.

Objectives: Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine.

Multisite Validation of a Functional Assay to Adjudicate Brugada Syndrome-Associated Variants.

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants is challenging, and ≈79% of missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.

Benchmarking computational variant effect predictors by their ability to infer human traits.

Background: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts.

Invasive Assessment of Coronary Artery Disease in Clonal Hematopoiesis of Indeterminate Potential.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes.

Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association.

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy.

Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use).

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels.

High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.

Background: KCNE1 encodes a 129-residue cardiac potassium channel (I) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.