Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Reduced Leukoaraiosis, Noncardiac Embolic Stroke Etiology, and Shorter Thrombus Length Indicate Good Leptomeningeal Collateral Flow in Embolic Large-Vessel Occlusion

Background and purposeAcute leptomeningeal collateral flow is vital for maintaining perfusion to penumbral tissue in acute ischemic stroke caused by large-vessel occlusion. In this study, we aimed to investigate the clinically available indicators of leptomeningeal collateral variability in embolic large-vessel occlusion.Materials and methodsAmong prospectively registered consecutive patients with acute embolic anterior circulation large-vessel occlusion treated with thrombectomy, we analyzed 108 patients admitted from January 2015 to December 2019 who underwent evaluation of leptomeningeal collateral status on pretreatment CTA. Clinical characteristics, extent of leukoaraiosis on MR imaging, embolic stroke subtype, time of imaging, occlusive thrombus characteristics, presenting stroke severity, and clinical outcome were collected. The clinical indicators of good collateral status (>50% collateral filling of the occluded territory) were analyzed using multivariate logistic regression analysis.ResultsGood collateral status was present in 67 patients (62%) and associated with independent functional outcomes at 3 months. Reduced leukoaraiosis (total Fazekas score, 0-2) was positively related to good collateral status (OR, 9.57; 95% CI, 2.49-47.75), while the cardioembolic stroke mechanism was inversely related to good collateral status (OR, 0.17; 95% CI, 0.02-0.87). In 82 patients with cardioembolic stroke, shorter thrombus length (OR, 0.91 per millimeter increase; 95% CI, 0.82-0.99) and reduced leukoaraiosis (OR, 5.79; 95% CI, 1.40-29.61) were independently related to good collateral status.ConclusionsAmong patients with embolic large-vessel occlusion, reduced leukoaraiosis, noncardiac embolism mechanisms including embolisms of arterial or undetermined origin, and shorter thrombus length in cardioembolism are indicators of good collateral flow

Abstract TP7: Association of Retrieved Thrombus Composition With Measures of Thrombectomy Success

Introduction: Emboli retrieved from stroke patients undergoing mechanical thrombectomy vastly differ in histopathologic appearance, likely reflecting varying etiologies of stroke. We investigated whether clot components correlated with clinical features and thrombectomy outcomes. Methods: Retrieved thrombi from endovascular thrombectomy in consecutive AIS-LVO patients at 2 academic medical centers were fixed in formalin and sections stained by hematoxylin and eosin. The RBC, WBC and fibrin percentages of the clot were quantified by a neuropathologist blinded to the clinical details. We evaluated the association of these clot components, patient demographic and clinical features, with TICI score (both ordinal and dichotomized at 2c), AOL score, number of thrombectomy passes, and first-pass substantial recanalization (≥TICI 2b result on the first thrombectomy device pass). Non-parametric values were computed via Spearman correlation and pairwise interaction of clinical features was analyzed by ordinal logistic regression. Results: Among the 75 analyzed patients, mean age was 71.4 (SD 17.7), 50.7% were female and presenting NIHSS mean was 16.1 (SD 7.6). Devices employed were stent retrievers in 71% of patients, aspiration in 10%, and both stent retrievers and aspiration in 19%. Number of passes per procedure was mean 2.16 (SD 1.21). Substantial reperfusion (TICI 2B-3) was achieved in 88% and excellent reperfusion (TICI 2C-3) in 44%. In retrieved thrombi, mean RBC% was 44.8% (SD 31.9) and mean fibrin% was 49.8% (SD 31.4). Rates of first-pass substantial reperfusion, final substantial reperfusion, and final excellent reperfusion were homogenous across wide ranges of retrieved thrombus RBC% and fibrin% in correlation analysis. Conclusion: RBC and fibrin composition range widely among retrieved thrombi causing acute ischemic stroke. Current generation thrombectomy devices perform well across a broad range of clot compositions

Herbal medicine in diabetes mellitus with cardiovascular diseases

[No abstract available

Euclid. I. Overview of the Euclid mission

The current standard model of cosmology successfully describes a variety ofmeasurements, but the nature of its main ingredients, dark matter and darkenergy, remains unknown. Euclid is a medium-class mission in the Cosmic Vision2015-2025 programme of the European Space Agency (ESA) that will providehigh-resolution optical imaging, as well as near-infrared imaging andspectroscopy, over about 14,000 deg^2 of extragalactic sky. In addition toaccurate weak lensing and clustering measurements that probe structureformation over half of the age of the Universe, its primary probes forcosmology, these exquisite data will enable a wide range of science. This paperprovides a high-level overview of the mission, summarising the surveycharacteristics, the various data-processing steps, and data products. We alsohighlight the main science objectives and expected performance