Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Ocean current connectivity propelling the secondary spread of a marine invasive comb jelly across western Eurasia

Aim: Invasive species are of increasing global concern. Nevertheless, the mechanisms driving furtherdistribution after the initial establishment of non-native species remain largely unresolved, especiallyin marine systems. Ocean currents can be a major driver governing range occupancy, but this hasnot been accounted for in most invasion ecology studies so far. We investigate how well initialestablishment areas are interconnected to later occupancy regions to test for the potential role ofocean currents driving secondary spread dynamics in order to infer invasion corridors and thesource–sink dynamics of a non-native holoplanktonic biological probe species on a continental scale.Location: Western Eurasia.Time period: 1980s–2016.Major taxa studied: ‘Comb jelly’ Mnemiopsis leidyi.Methods: Based on 12,400 geo-referenced occurrence data, we reconstruct the invasion historyof M. leidyi in western Eurasia. We model ocean currents and calculate their stability to match thetemporal and spatial spread dynamics with large-scale connectivity patterns via ocean currents.Additionally, genetic markers are used to test the predicted connectivity between subpopulations.Results: Ocean currents can explain secondary spread dynamics, matching observed range expansionsand the timing of first occurrence of our holoplanktonic non-native biological probe species,leading to invasion corridors in western Eurasia. In northern Europe, regional extinctions after coldwinters were followed by rapid recolonizations at a speed of up to 2,000 km per season. SourceJASPERS ET AL. | 815areas hosting year-round populations in highly interconnected regions can re-seed genotypes overlarge distances after local extinctions.Main conclusions: Although the release of ballast water from container ships may contribute tothe dispersal of non-native species, our results highlight the importance of ocean currents drivingsecondary spread dynamics. Highly interconnected areas hosting invasive species are crucial forsecondary spread dynamics on a continental scale. Invasion risk assessments should considerlarge-scale connectivity patterns and the potential source regions of non-native marine species

2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects

Objective. The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods. Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data. Results. Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference. Conclusion. Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis

Human rotavirus-specific IgM memory B cells have differential cloning efficiencies and switch capacities and play a role in antiviral immunity in vivo

Q1Q110829-10840Protective immunity to rotavirus (RV) is primarily mediated by antibodies produced by RV-specific memory B cells (RV-mBc). Of note, most of these cells express IgM, but the function of this subset is poorly understood. Here, using limiting dilution assays of highly sort-purified human IgM mBc, we found that 62% and 21% of total (non-antigen-specific) IgM and RV-IgM mBc, respectively, switched in vitro to IgG production after polyclonal stimulation. Moreover, in these assays, the median cloning efficiencies of total IgM (17%) and RV-IgM (7%) mBc were lower than those of the corresponding switched (IgG IgA) total (34%) and RV-mBc (17%), leading to an underestimate of their actual frequency. In order to evaluate the in vivo role of IgM RV mBc in antiviral immunity, NOD/Shi-scid interleukin-2 receptor-deficient (IL-2Rnull) immunodeficient mice were adoptively transferred highly purified human IgM mBc and infected with virulent murine rotavirus. These mice developed high titers of serum human RV-IgM and IgG and had significantly lower levels than control mice of both antigenemia and viremia. Finally, we determined that human RV-IgM mBc are phenotypically diverse and significantly enriched in the IgMhi IgDlow subset. Thus, RV IgM mBc are heterogeneous, occur more frequently than estimated by traditional limiting dilution analysis, have the capacity to switch Ig class in vitro as well as in vivo, and can mediate systemic antiviral immunity

Linking soil microbial community structure to potential carbon mineralization: A continental scale assessment of reduced tillage

Potential carbon mineralization (Cmin) is a commonly used indicator of soil health, with greater Cmin values interpreted as healthier soil. While Cmin values are typically greater in agricultural soils managed with minimal physical disturbance, the mechanisms driving the increases remain poorly understood. This study assessed bacterial and archaeal community structure and potential microbial drivers of Cmin in soils maintained under various degrees of physical disturbance. Potential carbon mineralization, 16S rRNA sequences, and soil characterization data were collected as part of the North American Project to Evaluate Soil Health Measurements (NAPESHM). Results showed that type of cropping system, intensity of physical disturbance, and soil pH influenced microbial sensitivity to physical disturbance. Furthermore, 28% of amplicon sequence variants (ASVs), which were important in modeling Cmin, were enriched under soils managed with minimal physical disturbance. Sequences identified as enriched under minimal disturbance and important for modeling Cmin, were linked to organisms which could produce extracellular polymeric substances and contained metabolic strategies suited for tolerating environmental stressors. Understanding how physical disturbance shapes microbial communities across climates and inherent soil properties and drives changes in Cmin provides the context necessary to evaluate management impacts on standardized measures of soil microbial activity

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Ocean current connectivity propelling the secondary spread of a marine invasive comb jelly across western Eurasia

Publication history: Accepted - 15 February 2018; Published - 16 May 2018.Aim: Invasive species are of increasing global concern. Nevertheless, the mechanisms driving further distribution after the initial establishment of non-native species remain largely unresolved, especially in marine systems. Ocean currents can be a major driver governing range occupancy, but this has not been accounted for in most invasion ecology studies so far. We investigate how well initial establishment areas are interconnected to later occupancy regions to test for the potential role of ocean currents driving secondary spread dynamics in order to infer invasion corridors and the source–sink dynamics of a non-native holoplanktonic biological probe species on a continental scale. Location: Western Eurasia. Time period: 1980s–2016. Major taxa studied: ‘Comb jelly’ Mnemiopsis leidyi. Methods: Based on 12,400 geo-referenced occurrence data, we reconstruct the invasion history of M. leidyi in western Eurasia. We model ocean currents and calculate their stability to match the temporal and spatial spread dynamics with large-scale connectivity patterns via ocean currents. Additionally, genetic markers are used to test the predicted connectivity between subpopulations. Results: Ocean currents can explain secondary spread dynamics, matching observed range expansions and the timing of first occurrence of our holoplanktonic non-native biological probe species, leading to invasion corridors in western Eurasia. In northern Europe, regional extinctions after cold winters were followed by rapid recolonizations at a speed of up to 2,000 km per season. Source areas hosting year-round populations in highly interconnected regions can re-seed genotypes over large distances after local extinctions. Main conclusions: Although the release of ballast water from container ships may contribute to the dispersal of non-native species, our results highlight the importance of ocean currents driving secondary spread dynamics. Highly interconnected areas hosting invasive species are crucial for secondary spread dynamics on a continental scale. Invasion risk assessments should consider large-scale connectivity patterns and the potential source regions of non-native marine species.Danish Council for Independent Research; Grant/Award Number: DFF-1325-00102B; FP7 People: Marie-Curie Actions, Grant/Award Number: MOBILEX, DFF - 1325-00025; EU, BONUS, BMBF, Grant/ Award Number: 03F0682; Excellence Cluster “Future Ocean”, Grant/Award Number: CP153