75 research outputs found

    The trans-ancestral genomic architecture of glycemic traits

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    Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    La simulation de Monte-Carlo et l'industrie pétroliÚre (développement de potentiel pour les composés organomercurés)

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    L'Ă©tude des propriĂ©tĂ©s d'Ă©quilibre de phases de mĂ©langes molĂ©culaires tels que les hydrocarbures par simulation molĂ©culaire est intĂ©ressante Ă  plus d'un titre. Elle permet notamment de modĂ©liser des fluides d'intĂ©rĂȘts pĂ©trolier et gazier et de fournir des donnĂ©es Ă  l'industrie dans un domaine de tempĂ©rature et de pression difficilement accessible par l'expĂ©rience ou lorsqu'il s'agit de composĂ©s toxiques oĂč les expĂ©riences sont difficiles Ă  rĂ©aliser. La dĂ©termination et l'utilisation de modĂšles numĂ©riques rĂ©alistes et prĂ©dictifs pour des systĂšmes rĂ©els restent aujourd'hui des problĂšmes encore non rĂ©solus. Outre les questions de potentiel d'interaction intermolĂ©culaire, l'obtention d'une bonne statistique sur ces systĂšmes comprenant de nombreux degrĂ©s de libertĂ©s est trĂšs dĂ©licate. Ce travail de recherche s'est concentrĂ© dans trois directions. La premiĂšre partie concerne la prĂ©diction de propriĂ©tĂ©s d'Ă©quilibre de phase, par simulation molĂ©culaire de Monte Carlo, de composĂ©s particuliĂšrement toxiques prĂ©sents Ă  l'Ă©tat de traces dans certains gaz naturels: les composĂ©s organomercurĂ©s. Sa mise en Ɠuvre passe par le dĂ©veloppement d'un potentiel intermolĂ©culaire adaptĂ© Ă  ces composĂ©s pour ensuite Ă©tablir des diagrammes d'Ă©quilibre liquide-vapeur comme celui du mĂ©lange dimĂ©thylmercure-pentane. La deuxiĂšme partie du travail consiste Ă  calculer les dĂ©rivĂ©es secondes du potentiel thermodynamique et plus particuliĂšrement le coefficient de Joule-Thomson. Pour obtenir ces propriĂ©tĂ©s thermodynamiques dĂ©rivĂ©es, une mĂ©thode de calcul direct de ces grandeurs Ă  partir de fluctuations statistiques de donnĂ©es microscopiques a Ă©tĂ© mise au point. AppliquĂ©e aux corps purs puis Ă  des gaz naturels, cette mĂ©thode montre de bons rĂ©sultats. Enfin, la troisiĂšme partie de ce travail concerne le calcul prĂ©liminaire de certaines grandeurs thermodynamiques, le but Ă©tant de reproduire qualitativement et quantitativement leur divergence au voisinage du point critique.Prediction by molecular simulations is planned to be a serious complement to experimental measurements. Indeed, the study of equilibrium properties of molecular mixtures, such as hydrocarbons, by molecular simulation enables to model fluids of petroleum and gas relevance and to give data to the industry especially when the desired range of temperature and pressure is not easy to access by experimental processes and when toxic compounds are studied. The determination and the use of realistic and predictive numerical models for real systems remain today an unsolved problem. Besides the question of intermolecular interaction potential, the achieving of a good statistic on these systems containing a lot of degrees of freedom is very delicate. This research work is concentrated on three directions. The first part is devoted to the prediction of phase equilibrium properties, by Monte Carlo simulation, of toxic compounds that are present in some natural gases : the organomercury compounds. Its implementation go through the development of a realistic intermolecular force field in order to determine liquid vapour diagrams for mixtures. The second part consists in calculating second order derivatives of the thermodynamic potential and particularly the Joule-Thomson coefficient. To obtain these thermodynamic derivatives properties, a method based on statistical fluctuations of microscopic quantities have been developed. This method was applied to pure molecular fluids and natural gas and leads to good agreement with available experimental data. Finally, the last part of the work is devoted to the prediction of these properties near the critical point in order to reveal their critical divergence qualitatively and quantitatively.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

    Jeux institutionnels

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    Darkode: Recruitment Patterns and Transactional Features of “the Most Dangerous Cybercrime Forum in the World”

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    This article explores the social and market dynamics of Darkode, an invitation-only cybercrime forum that was dismantled by the FBI in July 2015 and was described by a U.S. Attorney as “the most sophisticated English-speaking forum for criminal computer hackers in the world.” Based on a leaked database of 4,788 discussion threads, we examine the selection process through which 344 potential new members introduced themselves to the community in order to be accepted into this exclusive group. Using a qualitative approach, we attempt to assess whether this rigorous procedure significantly enhanced the trust between traders, and therefore, contributed to the efficiency of this online illicit marketplace. We find that trust remained elusive and interactions were often fraught with suspicion and accusations. Even hackers who were considered successful faced significant challenges in trying to profit from the sale of malicious software and stolen data.</jats:p

    New Molecular Simulation Method To Determine Both Aluminum and Cation Location in Cationic Zeolites

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    The knowledge of aluminum distribution in zeolites is a difficult task due to limitations in experimental measurements. In the present paper, we propose a new methodology to simultaneously determined aluminum atoms distribution as well as the extraframework cation location in a given experimental structure of the framework and thus allows comparison of different synthesis routes. Aluminum mean distribution is obtained over a great number of configurations that are generated during the course of the simulations at finite temperature. The obtained aluminum atom repartition is in agreement with the experimental and model data available. The consequences of aluminum distribution on solid properties such as extraframework Na<sup>+</sup> cation location have been analyzed and successfully compared with the available information for different zeolite topologies. The proposed methodology can be used as a powerful complementary tool for aluminum location on X-Ray or neutron experimental structure determinations

    The Behavior of Flexible MIL-53(Al) upon CH4 and CO2 Adsorption

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    International audienceThe use of the osmotic thermodynamic model, combined with a series of methane and carbon dioxide gas adsorption experiments at various temperatures, has allowed shedding some new light on the fascinating phase behavior of flexible MIL-53(Al) metal−organic frameworks. A generic temperature-loading phase diagram has been derived; it is shown that the breathing effect in MIL-53 is a very general phenomenon, which should be observed in a limited temperature range regardless of the guest molecule. In addition, the previously proposed stress model for the structural transitions of MIL-53 is shown to be transferable from xenon to methane adsorption. The stress model also provides a theoretical framework for understanding the existence of lp/np phase mixtures at pressures close to the breathing transition pressure, without having to invoke an inhomogeneous distribution of the adsorbate in the porous sample
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