Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory

The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and administrative staff in Malargue. We are very grateful to the following agencies and organizations for financial support: Argentina-Comision Nacional de Energia Atomica, Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Gobierno de la Provincia de Mendoza, Municipalidad de Malargue, NDM Holdings and Valle Las Lenas; in gratitude for their continuing cooperation over land access; Australia-the Australian Research Council; BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacao de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ), Sao Paulo Research Foundation (FAPESP) Grants No. 2019/10151-2, No. 2010/07359-6, and No. 1999/05404-3, Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC); Ministry of Education, Youth and Sports of the Czech RepublicGrants No. MSMT CR LTT18004, No. LM2015038, No. LM2018102, No. CZ.02.1.01/0.0/0.0/16_013/0001402, No. CZ.02.1.01/0.0/0.0/18_046/0016010, and No. CZ.02.1.01/0.0/0.0/17_049/0008422; France-Centre de Calcul IN2P3/CNRS, Centre National de la Recherche Scientifique (CNRS), Conseil Regional Ile-de-France, Departement Physique Nucl ' eaire et Corpusculaire (PNC-IN2P3/CNRS), Departement Sciences de l'Univers (SDU-INSU/CNRS), Institut Lagrange de Paris (ILP) Grant No. LABEX ANR-10-LABX-63 within the Investissements d'Avenir Programme Grant No. ANR11-IDEX-0004-02; Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministerium Baden-Wurttemberg, Helmholtz Alliance for Astroparticle Physics (HAP), Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Ministerium fur Wissenschaft, Forschung und Kunst des Landes Baden-Wurttemberg; Italy-Istituto Nazionale di Fisica Nucleare (INFN), Istituto Nazionale di Astrofisica (INAF), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), CETEMPS Center of Excellence, Ministero degli Affari Esteri (MAE); Mexico-Consejo Nacional de Ciencia y Tecnologia (CONACYT) Grant No. 167733, Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAM; The Netherlands-Ministry of Education, Culture and Science, Netherlands Organisation for Scientific Research (NWO), Dutch national e-infrastructure with the support of SURF Cooperative; Poland-Ministry of Science and Higher Education, Grant No. DIR/WK/2018/11, National Science Centre, Grants No. 2013/08/M/ST9/00322, No. 2016/23/B/ST9/01635, and No. HARMONIA 5-2013/10/M/ST9/00062, UMO-2016/22/M/ST9/00198; Portugal -Portuguese national funds and FEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE); Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI (PN19150201/16N/2019 and PN19060102), and project PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018 within PNCDI III; Slovenia-Slovenian Research Agency, Grants No. P1-0031, No. P1-0385, No. I00033, No. N1-0111; Spain-Ministerio de Economia, Industria y Competitividad (FPA2017-85114-P and FPA2017-85197-P), Xunta de Galicia (ED431C 2017/07), Junta de Andalucia (SOMM17/6104/UGR), Feder Funds, RENATA Red Nacional Tematica de Astroparticulas (FPA2015-68783-REDT), and Maria de Maeztu Unit of Excellence (MDM-2016-0692); U.S.Department of Energy, Awards No. DE-AC0207CH11359, No. DE-FR02-04ER41300, No. DE-FG0299ER41107, and No. DE-SC0011689, National Science Foundation, Grant No. 0450696, The Grainger Foundation, Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, and UNESCO.We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.Argentina-Comision Nacional de Energia AtomicaANPCyTConsejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)Gobierno de la Provincia de MendozaMunicipalidad de MalargueNDM HoldingsValle Las LenasAustralian Research CouncilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF)Financiadora de Inovacao e Pesquisa (Finep)Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2019/10151-2 2010/07359-6 1999/05404-3Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC)Ministry of Education, Youth & Sports - Czech Republic MSMT CR LTT18004 LM2015038 LM2018102 CZ.02.1.01/0.0/0.0/16_013/0001402 CZ.02.1.01/0.0/0.0/18_046/0016010 CZ.02.1.01/0.0/0.0/17_049/0008422France-Centre de Calcul IN2P3/CNRSCentre National de la Recherche Scientifique (CNRS)Region Ile-de-FranceCentre National de la Recherche Scientifique (CNRS)Departement Sciences de l'Univers (SDU-INSU/CNRS)French National Research Agency (ANR) LABEX ANR-10-LABX-63 ANR11-IDEX-0004-02Federal Ministry of Education & Research (BMBF)German Research Foundation (DFG)Finanzministerium Baden-WurttembergHelmholtz Alliance for Astroparticle Physics (HAP)Helmholtz AssociationMinisterium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMinisterium fur Wissenschaft, Forschung und Kunst des Landes Baden-WurttembergItaly-Istituto Nazionale di Fisica Nucleare (INFN)Istituto Nazionale Astrofisica (INAF)Ministry of Education, Universities and Research (MIUR)CETEMPS Center of ExcellenceMinistry of Foreign Affairs and International Cooperation (Italy)Consejo Nacional de Ciencia y Tecnologia (CONACyT) 167733Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAMNetherlands-Ministry of Education, Culture and ScienceNetherlands Organization for Scientific Research (NWO)Dutch national e-infrastructureSURF CooperativePoland-Ministry of Science and Higher Education DIR/WK/2018/11National Science Centre, Poland 2013/08/M/ST9/00322 2016/23/B/ST9/01635 HARMONIA 5-2013/10/M/ST9/00062 UMO-2016/22/M/ST9/00198Portugal -Portuguese national fundsFEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE)Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI PN19150201/16N/2019 PN19060102Romania-Romanian Ministry of Educatio n and Research, the Program Nucleu within PNCDI III PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018Slovenian Research Agency - Slovenia P1-0031 P1-0385 I00033 N1-0111Spain-Ministerio de Economia, Industria y Competitividad FPA2017-85114-P FPA2017-85197-PXunta de Galicia European Commission ED431C 2017/07Junta de Andalucia SOMM17/6104/UGREuropean CommissionRENATA Red Nacional Tematica de Astroparticulas FPA2015-68783-REDTMaria de Maeztu Unit of Excellence MDM-2016-0692United States Department of Energy (DOE) DE-AC0207CH11359 DE-FR02-04ER41300 DE-FG0299ER41107 DE-SC0011689National Science Foundation (NSF) 0450696Grainger FoundationMarie Curie-IRSES/EPLANETEuropean Particle Physics Latin American NetworkUNESC

Health- and Vision-Related Quality of Life in a Randomized Controlled Trial Comparing Methotrexate and Mycophenolate Mofetil for&nbsp;Uveitis

PurposeTo evaluate changes in health-related and vision-related quality of life (VRQoL) among patients with noninfectious uveitis who were treated with antimetabolites.DesignSecondary analysis of a randomized controlled trial.ParticipantsPatients with noninfectious uveitis from India, the United States, Australia, Saudi Arabia, and Mexico.MethodsFrom 2013 through 2017, 216 participants were randomized to receive 25 mg weekly oral methotrexate or 1.5 g twice daily oral mycophenolate mofetil. Median changes in quality of life (QoL) were measured using Wilcoxon signed-rank tests, and differences between treatment groups were measured using linear mixed models, adjusting for baseline QoL score, age, gender, and site. Among Indian patients, VRQoL scores from a general scale (the National Eye Institute Visual Function Questionnaire [NEI-VFQ]) and a culturally specific scale (the Indian Visual Function Questionnaire [IND-VFQ]) were compared using Pearson correlation tests.Main outcome measuresVision-related QoL (NEI-VFQ and IND-VFQ) and health-related QoL (HRQoL; physical component score [PCS] and mental component score [MCS] of the Medical Outcomes Study 36-Item Short Form Survey [SF-36v2]) were measured at baseline, the primary end point (6 months or treatment failure before 6 months), and the secondary end point (12 months or treatment failure between 6 and 12 months).ResultsAmong 193 participants who reached the primary end point, VRQoL increased from baseline by a median of 12.0 points (interquartile range [IQR], 1.0-26.1, NEI-VFQ scale), physical HRQoL increased by a median of 3.6 points (IQR, -1.4 to 14.9, PCS SF-36v2), and mental HRQoL increased by a median of 3.0 points (IQR, -3.7 to 11.9, MCS SF-36v2). These improvements in NEI-VFQ, SF-36v2 PCS, and SF-36v2 MCS scores all were significant (P &lt; 0.01). The linear mixed models showed that QoL did not differ between treatment groups for each QoL assessment (NEI-VFQ, IND-VFQ, PCS SF-36v2, and MCS SF-36v2; P &gt; 0.05 for all). The NEI-VFQ and IND-VFQ scores for Indian participants were correlated highly at baseline and the primary and secondary end points (correlation coefficients, 0.87, 0.80, and 0.90, respectively).ConclusionsAmong patients treated with methotrexate or mycophenolate mofetil for uveitis, VRQoL and HRQoL improved significantly over the course of 1 year and did not differ by treatment allocation. These findings suggest that antimetabolites could improve overall patient well-being and daily functioning

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Agencia Española del Medicamento; Consejería de Salud de Andalucía.Background & Aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). Conclusions: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. Lay summary: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided

A Search for Ultra-high-energy Neutrinos from TXS 0506+056 Using the Pierre Auger Observatory

International audienceResults of a search for ultra-high-energy neutrinos with the Pierre Auger Observatory from the direction of the blazar TXS 0506+056 are presented. They were obtained as part of the follow-up that stemmed from the detection of high-energy neutrinos and gamma rays with IceCube, Fermi-LAT, MAGIC, and other detectors of electromagnetic radiation in several bands. The Pierre Auger Observatory is sensitive to neutrinos in the energy range from 100 PeV to 100 EeV and in the zenith-angle range from θ = 60° to θ = 95°, where the zenith angle is measured from the vertical direction. No neutrinos from the direction of TXS 0506+056 have been found. The results were analyzed in three periods: one of 6 months around the detection of IceCube-170922 A, coinciding with a flare period of TXS 0506+056, a second one of 110 days during which the IceCube collaboration found an excess of 13 neutrinos from a direction compatible with TXS 0506+056, and a third one from 2004 January 1 up to 2018 August 31, over which the Pierre Auger Observatory has been taking data. The sensitivity of the Observatory is addressed for different spectral indices by considering the fluxes that would induce a single expected event during the observation period. For indices compatible with those measured by the IceCube collaboration the expected number of neutrinos at the Observatory is well below one. Spectral indices as hard as 1.5 would have to apply in this energy range to expect a single event to have been detected

Design, upgrade and characterization of the silicon photomultiplier front-end for the AMIGA detector at the Pierre Auger Observatory

International audienceAMIGA (Auger Muons and Infill for the Ground Array) is an upgrade of the Pierre Auger Observatory to complement the study of ultra-high-energy cosmic rays (UHECR) by measuring the muon content of extensive air showers (EAS). It consists of an array of 61 water Cherenkov detectors on a denser spacing in combination with underground scintillation detectors used for muon density measurement. Each detector is composed of three scintillation modules, with 10 m2 detection area per module, buried at 2.3 m depth, resulting in a total detection area of 30 m2. Silicon photomultiplier sensors (SiPM) measure the amount of scintillation light generated by charged particles traversing the modules. In this paper, the design of the front-end electronics to process the signals of those SiPMs and test results from the laboratory and from the Pierre Auger Observatory are described. Compared to our previous prototype, the new electronics shows a higher performance, higher efficiency and lower power consumption, and it has a new acquisition system with increased dynamic range that allows measurements closer to the shower core. The new acquisition system is based on the measurement of the total charge signal that the muonic component of the cosmic ray shower generates in the detector