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144 results on '"Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)"'

1. Additive effect of calcium depletion and low resource quality on Gammarus fossarum (Crustacea, Amphipoda) life history traits

Author

Alexandre Bec, Arnaud Chaumot, Bénédicte Sohm, Justine Flayac, Marc Rollin, Vincent Felten, Olivier Geffard, Romain Coulaud, Michael Danger, Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Stress Environnementaux et BIOsurveillance des milieux aquatiques (SEBIO), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Reims Champagne-Ardenne (URCA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Biocenter, Div. of Developmental Immunology, Biocenter, Innsbruck Medical University [Austria] (IMU)-Innsbruck Medical University [Austria] (IMU), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Milieux aquatiques, écologie et pollutions (UR MALY), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
0106 biological sciences, Amphipoda, MULTIPLE STRESSORS, Health, Toxicology and Mutagenesis, Cuticle, [SDE.MCG]Environmental Sciences/Global Changes, Heterotroph, chemistry.chemical_element, 010501 environmental sciences, Biology, MRNA EXPRESSION, 01 natural sciences, Animal science, Rivers, Botany, Environmental Chemistry, Ecotoxicology, Animals, Life History Traits, Unsaturated fatty acid, ComputingMilieux_MISCELLANEOUS, Ecosystem, 0105 earth and related environmental sciences, 2. Zero hunger, 010604 marine biology & hydrobiology, Phosphorus, Detritivore, General Medicine, 15. Life on land, Plant litter, HIGHLY UNSATURATED ACIDS, biology.organism_classification, Pollution, [SDE.ES]Environmental Sciences/Environmental and Society, Plant Leaves, PHOSPHORUS, REPRODUCTION, chemistry, Calcium, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, CALCIUM DEPLETION
Abstract

Gammarus fossarum is an often-abundant crustacean detritivore that contributes importantly to leaf litter breakdown in oligotrophic, mainly heterotrophic, headwater streams. This species requires large amounts of Ca to moult, thus allowing growth and reproduction. Because resource quality is tightly coupled to the organism’s growth and physiological status, we hypothesised that low Ca concentration [Ca] and low food resource quality (low phosphorus [P] and/or reduced highly unsaturated fatty acid [HUFA] contents) would interactively impair molecular responses (gene expression) and reproduction of G. fossarum. To investigate the effects of food resources quality, we experimentally manipulated the P content of sycamore leaves and also used diatoms because they contain high amounts of HUFAs. Three resource quality treatments were tested: low quality (LQ, unmanipulated leaves: low P content), high quality 1 (HQ1; P-manipulated leaves: high P content), and high quality 2 (unmanipulated leaves supplemented with a pellet containing diatoms: high P and HUFA content). Naturally, demineralised stream water was supplemented with CaSO4 to obtain three Ca concentrations (2, 3.5, and 10.5 mg Ca L−1). For 21 days, pairs of G. fossarum were individually exposed to one of the nine treatments (3 [Ca] × 3 resource qualities). At the individual level, strong and significant delays in moult stage were observed in gammarids exposed to lower [Ca] and to lower resource quality, with additive effects lengthening the duration of the reproductive cycle. Effects at the molecular level were investigated by measuring expression of 12 genes involved in energy production, translation, or Ca or P homeostasis. Expression of ATP synthase beta (higher in HQ2), calcified cuticle protein (higher in HQ1 and HQ2), and tropomyosin (higher in HQ2 compared to HQ1) was significantly affected by resource quality, and significant additive effects on Ca transporting ATPase expression were induced by [Ca] and resource quality (higher for low [Ca] and higher resource quality). These results highlight the potential drastic deleterious effects of water [Ca] depletion on G. fossarum physiology, populations, and ecosystem functioning, especially in oligotrophic environments.

Published
2016

2. Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome

Author

Amberger, Albert, Pertoll, Johanna, Traunfellner, Pia, Kapferer-Seebacher, Ines, Stoiber, Heribert, Klimaschewski, Lars, Thielens, Nicole, Gaboriaud, Christine, Zschocke, Johannes, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Groupe Complément, anticorps et maladies infectieuses / Complement, antibodies and infectious disease Group (IBS-CAID), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and ANR-16-CE91-0004,C1rsinEDS,Implications fonctionnelles des altérations des protéases C1r et C1s identifiées chez des patients atteints du syndrome Ehlers-Danlos de type parodontal.(2016)

Subjects
MESH: Complement C1s, complement activation, MESH: Mutation, Missense, collagen I, MESH: Humans, MESH: Ehlers-Danlos Syndrome, C1r protease, [SDV]Life Sciences [q-bio], Immunology, MESH: Collagen Type I, Immunology and Allergy, Ehlers-Danlos Syndrome, periodontites, MESH: Longitudinal Studies
Abstract

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, lack of attached gingiva and thin and fragile gums leading to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. Previously we showed that pEDS pathogenic variants trigger intracellular activation of C1r and/or C1s, leading to extracellular presence of activated C1s. However, the molecular link relating activated C1r and C1s proteases to the dysregulated connective tissue homeostasis in pEDS is unknown. Using cell- and molecular-biological assays, we identified activated C1s (aC1s) as an enzyme which degrades collagen I in cell culture and in in vitro assays. Matrix collagen turnover in cell culture was assessed using labelled hybridizing peptides, which revealed fast and comprehensive collagen protein remodeling in patient fibroblasts. Furthermore, collagen I was completely degraded by aC1s when assays were performed at 40°C, indicating that even moderate elevated temperature has a tremendous impact on collagen I integrity. This high turnover is expected to interfere with the formation of a stable ECM and result in tissues with loose compaction a hallmark of the EDS phenotype. Our results indicate that pathogenesis in pEDS is not solely mediated by activation of the complement cascade but by inadequate C1s-mediated degradation of matrix proteins, confirming pEDS as a primary connective tissue disorder.

Published
2023

3. Consensus Statement on the definition and classification of metabolic hyperferritinaemia

Author

Luca Valenti, Elena Corradini, Leon A. Adams, Elmar Aigner, Saleh Alqahtani, Marco Arrese, Edouard Bardou-Jacquet, Elisabetta Bugianesi, Jose-Manuel Fernandez-Real, Domenico Girelli, Hannes Hagström, Benjamin Henninger, Kris Kowdley, Guido Ligabue, Donald McClain, Fabrice Lainé, Koji Miyanishi, Martina U. Muckenthaler, Alessia Pagani, Patrizia Pedrotti, Antonello Pietrangelo, Daniele Prati, John D. Ryan, Laura Silvestri, C. Wendy Spearman, Per Stål, Emmanuel A. Tsochatzis, Francesca Vinchi, Ming-Hua Zheng, Heinz Zoller, Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), The University of Western Australia (UWA), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Johns Hopkins University (JHU), Pontificia Universidad Católica de Chile (UC), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Torino = University of Turin (UNITO), Universitat de Girona [Girona], Universitat de Girona (UdG), Università degli studi di Verona = University of Verona (UNIVR), Karolinska University Hospital [Stockholm], Leopold Franzens Universität Innsbruck - University of Innsbruck, Washington State University (WSU), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Sapporo Medical University School of Medicine, Sapporo Medical University, Heidelberg University, IRCCS Ospedale San Raffaele [Milan, Italy], ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Royal College of Surgeons in Ireland (RCSI), University of Cape Town, University College of London [London] (UCL), Weill Cornell Medicine [New York], The First Affiliated Hospital of Wenzhou Medical University [Wenzhou, China], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Ministero della Salute, Ricerca Finalizzata RF-2016-02364358, RC Rete cardiologica ‘CV PREVITAL’, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico ‘Liver BIBLE’ (PR-0391), Innovative Medicines Initiative 2 joint undertaking of European Union’s Horizon 2020 research and innovation programme and EFPIA European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS, H2020 under grant agreement ‘101016726’, the European Union, programme ‘Photonics’ under grant agreement ‘101016726’ for L.V. Fondo Nacional de Ciencia y Tecnología de Chile (FONDECYT #1191145 to M.A.) and from the Agencia Nacional de Investigación y Desarrollo, ANID through ANID ACE 210009 grant for M.A. NIH (P30DK124723), and Veterans Administration (2I01 BX001140) for D.M. SFB1036, SFB1118 and DFG (FerrOs — FOR5146, SPP2306) as well as Marsilius Kolleg for M.U.M. National Natural Science Foundation of China (82070588), High Level Creative Talents from Department of Public Health in Zhejiang Province (S2032102600032) for M.-H.Z. Swedish Cancer Society (170690) and Stockholm County Council (K2017-4579) for P.S., Jonchère, Laurent, Weill Cornell Medicine [Cornell University], and Cornell University [New York]

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, iron, Endocrinology, iron, hyperferritinemia, metabolic syndrome, Endocrinology, Diabetes and Metabolism, hyperferritinemia, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, metabolic syndrome
Abstract

International audience; Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Published
2023

4. An overview of using fungal DNA for the diagnosis of invasive mycoses

Author

P. Lewis White, Alexandre Alanio, Lottie Brown, Mario Cruciani, Ferry Hagen, Rebecca Gorton, Michaela Lackner, Laurence Millon, C. Oliver Morton, Riina Rautemaa-Richardson, Rosemary A. Barnes, J Peter Donnelly, Juergen Loffler, Public Health Wales [Cardiff, Royaume uni], Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Manchester University NHS Foundation Trust (MFT), Fungal PCR Initiative (FPCRI), University Medical Center [Utrecht], National Health Laboratory Services, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Western Sydney University, Cardiff University, and University Hospital Wuerzburg / Universitäts­klinikum Würzburg

Subjects
MESH: Fungi, mucorales PCR, MESH: Molecular Diagnostic Techniques, Polymerase Chain Reaction, Pathology and Forensic Medicine, Genetics, Humans, candida PCR, Fungi/genetics, DNA, Fungal, Molecular Biology, aspergillus PCR, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Fungal/genetics, PCP PCR, Fungi, MESH: Polymerase Chain Reaction, DNA, fungal PCR, MESH: DNA, Fungal, Molecular Diagnostic Techniques, Molecular Medicine, Invasive fungal disease, Invasive Fungal Infections/diagnosis, Invasive Fungal Infections, MESH: Invasive Fungal Infections
Abstract

Introduction: Fungal PCR has undergone considerable standardization and together with the availability of commercial assays, external quality assessment schemes and extensive performance validation data, is ready for widespread use for the screening and diagnosis of invasive fungal disease (IFD).Areas Covered: Drawing on the experience and knowledge of the leads of the various working parties of the Fungal PCR initiative, this review will address general considerations concerning the use of molecular tests for the diagnosis of IFD, before focussing specifically on the technical and clinical aspects of molecular testing for the main causes of IFD and recent technological developments.Expert Opinion: For infections caused by Aspergillus, Candida and Pneumocystis jirovecii, PCR testing is recommended, combination with serological testing will likely enhance the diagnosis of these diseases. For other IFD (e.g. Mucormycosis) molecular diagnostics, represent the only non-classical mycological approach towards diagnoses and continued performance validation and standardization has improved confidence in such testing. The emergence of antifungal resistance can be diagnosed, in part, through molecular testing. Next-generation sequencing has the potential to significantly improve our understanding of fungal phylogeny, epidemiology, pathogenesis, mycobiome/microbiome and interactions with the host, while identifying novel and existing mechanisms of antifungal resistance and novel diagnostic/therapeutic targets.

Published
2022

5. Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies : A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

Author

Mariann Gyöngyösi, Pilar Alcaide, Folkert W Asselbergs, Bianca J J M Brundel, Giovanni G Camici, Paula da Costa Martins, Péter Ferdinandy, Marianna Fontana, Henrique Girao, Massimiliano Gnecchi, Can Gollmann-Tepeköylü, Petra Kleinbongard, Thomas Krieg, Rosalinda Madonna, Melanie Paillard, Antonis Pantazis, Cinzia Perrino, Maurizio Pesce, Gabriele G Schiattarella, Joost P G Sluijter, Sabine Steffens, Carsten Tschöpe, Sophie Van Linthout, Sean M Davidson, Martins, Paula da Costa [0000-0002-0695-1187], Fontana, Marianna [0000-0002-9233-9831], Girao, Henrique [0000-0002-5786-8447], Gnecchi, Massimiliano [0000-0001-7435-4328], Kleinbongard, Petra [0000-0003-3576-3772], Krieg, Thomas [0000-0002-5192-580X], Perrino, Cinzia [0000-0002-2274-0048], Pesce, Maurizio [0000-0002-3097-8961], Sluijter, Joost PG [0000-0003-2088-9102], Steffens, Sabine [0000-0002-6892-9751], Van Linthout, Sophie [0000-0002-7581-7870], Apollo - University of Cambridge Repository, Medizinische Universität Wien = Medical University of Vienna, Tufts University School of Medicine [Boston], University Medical Center [Utrecht], Utrecht University [Utrecht], University College of London [London] (UCL), Amsterdam UMC - Amsterdam University Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Maastricht University [Maastricht], Semmelweis University [Budapest], Pharmahungary Group [Szeged, Hungary] (PG), University of Coimbra [Portugal] (UC), Coimbra Institute for Clinical and Biomedical Research [Coimbra, Portugal] (iCBR - Faculty of Medicine), Università degli Studi di Pavia = University of Pavia (UNIPV), Fondazione IRCCS Policlinico San Matteo [Pavia], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Addenbrooke's Hospital, Cambridge University NHS Trust, University of Pisa - Università di Pisa, Jefferson (Philadelphia University + Thomas Jefferson University), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, University of Naples Federico II = Università degli studi di Napoli Federico II, Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Utrecht Brain Center [UMC], Ludwig-Maximilians-Universität München (LMU), Charité Campus Virchow-Klinikum (CVK), The Hatter Cardiovascular Institute (THCI), CarMeN, laboratoire, Gyöngyösi, Mariann, Alcaide, Pilar, Asselbergs, Folkert W, Brundel, Bianca J J M, Camici, Giovanni G, da Costa Martins, Paula, Ferdinandy, Péter, Fontana, Marianna, Girao, Henrique, Gnecchi, Massimiliano, Gollmann-Tepeköylü, Can, Kleinbongard, Petra, Krieg, Thoma, Madonna, Rosalinda, Paillard, Melanie, Pantazis, Antoni, Perrino, Cinzia, Pesce, Maurizio, Schiattarella, Gabriele G, Sluijter, Joost P G, Steffens, Sabine, Tschöpe, Carsten, Van Linthout, Sophie, and Davidson, Sean M

Subjects
Long COVID, Heart Diseases, Physiology, SARS-CoV-2, [SDV]Life Sciences [q-bio], Myocardium, Medizin, COVID-19, Heart, virus, Post COVID, Cardiovascular, [SDV] Life Sciences [q-bio], Post-Acute COVID-19 Syndrome, COVID-19 Testing, Cardiovascular and Metabolic Diseases, Physiology (medical), Humans, Cardiology and Cardiovascular Medicine, Cardiac
Abstract

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

Published
2023

6. Consensus guidelines for the definition of time-to-event end points in image-guided tumor ablation

Author

Puijk, Robbert, Ahmed, Muneeb, Adam, Andreas, Arai, Yasuaki, Arellano, Ronald, de Baère, Thierry, Bale, Reto, Bellera, Carine, Binkert, Christoph, Brace, Christopher, Breen, David, Brountzos, Elias, Callstrom, Matthew, Carrafiello, Gianpaolo, Chapiro, Julius, de Cobelli, Francesco, Coupé, Veerle, Crocetti, Laura, Denys, Alban, Dupuy, Damian, Erinjeri, Joseph, Filippiadis, Dimitris, Gangi, Afshin, Gervais, Debra, Gillams, Alice, Greene, Tissy, Guiu, Boris, Helmberger, Thomas, Iezzi, Roberto, Kang, Tae Wook, Kelekis, Alexis, Kim, Hyun, Kröncke, Thomas, Kwan, Sharon, Lee, Min Woo, Lee, Fred, Lee, Edward, Liang, Ping, Lissenberg-Witte, Birgit, Lu, David, Madoff, David, Mauri, Giovanni, Meloni, Maria Franca, Morgan, Robert, Nadolski, Gregory, Narayanan, Govindarajan, Newton, Isabel, Nikolic, Boris, Orsi, Franco, Pereira, Philippe, Pua, Uei, Rhim, Hyunchul, Ricke, Jens, Rilling, William, Salem, Riad, Scheffer, Hester, Sofocleous, Constantinos, Solbiati, Luigi, Solomon, Stephen, Soulen, Michael, Sze, Daniel, Uberoi, Raman, Vogl, Thomas, Wang, David, Wood, Bradford, Goldberg, S Nahum, Meijerink, Martijn, Goldberg, S. Nahum, Amsterdam UMC - Amsterdam University Medical Center, Harvard Medical School [Boston] (HMS), Guy's and St Thomas' Hospital [London], National Cancer Center Hospital (NCCJ), Department of radiology (Massachusetts General Hospital), Massachusetts General Hospital [Boston], Institut Gustave Roussy (IGR), Imagerie thérapeutique (radiologie interventionnelle), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut Bergonié [Bordeaux], UNICANCER, Kantonsspital Winterthur (KSW), University of Wisconsin School of Medicine and Public Health, University Hospital Southampton NHS Foundation Trust, National and Kapodistrian University of Athens (NKUA), Mayo Clinic [Rochester], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Yale University [New Haven], IRCCS Ospedale San Raffaele [Milan, Italy], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Pisa - Università di Pisa, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Warren Alpert Medical School of Brown University, Memorial Sloan Kettering Cancer Center (MSKCC), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, The London Clinic cancer, Society of Interventional Oncology (SIO), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), and Kiel University

Subjects
Ablation Techniques, medicine.medical_specialty, Consensus, [SDV]Life Sciences [q-bio], MESH: Societies, Medical, MEDLINE, Outcome (game theory), Session (web analytics), Quality of life (healthcare), Humans, Neoplasms, Reproducibility of Results, Societies, Medical, Medical, medicine, MESH: Neoplasms, Radiology, Nuclear Medicine and imaging, Medical physics, ddc:610, MESH: Consensus, License, MESH: Humans, Health economics, business.industry, MESH: Ablation Techniques, Opinion leadership, MESH: Reproducibility of Results, Clinical trial, business, Societies
Abstract

International audience; There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Published
2021

7. Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism

Author

Florent Arbogast, Raquel Sal-Carro, Wacym Boufenghour, Quentin Frenger, Delphine Bouis, Louise Filippi De La Palavesa, Jean-Daniel Fauny, Olivier Griso, Hélène Puccio, Rebecca Fima, Thierry Huby, Emmanuel L. Gautier, Anne Molitor, Raphaël Carapito, Seiamak Bahram, Nikolaus Romani, Björn E. Clausen, Benjamin Voisin, Christopher G. Mueller, Frédéric Gros, Vincent Flacher, Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Helmholtz-Institut Mainz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), and FLACHER, Vincent

Subjects
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity
Abstract

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs), a proliferating skin DC subset with extended lifespan. Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Metabolically impaired LCs upregulated proinflammatory transcripts, in line with exacerbated inflammasome-dependent priming. Moreover, they decreased expression of neuronal interaction receptors, in line with a reduction of epidermal nerves upon LC depletion. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

Published
2022

8. Crystal structures of free and ligand‐bound forms of the TetR/ AcrR‐like</scp> regulator SCO3201 from Streptomyces coelicolor suggest a novel allosteric mechanism

Author

Werten, Sebastiaan, Waack, Paul, Palm, Gottfried, Hinrichs, Winfried, Virolle, Marie-Jöelle, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Universität Greifswald - University of Greifswald, Department of Molecular Structural Biology [Greifswald, Germany] (Institute for Biochemistry), Universität Greifswald - University of Greifswald-Institute for Biochemistry [Greifswald, Germany], Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
polyamine, [SDV]Life Sciences [q-bio], SAXS, gene regulation, transcription, X-ray crystallography
Abstract

International audience; TetR/AcrR-like transcription regulators enable bacteria to sense a wide variety of chemical compounds and to dynamically adapt the expression levels of specific genes in response to changing growth conditions. Here, we describe the structural characterisation of SCO3201, an atypical TetR/ AcrR family member from Streptomyces coelicolor that strongly represses antibiotic production and morphological development under conditions of overexpression. We present crystal structures of SCO3201 in its ligand-free state as well as in complex with an unknown inducer, potentially a polyamine. In the ligand-free state, the DNA-binding domains of the SCO3201 dimer are held together in an unusually compact conformation and, as a result, the regulator cannot span the distance between the two half-sites of its operator. Interaction with the ligand coincides with a major structural rearrangement and partial conversion of the so-called hinge helix (a4) to a 3 10-conformation, markedly increasing the distance between the DNAbinding domains. In sharp contrast to what was observed for other TetR/ AcrR-like regulators, the increased interdomain distance might facilitate rather than abrogate interaction of the dimer with the operator. Such a 'reverse' induction mechanism could expand the regulatory repertoire of the TetR/AcrR family and may explain the dramatic impact of SCO3201 overexpression on the ability of S. coelicolor to generate antibiotics and sporulate.

Published
2022

9. COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart

Author

Can Gollmann-Tepeköylü, Sabine Steffens, Ivan Tancevski, Sean M. Davidson, Maurizio Pesce, Joost P.G. Sluijter, Piergiuseppe Agostoni, Raffaele De Caterina, Sandrine Lecour, Bianca J.J.M. Brundel, Jean-Sébastien Hulot, Cinzia Perrino, Péter Ferdinandy, Hans-Erik Bøtker, Henrique Girão, Mariann Gyöngyösi, Rainer Schulz, Rosalinda Madonna, Carsten Tschöpe, Sophie Van Linthout, Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Università degli Studi di Milano = University of Milan (UNIMI), Aarhus University Hospital, Amsterdam UMC - Amsterdam University Medical Center, University College of London [London] (UCL), University of Pisa - Università di Pisa, Semmelweis University [Budapest], University of Coimbra [Portugal] (UC), Medizinische Universität Wien = Medical University of Vienna, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CArdiovasculaire Rénal Transplantation nEurovasculaire [Paris] (DMU CARTE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Cape Town, University of Naples Federico II = Università degli studi di Napoli Federico II, Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Utrecht University [Utrecht], Ludwig-Maximilians-Universität München (LMU), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Charité Campus Virchow-Klinikum (CVK), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), The University of Texas Medical School at Houston, and HULOT, Jean-Sébastien

Subjects
0301 basic medicine, Heart Diseases, Physiology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Inflammation, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Vascular occlusion, 03 medical and health sciences, 0302 clinical medicine, Viral entry, Physiology (medical), medicine, Coagulopathy, Animals, Humans, Myocytes, Cardiac, Blood Coagulation, Cause of death, Myocytes, Ventricular Remodeling, SARS-CoV-2, business.industry, COVID-19, Heart, medicine.disease, Omics, Disease modelling, Infection, Myocardial injury, Biomarkers, Fibrosis, Host-Pathogen Interactions, Inflammation Mediators, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cytokine, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Cardiac
Abstract

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.

Published
2021

10. Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease

Author

Jacques Montplaisir, Paul C. Timm, Erik K. St. Louis, Evi Holzknecht, Petr Dusek, Klaus Seppi, Evžen Růžička, Luke N. Teigen, Tereza Tykalová, Sara Marelli, Ronald B. Postuma, Andrea Galbiati, Karel Sonka, Michal Novotný, Amélie Pelletier, Mahboubeh Habibi, Yves Dauvilliers, Annette Janzen, Wolfgang H. Oertel, Jan Rusz, Luigi Ferini-Strambi, Jan Hlavnička, Birgit Högl, Ambra Stefani, Jean Gagnon, Elisa Evangelista, Anna Laura Rassu, Rusz, Jan, Hlavnička, Jan, Novotný, Michal, Tykalová, Tereza, Pelletier, Amelie, Montplaisir, Jacque, Gagnon, Jean-Francoi, Dušek, Petr, Galbiati, Andrea, Marelli, Sara, Timm, Paul C, Teigen, Luke N, Janzen, Annette, Habibi, Mahboubeh, Stefani, Ambra, Holzknecht, Evi, Seppi, Klau, Evangelista, Elisa, Rassu, Anna Laura, Dauvilliers, Yve, Högl, Birgit, Oertel, Wolfgang, St Louis, Erik K, Ferini-Strambi, Luigi, Růžička, Evžen, Postuma, Ronald B, Šonka, Karel, Czech Technical University in Prague (CTU), First Faculty of Medicine Charles University [Prague], Hôpital du Sacré-Coeur de Montréal, McGill University Health Center [Montreal] (MUHC), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Mayo Clinic [Rochester], Philipps Universität Marburg = Philipps University of Marburg, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Retiveau, Nolwenn

Subjects
0301 basic medicine, Male, Disease, REM Sleep Behavior Disorder, Audiology, Behavior disorder, Dysarthria, MESH: Aged, 80 and over, 0302 clinical medicine, Research Articles, MESH: Aged, Aged, 80 and over, MESH: Middle Aged, MESH: Speech, Parkinsonism, Parkinson Disease, Middle Aged, Europe, Neurology, Disease Progression, Biomarker (medicine), MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Research Article, medicine.medical_specialty, Rapid eye movement sleep, Prodromal Symptoms, REM sleep behavior disorder, 03 medical and health sciences, medicine, Humans, Speech, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Prodromal Symptoms, Aged, MESH: Humans, business.industry, Disease progression, medicine.disease, MESH: Male, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, MESH: Biomarkers, MESH: Europe, Neurology (clinical), business, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery, Biomarkers
Abstract

International audience; Objective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Published
2021

11. Changes in mitochondrial redox state, membrane potential and calcium precede mitochondrial dysfunction in doxorubicin-induced cell death

Author

Albert Amberger, Raimund Margreiter, Andrey V. Kuznetsov, Michael Grimm, Valdur Saks, Cardiac Surgery Research Laboratory, Innsbruck Medical University [Austria] (IMU)-Department of Heart Surgery, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University [Austria] (IMU), Section of Human Genetics, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hamant, Sarah, Department of Heart Surgery-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
Mitochondrial ROS, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, MESH: Oxidation-Reduction, Redox state, Time Factors, MESH: HT29 Cells, Apoptosis, MESH: Cell Cycle, Mitochondrion, Mitochondrial apoptosis-induced channel, MESH: Dose-Response Relationship, Drug, Reactive oxygen species, ROS, 0302 clinical medicine, Adenosine Triphosphate, MESH: Membrane Potential, Mitochondrial, MESH: Uncoupling Agents, MESH: Adenosine Triphosphate, MESH: Microscopy, Confocal, Membrane Potential, Mitochondrial, 0303 health sciences, MESH: Electron Transport Complex I, Antibiotics, Antineoplastic, Microscopy, Confocal, Cell Cycle, MESH: Reactive Oxygen Species, Confocal imaging, Cell cycle, 3. Good health, Cell biology, Mitochondria, Biochemistry, MESH: Cell Survival, 030220 oncology & carcinogenesis, MESH: Calcium, ATP–ADP translocase, MESH: Citrate (si)-Synthase, HT29 Cells, Oxidation-Reduction, Programmed cell death, MESH: Cell Line, Tumor, Cell Survival, MESH: Mitochondria, Cell Respiration, Citrate (si)-Synthase, Biology, 03 medical and health sciences, MESH: Doxorubicin, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Antibiotics, Antineoplastic, Molecular Biology, 030304 developmental biology, Electron Transport Complex I, MESH: Humans, Dose-Response Relationship, Drug, Uncoupling Agents, MESH: Apoptosis, MESH: Time Factors, Cell Biology, MESH: Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Mitochondrial permeability transition pore, Doxorubicin, Calcium, MESH: Cell Respiration, Mitochondrial function, Reactive Oxygen Species
Abstract

International audience; Mitochondria play central roles in cell life as a source of energy and in cell death by inducing apoptosis. Many important functions of mitochondria change in cancer, and these organelles can be a target of chemotherapy. The widely used anticancer drug doxorubicin (DOX) causes cell death, inhibition of cell cycle/proliferation and mitochondrial impairment. However, the mechanism of such impairment is not completely understood. In our study we used confocal and two-photon fluorescence imaging together with enzymatic and respirometric analysis to study short- and long-term effects of doxorubicin on mitochondria in various human carcinoma cells. We show that short-term (

Published
2011

12. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Author

Bastard, Paul, Vazquez, Sara, Liu, Jamin, Laurie, Matthew, Wang, Chung, Gervais, Adrian, Le Voyer, Tom, Bizien, Lucy, Zamecnik, Colin, Philippot, Quentin, Rosain, Jérémie, Catherinot, Emilie, Willmore, Andrew, Mitchell, Anthea, Bair, Rebecca, Garçon, Pierre, Kenney, Heather, Fekkar, Arnaud, Salagianni, Maria, Poulakou, Garyphallia, Siouti, Eleni, Sahanic, Sabina, Tancevski, Ivan, Weiss, Günter, Nagl, Laurenz, Manry, Jérémy, Duvlis, Sotirija, Arroyo-Sánchez, Daniel, Paz Artal, Estela, Rubio, Luis, Perani, Cristiano, Bezzi, Michela, Sottini, Alessandra, Quaresima, Virginia, Roussel, Lucie, Vinh, Donald, Reyes, Luis, Garzaro, Margaux, Hatipoglu, Nevin, Boutboul, David, Tandjaoui-Lambiotte, Yacine, Borghesi, Alessandro, Aliberti, Anna, Cassaniti, Irene, Venet, Fabienne, Monneret, Guillaume, Halwani, Rabih, Sharif-Askari, Narjes, Danielson, Jeffrey, Burrel, Sonia, Morbieu, Caroline, Stepanovskyy, Yurii, Bondarenko, Anastasia, Volokha, Alla, Boyarchuk, Oksana, Gagro, Alenka, Neuville, Mathilde, Neven, Bénédicte, Keles, Sevgi, Hernu, Romain, Bal, Antonin, Novelli, Antonio, Novelli, Giuseppe, Saker, Kahina, Ailioaie, Oana, Antolí, Arnau, Jeziorski, Eric, Rocamora-Blanch, Gemma, Teixeira, Carla, Delaunay, Clarisse, Lhuillier, Marine, Le Turnier, Paul, Zhang, Yu, Mahevas, Matthieu, Pan-Hammarström, Qiang, Abolhassani, Hassan, Bompoil, Thierry, Dorgham, Karim, Gorochov, Guy, Laouenan, Cédric, Rodríguez-Gallego, Carlos, Ng, Lisa, Renia, Laurent, Pujol, Aurora, Belot, Alexandre, Raffi, François, Allende, Luis, Martinez-Picado, Javier, Ozcelik, Tayfun, Imberti, Luisa, Notarangelo, Luigi, Troya, Jesus, Solanich, Xavier, Zhang, Shen-Ying, Puel, Anne, Wilson, Michael, Trouillet-Assant, Sophie, Abel, Laurent, Jouanguy, Emmanuelle, Ye, Chun, Cobat, Aurélie, Thompson, Leslie, Andreakos, Evangelos, Zhang, Qian, Anderson, Mark, Casanova, Jean-Laurent, Derisi, Joseph, Achille, Cristian, Aiuti, Alessandro, Al-Muhsen, Saleh, Al-Mulla, Fahd, Angelini, Micol, Arias, Andrés, Aytekin, Gokhan, Baldanti, Fausto, Feldman, Hagit, Bergami, Federica, Biggs, Catherine, Bogunovic, Dusan, Bolze, Alexandre, Bondarenko, Anastasiia, Bousfiha, Ahmed, Brodin, Petter, Bryceson, Yenan, Bustamante, Carlos, Butte, Manish, Casari, Giorgio, Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan, Conti, Francesca, Cooper, Megan, Dalgard, Clifton, Desai, Murkesh, Drolet, Beth, El Baghdadi, Jamila, Ergun, Recai, Ergun, Dilek, Espinosa-Padilla, Sara, Fellay, Jacques, Flores, Carlos, Franco, José, Froidure, Antoine, Ghirardello, Stefano, Gregersen, Peter, Grimbacher, Bodo, Haerynck, Filomeen, Hagin, David, Hammarström, Lennart, Heath, James, Henrickson, Sarah, Hsieh, Elena, Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich, Kanat, Fikret, Karamitros, Timokratis, Kisand, Kai, Kopcha, Vasyl, Korda, Mykhaylo, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie, Maniatis, Tom, Mansouri, Davood, Maródi, László, Meyts, Isabelle, Milner, Joshua, Mironska, Kristina, Mogensen, Trine, Mojoli, Francesco, Morandeira, Francisco, Morio, Tomohiro, O'Farrelly, Cliona, Okada, Satoshi, Okamoto, Keisuke, Pagani, Michele, Pape, Jean, de Diego, Rebeca, Perlin, David, Pesole, Graziano, Pession, Andrea, Piralla, Antonio, Planas, Anna, Prando, Carolina, Quintana-Murci, Lluis, Ramaswamy, Sathishkumar, Resnick, Igor, Rigo-Bonnin, Raúl, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko, Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Snow, Andrew, Soler-Palacín, Pere, Spaan, András, Tangye, Stuart, Abou Tayoun, Ahmad, Tulek, Baykal, Turvey, Stuart, Uddin, K, Uddin, Mohammed, Clément, Bénédicte, Abe-Jones, Yumiko, Asthana, Saurabh, Bhide, Sharvari, Calfee, Carolyn, Carrillo, Sidney, Chak, Suzanna, Collins, Zachary, Erle, David, Fragiadakis, Gabriela, Ghale, Rajani, Hendrickson, Carolyn, Jauregui, Alejandra, Kangelaris, Kirsten, Krummel, Matthew, Langelier, Charles, Lea, Tasha, Lee, Deanna, Leligdowicz, Aleksandra, Leroux, Carolyn, Lota, Raphael, Matthay, Michael, Nguyen, Viet, Patel, Ravi, Pierce, Logan, Prasad, Priya, Rao, Arjun, Rashid, Ahmad, Rodriguez, Nicklaus, Samad, Bushra, Shaw, Cole, Sigman, Austin, Tang, Kevin, Altamirano, Luz, Ward, Alyssa, Woodruff, Prescott, Allavena, Clotilde, Andrejak, Claire, Angoulvant, François, Azoulay, Cecile, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behilill, Sylvie, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bhavsar, Krishna, Bitker, Laurent, Bouadma, Lila, Bouscambert, Maude, Paz, Pauline, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Cordel, Hugues, Couffignal, Camille, Couffin-Cadiergues, Sandrine, D’ortenzio, Eric, de Montmollin, Etienne, Debard, Alexa, Debray, Marie-Pierre, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diehl, Jean-Luc, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Eloy, Philippine, Enouf, Vincent, Epaulard, Olivier, Esperou, Hélène, Esposito-Farese, Marina, Etienne, Manuel, Garot, Denis, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Goehringer, François, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Kerroumi, Younes, Khalil, Antoine, Khan, Coralie, Kimmoun, Antoine, Laine, Fabrice, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Bris, Cyril, Le Gac, Sylvie, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lemaignen, Adrien, Lemee, Véronique, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean, Machado, Moïse, Malvy, Denis, Mambert, Marina, Manuel, Aldric, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Peigne, Vincent, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Poissy, Julien, Puéchal, Oriane, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Tubiana, Sarah, van der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], Grand Hôpital de l'Est Francilien (GHEF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 4th Department of Internal Medicine, ATTIKON University General Hospital, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Goce Delchev University (UGD), Génétique Evolutive Humaine - Human Evolutionary Genetics, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Basic medicine, Settore MED/03, [SDV]Life Sciences [q-bio], Immunology, COVID-19, Pneumònia, Pneumonia, General Medicine
Abstract

International audience; Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Published
2022

13. Association between tracheostomy timing and outcomes for older critically ill COVID-19 patients:prospective observational study in European intensive care units

Author

Raphael Romano Bruno, Bertrand Guidet, Michael Beil, Peter Vernon van Heerden, Kamil Polok, Bernardo Bollen Pinto, Bernhard Wernly, Finn H. Andersen, Antonio Artigas, Michael Joannidis, Wojciech Szczeklik, Brian Marsh, Rui Moreno, Dorota Studzińska, Maurizio Cecconi, Joerg C. Schefold, Hans Flaatten, Sigal Sviri, Sandra Oeyen, Dylan W. de Lange, Jakub Fronczek, Jesper Fjølner, Christian Jung, Susannah Leaver, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), The Hebrew University of Jerusalem (HUJ), University of Bergen (UiB), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Réanimation Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University Medical Center [Utrecht], Aarhus University Hospital, St George’s University Hospitals, Hadassah Hebrew University Medical Center [Jerusalem], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), CIBER de Epidemiología y Salud Pública (CIBERESP), Hôpitaux Universitaires de Genève (HUG), Bern University Hospital [Berne] (Inselspital), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Ghent University Hospital, Mater Misericordiae University Hospital (The Mater Hospital), Norwegian University of Science and Technology (NTNU), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Humanitas University [Milan] (Hunimed), and Gestionnaire, Hal Sorbonne Université

Subjects
Male, medicine.medical_specialty, Time Factors, Critical Care, Coronavirus disease 2019 (COVID-19), intensive care units, Critical Illness, medicine.medical_treatment, [SDV]Life Sciences [q-bio], tracheostomy, mechanical ventilation, law.invention, law, Intensive care, medicine, Humans, Intubation, Prospective Studies, Clinical Investigation, Correlation of Data, 610 Medicine & health, Prospective cohort study, outcome assessment, Aged, Mechanical ventilation, business.industry, Critically ill, COVID-19, healthcare, Length of Stay, Respiration, Artificial, Intensive care unit, Europe, Survival Rate, Health Care, [SDV] Life Sciences [q-bio], Treatment Outcome, Anesthesiology and Pain Medicine, Emergency medicine, Female, Observational study, business
Abstract

BACKGROUND Tracheostomy is performed in patients expected to require prolonged mechanical ventilation, but to date optimal timing of tracheostomy has not been established. The evidence concerning tracheostomy in COVID-19 patients is particularly scarce. We aimed to describe the relationship between early tracheostomy (���10 days since intubation) and outcomes for patients with COVID-19. METHODS This was a prospective cohort study performed in 152 centres across 16 European countries from February to December 2020. We included patients aged ���70 yr with confirmed COVID-19 infection admitted to an intensive care unit, requiring invasive mechanical ventilation. Multivariable analyses were performed to evaluate the association between early tracheostomy and clinical outcomes including 3-month mortality, intensive care length of stay, and duration of mechanical ventilation. RESULTS The final analysis included 1740 patients with a mean age of 74 yr. Tracheostomy was performed in 461 (26.5%) patients. The tracheostomy rate varied across countries, from 8.3% to 52.9%. Early tracheostomy was performed in 135 (29.3%) patients. There was no difference in 3-month mortality between early and late tracheostomy in either our primary analysis (hazard ratio [HR]=0.96; 95% confidence interval [CI], 0.70-1.33) or a secondary landmark analysis (HR=0.78; 95% CI, 0.57-1.06). CONCLUSIONS There is a wide variation across Europe in the timing of tracheostomy for critically ill patients with COVID-19. However, we found no evidence that early tracheostomy is associated with any effect on survival amongst older critically ill patients with COVID-19. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT04321265.

Published
2022

14. Bloodstream Infections Caused by Magnusiomyces capitatus and Magnusiomyces clavatus : Epidemiological, Clinical, and Microbiological Features of Two Emerging Yeast Species

Author

Janina Noster, Martin B. Koeppel, Marie Desnos-Olivier, Maria Aigner, Oliver Bader, Karl Dichtl, Stephan Göttig, Andrea Haas, Oliver Kurzai, Arthur B. Pranada, Yvonne Stelzer, Grit Walther, Axel Hamprecht, Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), Ludwig-Maximilians-Universität München (LMU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Medical Center Göttingen (UMG), Goethe-Universität Frankfurt am Main, Julius-Maximilians-Universität Würzburg (JMU), Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute), MVZ Dr. Eberhard & Partner Dortmund, German Centre for Infection Research (DZIF), Universität zu Köln = University of Cologne, and Work in the NRZMyk is supported by the Robert-Koch-Institute from funds provided by the German Ministry of Health (grant no. 1369-240). This study was supported by internal funding.

Subjects
Pharmacology, Saprochaete capitata, Infectious Diseases, Magnusiomyces clavatus, [SDV]Life Sciences [q-bio], Saprochaete clavata, Pharmacology (medical), bloodstream infection, MIC, Magnusiomyces capitatus, Geotrichum
Abstract

International audience; Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. Our objectives were to determine the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. In seven institutions, a total of 34 Magnusiomyces BSI were identified. Identification was done by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/L), followed by posaconazole (MIC50, 0.125/0.25 mg/L). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, low essential agreement between gradient test and microdilution was recorded for all antifungals (0 to 70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.

Published
2022

15. The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies

Author

Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesús, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James, Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia, Zhang, Yu, Snow, Andrew, Holland, Steven, Biggs, Catherine, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila, Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel, Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam, Kennelly, Sean, Bourke, Nollaig, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András, Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard, Mane, Shrikant, Anderson, Mark, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine, Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charles, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter, Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi, Su, Helen, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Zhang, Peng, Seeleuthner, Yoann, Talouarn, Estelle, Marchal, Astrid, Matuozzo, Daniela, de la Chapelle, Aliénor, Chen, Jie, Chrabieh, Maya, Liu, Dana, Nemirowskaya, Yelena, Cruz, Inés Marín, Materna, Marie, Pelet, Sophie, Thibault, Chloé, Liu, Zhiyong, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Darazam, Ilad Alavi, Albisures, Jonathan Antonio Roblero, Aldave, Juan, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, Allardet-Servent, Jerome, Allende, Luis, Alonso-Arias, Rebeca, Alshahrani, Mohammed, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Feldman, Hagit Baris, Barrou, Benoit, Barzaghi, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P., Bukhari, Huda, Bustamante, Jacinta, Agra, Juan José Cáceres, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew, Clavé, Pere, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, de Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Flores, Carlos, Francois, Bruno, Fumadó, Victoria, Fung, Kitty, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Godínez, Karen Alejandra Cifuentes, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Gut, Marta, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-Ki, Holanda-Peña, María Soledad, Horcajada, Juan, Hraiech, Sami, Humbert, Linda, Hung, Ivan, Iglesias, Alejandro, Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Kanık-Yüksek, Saliha, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Daganou, Maria, Koukaki, Evangelia, Koutsoukou, Antonia, Rapti, Vasiliki, Syrigos, Konstantinos, Król, Zbigniew, Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur, Kwan, Yat Wah M., Kwok, Janette, Lam, David, Conti, Francesca, Pession, Andrea, Lampropoulou, Vicky, Lanternier, Fanny, Bourgeois, Fleur Le, Leo, Yee-Sin, Lopez, Rafael Leon, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Lima, Edson Jose Adrian Bolanos, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José, Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Lye, David, Magnone, Cinthia, Mansouri, Davood, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa Rb, Matthews, Gail, Mayaux, Julien, Mclaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morange, Pierre-Emmanuel, Mordacq, Clémence, Morelle, Guillaume, Mouly, Stéphane, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. Gonzalo, Okamoto, Keisuke, Oualha, Mehdi, Ouedrani, Amani, Özçelik, Tayfun, Ozkaya-Parlakay, Aslinur, Pagani, Michele, Papadaki, Maria, Parizot, Christophe, Parola, Philippe, Pascreau, Tiffany, Paz-Artal, Estela, Pedraza-Sánchez, Sigifredo, Gálvez-Romero, José Luis, Pellecer, Nancy Carolina González, Pellegrini, Silvia, Diego, Rebeca Pérez De, Pérez-Fernández, Xosé Luis, Philippe, Aurélien, Picod, Adrien, de Chambrun, Marc Pineton, Piralla, Antonio, Planas-Serra, Laura, Ploin, Dominique, Poncelet, Géraldine, Poulakou, Garyphallia, Pouletty, Marie, Pourshahnazari, Persia, Qiu-Chen, Jia Li, Quentric, Paul, Rambaud, Thomas, Raoult, Violette, Rebillat, Anne-Sophie, Redin, Claire, Resmini, Léa, Ricart, Pilar, Richard, Jean-Christophe, Rivet, Nadia, Rocamora-Blanch, Gemma, Rodero, Mathieu, Rodrigo, Carlos, Rodriguez, Luis Antonio, Rodriguez-Gallego, Carlos, Rodriguez-Palmero, Agustí, Romero, Carolina Soledad, Rothenbuhler, Anya, Roux, Damien, Rovina, Nikoletta, Rozenberg, Flore, Ruch, Yvon, Ruiz, Montse, Prado, Maria Yolanda Ruiz Del, Ruiz-Rodriguez, Juan Carlos, Sabater-Riera, Joan, Saks, Kai, Salagianni, Maria, Sanchez, Oliver, Sánchez-Montalvá, Adrián, Sánchez-Ramón, Silvia, Schidlowski, Laire, Schluter, Agatha, Schmidt, Julien, Schmidt, Matthieu, Schuetz, Catharina, Schweitzer, Cyril, Scolari, Francesco, Sediva, Anna, Seijo, Luis, Seminario, Analia Gisela, Seng, Piseth, Senoglu, Sevtap, Seppänen, Mikko, Llovich, Alex Serra, Shahrooei, Mohammad, Siguret, Virginie, Siouti, Eleni, Smadja, David, Smith, Nikaia, Sobh, Ali, Soler, Catherine, Soler-Palacín, Pere, Sözeri, Betül, Stella, Giulia Maria, Stepanovskiy, Yuriy, Stoclin, Annabelle, Taccone, Fabio, Taupin, Jean-Luc, Tavernier, Simon, Terrier, Benjamin, Thiery, Guillaume, Thorball, Christian, Thorn, Karolina, Thumerelle, Caroline, Tipu, Imran, Tolstrup, Martin, Tomasoni, Gabriele, Toubiana, Julie, Alvarez, Josep Trenado, Tsang, Owen, Tserel, Liina, Tso, Eugene, Tucci, Alessandra, Öz, Şadiye Kübra Tüter, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, van den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Veliz, Silvia Patricia Zuniga, Viel, Sébastien, Villain, Cédric, Vilaire-Meunier, Marie, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wu, Alan, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby, Yükselmiş, Ufuk, Ghirardello, Stefano, Zuccaro, Valentina, Andrés, Ana De, van Praet, Jens, Lambrecht, Bart, van Braeckel, Eva, Bosteels, Cédric, Hoste, Levi, Hoste, Eric, Bauters, Fré, Clercq, Jozefien De, Heijmans, Cathérine, Slabbynck, Hans, Naesens, Leslie, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Danielson, Jeffrey, Dobbs, Kerry, Kashyap, Anuj, Ding, Li, Dalgard, Clifton, Sottini, Alessandra, Quaresima, Virginia, Quiros-Roldan, Eugenia, Rossi, Camillo, Bettini, Laura Rachele, D’angio, Mariella, Beretta, Ilaria, Montagna, Daniela, Licari, Amelia, Marseglia, Gian Luigi, Batten, Isabella, Reddy, Conor, Mcelheron, Matt, Noonan, Claire, Connolly, Emma, Fallon, Aoife, Storgaard, Merete, Jørgensen, Sofie, Pedersen, Ole Birger, Sørensen, Erik, Mikkelsen, Susan, Dinh, Khoa Manh, Larsen, Margit Anita Hørup, Paulsen, Isabella Worlewenut, von Stemann, Jakob Hjorth, Hansen, Morten Bagge, Ostrowski, Sisse Rye, Townsend, Liam, Ni Cheallaigh, Cliona, Bergin, Colm, Martin-Loeches, Ignacio, Dunne, Jean, Conlon, Niall, O’farrelly, Cliona, Allavena, Clotilde, Andrejak, Claire, Angoulvant, François, Azoulay, Cecile, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behillill, Sylvie, Beluze, Marine, Benech, Nicolas, Benkerrou, Dehbia, Bhavsar, Krishna, Bitker, Laurent, Bouscambert-Duchamp, Maude, Paz, Pauline Caraux, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Cordel, Hugues, Couffignal, Camille, Couffin-Cadiergues, Sandrine, D’ortenzio, Eric, de Montmollin, Etienne, Debard, Alexa, Debray, Marie-Pierre, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Eloy, Philippine, Enouf, Vincent, Epaulard, Olivier, Esperou, Hélène, Esposito-Farase, Marina, Etienne, Manuel, Garot, Denis, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Goehringer, François, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Kerroumi, Younes, Khalil, Antoine, Khan, Coralie, Kimmoun, Antoine, Laine, Fabrice, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Bris, Cyril, Le Gac, Sylvie, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lemaignen, Adrien, Lemee, Véronique, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean Christophe, Machado, Moïse, Malvy, Denis, Mambert, Marina, Manuel, Aldric, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Peigne, Vincent, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Puéchal, Oriane, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Tubiana, Sarah, van der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, Annereau, Jean-Philippe, Briseño-Roa, Luis, Gribouval, Olivier, Jaïs, Jean-Philippe, Pelet, Anna, Alcover, Andres, Aschard, Hugues, Bousso, Philippe, Brodin, Petter, Bruhns, Pierre, Cerf-Bensussan, Nadine, Cumano, Ana, D’enfert, Christophe, Deriano, Ludovic, Dillies, Marie-Agnès, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gomperts-Boneca, Ivo, Hasan, Milena, Hedestam, Gunilla Karlsson, Hercberg, Serge, Ingersoll, Molly, Lantz, Olivier, Kenny, Rose Anne, Ménager, Mickaël, Michel, Frédérique, Patin, Etienne, Pellegrini, Sandra, Rausell, Antonio, Rieux-Laucat, Frédéric, Rogge, Lars, Fontes, Magnus, Sakuntabhai, Anavaj, Schwartz, Olivier, Schwikowski, Benno, Shorte, Spencer, Tangy, Frédéric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie-Noëlle, Zimmer, Christophe, Albert, Matthew, Alavoine, Loubna, Behillil, Sylvie, Charpentier, Charlotte, Dechanet, Aline, Ecobichon, Jean-Luc, Frezouls, Wahiba, Houhou, Nadhira, Lehacaut, Jonathan, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Quintin, Caroline, Thy, Michael, Vignali, Valérie, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Bourgeon, Marilou, Lefèvre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Kouakam, Christelle, Leturque, Nicolas, Roufai, Layidé, Amat, Karine, Espérou, Hélène, Hendou, Samia, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David, Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Dijkstra, Mirjam, Dongelmans, Dave, Dujardin, Romein, Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin, Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine, Heunks, Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe, de Jong, Menno, Lim, Endry, van Mourik, Niels, Nellen, Jeaninne, Nossent, Esther, Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan, van der Poll, Tom, Preckel, Bennedikt, Prins, Jan, Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits, Schinkel, Michiel, Schultz, Marcus, Schrauwen, Femke, Schuurman, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen, Smeele, Patrick, Smit, Marry, Stijnis, Cornelis, Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa, Tuinman, Pieter, van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke, van Vugt, Michèle, Wouters, Dorien, Zwinderman, A., Brouwer, Matthijs, Wiersinga, W. Joost, Vlaar, Alexander, Al-Muhsen, Saleh, Al-Mulla, Fahd, Arias, Andrés, Bogunovic, Dusan, Bolze, Alexandre, Bryceson, Yenan, Bustamante, Carlos, Butte, Manish, Chakravorty, Samya, Christodoulou, John, Constantinescu, Stefan, Cooper, Megan, Desai, Murkesh, Drolet, Beth, El Baghdadi, Jamila, Espinosa-Padilla, Sara, Froidure, Antoine, Henrickson, Sarah, Hsieh, Elena, Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich, Karamitros, Timokratis, Ku, Cheng-Lung, Ling, Yun, Lucas, Carrie, Maniatis, Tom, Maródi, László, Milner, Joshua, Mironska, Kristina, Novelli, Antonio, Novelli, Giuseppe, de Diego, Rebeca Perez, Perez-Tur, Jordi, Arkin, Lisa, Asano, Takaki, Oriol, Roger Colobran, Renia, Laurent, Resnick, Igor, Sancho-Shimizu, Vanessa, Seppänen, Mikko R.J., Shahrooei, Mohammed, Slaby, Ondrej, Tayoun, Ahmad Abou, Ramaswamy, Sathishkumar, Turvey, Stuart, Uddin, K., Uddin, Mohammed, von Bernuth, Horst, Zawadzki, Pawel, Grimbacher, Bodo, Pape, Jean, Perlin, David, Pesole, Graziano, García, Paula Andrea Gaviria, López, Gustavo Andrés Salguero, Rojas-Villaraga, Adriana, Vélez, Verónica Posada, Landinez, Lina Marcela Acevedo, Correales, Luisa Paola Duarte, Gómez, Oscar, Guaqueta, Jeser Santiago Grass, Pérez, Cristian Alejandro Ricaurte, Carrillo, Jorge, Vergara, José Alejandro Daza, Landinez, Sandra, Mantilla, Rubén, Yepes, Jairo David Torres, Ricaurte, Oscar Andrés Briceño, Pérez-Díaz, Carlos, Mateus, Yady Nataly, Navarro, Laura Mancera, Rodríguez, Yhojan, Acosta-Ampudia, Yeny, Monsalve, Diana, Rojas, Manuel, Nadif, Rachel, Goldberg, Marcel, Ozguler, Anna, Henny, Joseph, Lemonnier, Sylvie, Coeuret-Pellicer, Mireille, Got, Stéphane Le, Tzourio, Christophe, Dufouil, Carole, Soumaré, Aïcha, Lachaize, Morgane, Fievet, Nathalie, Flaig, Amandine, Martin, Fernando, Bonneaudeau, Brigitte, Cannet, Dorothée, Gallian, Pierre, Jeanne, Michel, Perroquin, Magali, Hamzeh-Cognasse, Hind, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Hiroshima University, Vall d’Hebron Research Institute (VHIR), University of Tartu, CHU Henri Mondor, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hospital Universitario Infanta Leonor [Madrid], Hospices Civils de Lyon (HCL), Grand Hôpital de l'Est Francilien (GHEF), Vall d'Hebron University Hospital [Barcelona], Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Assistance Publique - Hôpitaux de Marseille (APHM), National Institutes of Health [Bethesda] (NIH), Tokyo Medical and Dental University [Japan] (TMDU), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute for Systems Biology [Seattle] (ISB), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidad del Rosario [Bogota], Hospital Universitario de Gran Canaria Dr Negrin, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), Uniformed Services University of the Health Sciences (USUHS), University of British Columbia (UBC), CHU Necker - Enfants Malades [AP-HP], Spanish National Research Council (CSIC), Ghent University Hospital, Goce Delchev University (UGD), Invitae Corporation, Bilkent University [Ankara], Necmettin Erbakan University [Konya, Turquie], Centre Hospitalier Universitaire Hassan II (CHU HII), CHU Ibn Rochd [Casablanca], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institute, Réseau International des Instituts Pasteur (RIIP), Tel Aviv Sourasky Medical Center [Te Aviv], The Feinstein Institute for Medical Research, IRCCS San Raffaele Scientific Institute [Milan, Italie], IRCCS Ospedale San Raffaele [Milan, Italy], Universidade de São Paulo = University of São Paulo (USP), Fundacion Rioja Salud, Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Shupyk National Medical Academy of Postgraduate Education [Kiev] (SNMAPE), I.Horbachevsky Ternopil State Medical University, Ternopil, Ukraine, Hospital Donostia, Garvan Institute of medical research, Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Charles University [Prague] (CU), University Hospital Motol [Prague], Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia], The University of Hong Kong (HKU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of La Sabana = Universitad de la Sabana, Hôpital Robert Ballanger [Aulnay-sous-Bois], Sackler Faculty of Medicine, Tel Aviv University (TAU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Tallaght Hospital, Trinity College Dublin, University of Sharjah (UoS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire CERBA [Saint Ouen l'Aumône], King Fahad University, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), McGill University = Université McGill [Montréal, Canada], Aarhus University [Aarhus], Instituto de Pesquisa Pelé Pequeno Principe, Hôpital Jean Verdier [AP-HP], Ecole Polytechnique Fédérale de Lausanne (EPFL), Yale University [New Haven], University of California [San Francisco] (UC San Francisco), University of California (UC), Academy of Athens, Institució Catalana de Recerca i Estudis Avançats (ICREA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), IrsiCaixa (Institut de Recerca de la Sida), Hôpital Foch [Suresnes], Etablissement Français du Sang, EFS, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), George Mason University, Yale University, National Human Genome Research Institute (US), Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, JPB Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Scientific Committee on Oceanic Research, Ministre de l'Enseignement Supérieur, de la Recherche et de l'Innovation (France), Institut National de la Santé et de la Recherche Médicale (France), Université de Paris, Fondation Bettencourt Schueller, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, G. Harold & Leila Y. Mathers Foundation, Hospital Universitario Infanta Leonor, National Institute of Allergy and Infectious Diseases (US), National Institute of Dental and Craniofacial Research (US), Estonian Research Council, Al Jalila Foundation, American University of Sharjah, National Health and Medical Research Council (Australia), University of New South Wales (Australia), Regione Lombardia, Instituto de Salud Carlos III, Japan Agency for Medical Research and Development, Sorbonne Université, Université de Bordeaux, National Cancer Institute (US), Research Foundation - Flanders, Hellenic Foundation for Research and Innovation, Sao Paulo Research Foundation, The Meath Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), INSERM UMRS-1144, Université Paris Cité, Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, The Rockefeller University, the St. Giles Foundation, the NIH (Grants R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Awards program (Grant UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (Grant S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (Grant ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (Grant EQU201903007798), the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05), the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects, the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project 'Risposta immune in pazienti con COVID-19 e co-morbidità'). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program 'Cohortes et collections de données biologiques.' S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1, AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID), by the Katholieke Universiteit Leuven C1 Grant C16/18/007, by a Flanders Institute for Biotechnology-Grand Challenges - PID grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N, and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation., HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James's Hospital, SARS CoV2 Interest Group, French COVID Cohort Study Group, Imagine COVID-Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank Investigators, COVID Human Genetic Effort, CP-COVID-19 Group, CONSTANCES cohort, 3C-Dijon Study, Cerba Health-Care, Etablissement Français du Sang Study group, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), European Project: 948959,ERC-2020-STG,MORE2ADA2(2021), Manry, J, Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Michailidis, E, Hoffmann, H, Eto, S, Garcia-Prat, M, Bizien, L, Parra-Martínez, A, Yang, R, Haljasmägi, L, Migaud, M, Särekannu, K, Maslovskaja, J, de Prost, N, Tandjaoui-Lambiotte, Y, Luyt, C, Amador-Borrero, B, Gaudet, A, Poissy, J, Morel, P, Richard, P, Cognasse, F, Troya, J, Trouillet-Assant, S, Belot, A, Saker, K, Garçon, P, Rivière, J, Lagier, J, Gentile, S, Rosen, L, Shaw, E, Morio, T, Tanaka, J, Dalmau, D, Tharaux, P, Sene, D, Stepanian, A, Mégarbane, B, Triantafyllia, V, Fekkar, A, Heath, J, Franco, J, Anaya, J, Solé-Violán, J, Imberti, L, Biondi, A, Bonfanti, P, Castagnoli, R, Delmonte, O, Zhang, Y, Snow, A, Holland, S, Biggs, C, Moncada-Vélez, M, Arias, A, Lorenzo, L, Boucherit, S, Anglicheau, D, Planas, A, Haerynck, F, Duvlis, S, Ozcelik, T, Keles, S, Bousfiha, A, El Bakkouri, J, Ramirez-Santana, C, Paul, S, Pan-Hammarström, Q, Hammarström, L, Dupont, A, Kurolap, A, Metz, C, Aiuti, A, Casari, G, Lampasona, V, Ciceri, F, Barreiros, L, Dominguez-Garrido, E, Vidigal, M, Zatz, M, van de Beek, D, Sahanic, S, Tancevski, I, Stepanovskyy, Y, Boyarchuk, O, Nukui, Y, Tsumura, M, Vidaur, L, Tangye, S, Burrel, S, Duffy, D, Quintana-Murci, L, Klocperk, A, Kann, N, Shcherbina, A, Lau, Y, Leung, D, Coulongeat, M, Marlet, J, Koning, R, Reyes, L, Chauvineau-Grenier, A, Venet, F, Monneret, G, Nussenzweig, M, Arrestier, R, Boudhabhay, I, Baris-Feldman, H, Hagin, D, Wauters, J, Meyts, I, Dyer, A, Kennelly, S, Bourke, N, Halwani, R, Sharif-Askari, F, Dorgham, K, Sallette, J, Sedkaoui, S, Alkhater, S, Rigo-Bonnin, R, Morandeira, F, Roussel, L, Vinh, D, Erikstrup, C, Condino-Neto, A, Prando, C, Bondarenko, A, Spaan, A, Gilardin, L, Fellay, J, Lyonnet, S, Bilguvar, K, Lifton, R, Mane, S, Anderson, M, Boisson, B, Béziat, V, Zhang, S, Andreakos, E, Hermine, O, Pujol, A, Peterson, P, Mogensen, T, Rowen, L, Mond, J, Debette, S, de Lamballerie, X, Burdet, C, Bouadma, L, Zins, M, Soler-Palacin, P, Colobran, R, Gorochov, G, Solanich, X, Susen, S, Martinez-Picado, J, Raoult, D, Vasse, M, Gregersen, P, Piemonti, L, Rodríguez-Gallego, C, Notarangelo, L, Su, H, Kisand, K, Okada, S, Puel, A, Jouanguy, E, Rice, C, Tiberghien, P, Zhang, Q, Casanova, J, Abel, L, Cobat, A, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Neurology, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, Graduate School, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Gunst, Jan, Acibadem University Dspace, Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherio, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Lii, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicola, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesú, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Loui, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R, Franco, José Lui, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M, Zhang, Yu, Snow, Andrew L, Holland, Steven M, Biggs, Catherine M, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna M, Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A, Dominguez-Garrido, Elena, Vidigal, Mateu, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Llui, Klocperk, Adam, Kann, Nelli Y, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C, Arrestier, Romain, Boudhabhay, Idri, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H, Kennelly, Sean P, Bourke, Nollaig M, Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C, Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N, Gilardin, Laurent, Fellay, Jacque, Lyonnet, Stanisla, Bilguvar, Kaya, Lifton, Richard P, Mane, Shrikant, Anderson, Mark S, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelo, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H, Rowen, Lee, Mond, Jame, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charle, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K, Piemonti, Lorenzo, Rodríguez-Gallego, Carlo, Notarangelo, Luigi D, Su, Helen C, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M, Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, Cobat, Aurélie, Vougny, Marie-Christine, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Subjects
Adult, Male, Risk, infection fatality rate, [SDV.IMM] Life Sciences [q-bio]/Immunology, autoantibodies, chronic mucocutaneous candidiasis, CHRONIC MUCOCUTANEOUS CANDIDIASIS, Autoimmunity, IMMUNITY, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, DISEASE, Basic medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, INFECTION, Medicine and Health Sciences, Humans, IMUNOLOGIA, Aged, Autoantibodies, Aged, 80 and over, disease, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, SARS-CoV-2, type I IFNs, Age Factors, COVID-19, Type I IFNs, Middle Aged, autoantibodie, immunity, Antibodies, Neutralizing, infection, Infection fatality rate, Relative risk, relative risk, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, type I IFN
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.

Published
2022

16. Parameter estimates for trends and patterns of excess mortality among persons on antiretroviral therapy in high-income European settings

Author

Juan Berenguer, Christoph Wyen, M. John Gill, Sophie Abgrall, Ard van Sighem, Matthias Cavassini, Sophie Grabar, Jordi Casabona, Margaret T May, Julia del Amo, Antonella d'Arminio Monforte, Robert Zangerle, John Stover, Niels Obel, Jonathan A C Sterne, Fabrice Bonnet, Adam Trickey, Medical Research Council (Reino Unido), Department for International Development (Reino Unido), NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), National Institute for Health Research (Reino Unido), Unión Europea, Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Institut National de la Santé et de la Recherche Médicale (Francia), Ministero della Salute (Italia), Ministerio de Sanidad y Consumo (España), Ministerio de Ciencia e Innovación (España), Red de Investigación Cooperativa en Investigación en Sida (España), Swiss National Science Foundation, University of Bristol [Bristol], Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital General Universitario 'Gregorio Marañón' [Madrid], Instituto de Investigación Sanitaria Gregorio Marañón [Madrid, Spain] ( IiSGM), University Hospital of Cologne [Cologne], Centre d'Estudis Epidemiològics sobre les Infeccions de Transmissió Sexual i Sida de Catalunya (CEEISCAT), CIBER de Epidemiología y Salud Pública (CIBERESP), Università degli Studi di Milano = University of Milan (UNIMI), Ospedale San Paolo-Polo Universitario, ASST Santi Paolo e Carlo, Milan, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne = University of Lausanne (UNIL), Instituto de Salud Carlos III [Madrid] (ISC), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University of Calgary, Department of Infectious Diseases [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Gestionnaire, Hal Sorbonne Université, Medical Research Council (United Kingdom), Department for International Development (United Kingdom), National Institute on Alcohol Abuse and Alcoholism (United States), National Institute for Health Research (United Kingdom), European Union, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Institut National de la Santé et de la Recherche Médicale (France), and Red Española de Investigación en SIDA

Subjects
Adult, Male, 0301 basic medicine, Anti-HIV Agents, [SDV]Life Sciences [q-bio], Immunology, Population, HIV Infections, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Acquired immunodeficiency syndrome (AIDS), Risk Factors, death, cause-specific, medicine, Humans, Immunology and Allergy, 030212 general & internal medicine, Mortality, education, United Nations Programme on HIV/AIDS, education.field_of_study, Models, Statistical, business.industry, Developed Countries, Mortality rate, duration, HIV, cohort, Middle Aged, medicine.disease, Confidence interval, 3. Good health, AIDS, [SDV] Life Sciences [q-bio], Europe, Anti-HIV Agents/therapeutic use, Europe/epidemiology, Female, HIV Infections/drug therapy, HIV Infections/mortality, Mortality/trends, Editorial, 030104 developmental biology, Infectious Diseases, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Developed country, Demography, Cohort study
Abstract

Supplemental Digital Content is available in the text, Introduction: HIV cohort data from high-income European countries were compared with the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). Methods: Data from 2000 to 2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare all-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. Results: Analyses included 94 026 PLHIV with 585 784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000–2003 were 0.0121, reducing to 0.0078 in 2012–2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 [95% confidence interval (95% CI): 0.0130–0.0171] reducing to 0.0049 (95% CI: 0.0039–0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000–2003, dropping to 43.6% in 2012–2015. In the ART-CC, AIDS-related mortality constitutes 45.3% (95% CI: 38.4–52.9%) of mortality in 2000–2003 and 26.7% (95% CI: 19–46%) between 2012 and 2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95% CI: 60.3–95.2%) in 2000–2003 to 30.7% (95% CI: 25.5–63.7%) in 2012–2015. Conclusion: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000–2003 and decline more quickly to levels currently captured for recent years.

Published
2019

17. Surgical Treatment of Postinfarction Ventricular Septal Rupture

Author

Massimiliano Carrozzini, Nikolaos Bonaros, Bart Meyns, Roberto Scrofani, Giosuè Falcetta, Matteo Pozzi, Antonio Fiore, Stefano D'Alessandro, Salman Almobayedh, Giuseppe Filiberto Serraino, Matteo Matteucci, Vittoria Lodo, Matthias Thielmann, Piotr Suwalski, Carlo Fino, Nikolaos Kalampokas, Shabir Hussain Shah, Marek A. Deja, Dario Fina, Roberto Lorusso, Nawwar Al-Attar, Theodor Fischlein, Udo Boeken, Guglielmo Maria Actis Dato, Francesco Formica, Sandro Sponga, Adam Kowalówka, Fareed A Khouqeer, Carlo De Vincentiis, Giulio Massimi, Igor Vendramin, Jean-François Obadia, Thierry Folliguet, Daniele Ronco, Giovanni Troise, Federica Jiritano, Michele De Bonis, Cesare Beghi, Caterina Simon, Emmanuel Villa, Mariusz Kowalewski, Jurij M. Kalisnik, Shiho Naito, Marco Ranucci, Claudio Russo, CTC, RS: Carim - V04 Surgical intervention, MUMC+: MA Med Staf Spec CTC (9), CarMeN, laboratoire, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Central Clinical Hospital of the Ministry of the Interior & Administration [Warsaw, Poland] (2CHMIA), Ministry of the Interior and Administration [Warsaw, Poland] (MIA), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Università degli studi di Parma = University of Parma (UNIPR), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Università degli Studi di Milano, IRCCS Policlinico San Donato, CHU Henri Mondor, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Niguarda Hospital [Milan, Italy], Università degli Studi di Udine - University of Udine [Italie], University of Pisa - Università di Pisa, Klinikum Nürnberg Nord, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Fondazione Poliambulanza, Mauriziano Umberto Hospital [Turin, Italy] (MUH), King Fahad Medical City [Riyadh, Saudi Arabia], Luigi Sacco University Hospital [Milan], Medical University of Silesia (SUM), Upper Silesian Medical Centre [Katowice, Poland] (USMC), West German Heart Center, Universität Duisburg-Essen [Essen], University Hospitals Leuven [Leuven], King Faisal Specialist Hospital and Resarch Centre [Riyadh, Saudi Arabia] (KFSHRC), Golden Jubilee National Hospital, Glasgow, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University Hospital Düsseldorf, Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), University Heart Center [Hamburg], Cardiovascular Research Institute Maastricht (CARIM), Università degli Studi di Brescia = University of Brescia (UniBs), Services de Pneumologie, Exploration Fonctionnelle Respiratoire et Cardiologie (Hôpital Louis Pradel), Ronco, D., Matteucci, M., Kowalewski, M., De Bonis, M., Formica, F., Jiritano, F., Fina, D., Folliguet, T., Bonaros, N., Russo, C. F., Sponga, S., Vendramin, I., De Vincentiis, C., Ranucci, M., Suwalski, P., Falcetta, G., Fischlein, T., Troise, G., Villa, E., Dato, G. A., Carrozzini, M., Serraino, G. F., Shah, S. H., Scrofani, R., Fiore, A., Kalisnik, J. M., D'Alessandro, S., Lodo, V., Kowalowka, A. R., Deja, M. A., Almobayedh, S., Massimi, G., Thielmann, M., Meyns, B., Khouqeer, F. A., Al-Attar, N., Pozzi, M., Obadia, J. -F., Boeken, U., Kalampokas, N., Fino, C., Simon, C., Naito, S., Beghi, C., and Lorusso, R.

Subjects
Male, MORTALITY-RATES, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medizin, Myocardial Infarction, Cohort Studies, Odds Ratio, Myocardial infarction, Prospective Studies, Coronary Artery Bypass, Prospective cohort study, Original Investigation, Ventricular Septal Rupture, OUTCOMES, Cardiogenic shock, Mortality rate, CARDIAC RUPTURE, General Medicine, MECHANICAL CIRCULATORY SUPPORT, Middle Aged, [SDV] Life Sciences [q-bio], Online Only, Female, Life Sciences & Biomedicine, Cohort study, medicine.medical_specialty, Preoperative care, EXTRACORPOREAL MEMBRANE-OXYGENATION, Medicine, General & Internal, General & Internal Medicine, medicine, Extracorporeal membrane oxygenation, Humans, cardiovascular diseases, Aged, Retrospective Studies, REPAIR, Science & Technology, business.industry, Research, ELEVATION MYOCARDIAL-INFARCTION, Perioperative, medicine.disease, Surgery, DEFECT, RISK-FACTORS, business, TASK-FORCE
Abstract

Key Points Question What are the early outcomes of surgical treatment of postinfarction ventricular septal rupture? Findings In this cohort study of 475 patients from 26 different centers worldwide, the early mortality rate for surgically treated ventricular septal rupture was 40.4%, mostly due to low cardiac output, and it did not improve in the last 2 decades. Meaning The findings of this study suggest that patient-tailored preoperative and perioperative management of postinfarction ventricular septal rupture should be addressed to improve the current suboptimal survival rates., This cohort study assesses the clinical characteristics and early outcomes for patients who received surgery for postinfarction ventricular septal rupture and identifies factors independently associated with mortality., Importance Ventricular septal rupture (VSR) is a rare but life-threatening mechanical complication of acute myocardial infarction associated with high mortality despite prompt treatment. Surgery represents the standard of care; however, only small single-center series or national registries are usually available in literature, whereas international multicenter investigations have been poorly carried out, therefore limiting the evidence on this topic. Objectives To assess the clinical characteristics and early outcomes for patients who received surgery for postinfarction VSR and to identify factors independently associated with mortality. Design, Setting, and Participants The Mechanical Complications of Acute Myocardial Infarction: an International Multicenter Cohort (CAUTION) Study is a retrospective multicenter international cohort study that includes patients who were treated surgically for mechanical complications of acute myocardial infarction. The study was conducted from January 2001 to December 2019 at 26 different centers worldwide among 475 consecutive patients who underwent surgery for postinfarction VSR. Exposures Surgical treatment of postinfarction VSR, independent of the technique, alone or combined with other procedures (eg, coronary artery bypass grafting). Main Outcomes and Measures The primary outcome was early mortality; secondary outcomes were postoperative complications. Results Of the 475 patients included in the study, 290 (61.1%) were men, with a mean (SD) age of 68.5 (10.1) years. Cardiogenic shock was present in 213 patients (44.8%). Emergent or salvage surgery was performed in 212 cases (44.6%). The early mortality rate was 40.4% (192 patients), and it did not improve during the nearly 20 years considered for the study (median [IQR] yearly mortality, 41.7% [32.6%-50.0%]). Low cardiac output syndrome and multiorgan failure were the most common causes of death (low cardiac output syndrome, 70 [36.5%]; multiorgan failure, 53 [27.6%]). Recurrent VSR occurred in 59 participants (12.4%) but was not associated with mortality. Cardiogenic shock (survived: 95 [33.6%]; died, 118 [61.5%]; P

Published
2021

18. Management and outcomes in critically ill nonagenarian versus octogenarian patients

Author

Bruno, Raphael Romano, Wernly, Bernhard, Kelm, Malte, Boumendil, Ariane, Morandi, Alessandro, Andersen, Finn H., Artigas, Antonio, Finazzi, Stefano, Cecconi, Maurizio, Christensen, Steffen, Faraldi, Loredana, Lichtenauer, Michael, Muessig, Johanna M., Marsh, Brian, Moreno, Rui, Oeyen, Sandra, Öhman, Christina Agvald, Pinto, Bernardo Bollen, Soliman, Ivo W., Szczeklik, Wojciech, Valentin, Andreas, Watson, Ximena, Leaver, Susannah, Boulanger, Carole, Walther, Sten, Schefold, Joerg C., Joannidis, Michael, Nalapko, Yuriy, Elhadi, Muhammed, Fjølner, Jesper, Zafeiridis, Tilemachos, De Lange, Dylan W., Guidet, Bertrand, Flaatten, Hans, Jung, Christian, Eller, Philipp, Helbok, Raimund, Schmutz, René, Nollet, Joke, de Neve, Nikolaas, Buysscher, Pieter De, Swinnen, Walter, Mikačić, Marijana, Bastiansen, Anders, Husted, Andreas, Dahle, Bård E.S., Cramer, Christine, Sølling, Christoffer, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Karolinska Institutet [Stockholm], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), the Handmaids of Charity Nursing Home / Casa di Cura Ancelle della Carità [Cremona, Italia], NTNU [Ålesund], Hospital Universitari Parc Taulí [Sabadell, Spain] (HUPT), CIBER de Epidemiología y Salud Pública (CIBERESP), RCCS–Istituto di Ricerche Farmacologiche 'Mario Negri [Bergamo, Italy], Clinical Research Center for Rare Diseases 'Aldo e Cele Daccò' [Bergamo, Italy], Humanitas University [Milan] (Hunimed), Aarhus University Hospital, ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Mater Misericordiae University Hospital (The Mater Hospital), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ghent University Hospital, Karolinska University Hospital [Stockholm], Geneva University Hospitals and Geneva University, Utrecht University [Utrecht], Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Cardinal Schwarzenberg Hospital [Pongau, Austria] (CSH), St George’s University Hospitals, Royal Devon and Exeter NHS Foundation Trust [UK], Linköping university hospital, University of Bern, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), European Wellness International [Luhansk, Ukraine] (EWI), Alkhums Hospital [Tripoli, Libya] (AH), University Hospital of Larissa, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Bergen (UiB), Haukeland University Hospital, VIP2 study group: Michael Joannidis, Philipp Eller, Raimund Helbok, René Schmutz, Joke Nollet, Nikolaas de Neve, Pieter De Buysscher, Sandra Oeyen, Walter Swinnen, Marijana Mikačić, Anders Bastiansen, Andreas Husted, Bård E S Dahle, Christine Cramer, Christoffer Sølling, Dorthe Ørsnes, Jakob Edelberg Thomsen, Jonas Juul Pedersen, Mathilde Hummelmose Enevoldsen, Thomas Elkmann, Agnieszka Kubisz-Pudelko, Alan Pope, Amy Collins, Ashok S Raj, Carole Boulanger, Christian Frey, Ciaran Hart, Clare Bolger, Dominic Spray, Georgina Randell, Helder Filipe, Ingeborg D Welters, Irina Grecu, Jane Evans, Jason Cupitt, Jenny Lord, Jeremy Henning, Joanne Jones, Jonathan Ball, Julie North, Kiran Salaunkey, Laura Ortiz-Ruiz De Gordoa, Louise Bell, Madhu Balasubramaniam, Marcela Vizcaychipi, Maria Faulkner, Mc Donald Mupudzi, Megan Lea-Hagerty, Michael Reay, Michael Spivey, Nicholas Love, Nick Spittle Nick Spittle, Nigel White, Patricia Williams, Patrick Morgan, Phillipa Wakefield, Rachel Savine, Reni Jacob, Richard Innes, Ritoo Kapoor, Sally Humphreys, Steve Rose, Susan Dowling, Susannah Leaver, Tarkeshwari Mane, Tom Lawton, Vongayi Ogbeide, Waqas Khaliq, Yolanda Baird, Antoine Romen, Arnaud Galbois, Bertrand Guidet, Christophe Vinsonneau, Cyril Charron, Didier Thevenin, Emmanuel Guerot, Guillaume Besch, Guillaume Savary, Hervé Mentec, Jean-Luc Chagnon, Jean-Philippe Rigaud, Jean-Pierre Quenot, Jeremy Castanera, Jérémy Rosman, Julien Maizel, Kelly Tiercelet, Lucie Vettoretti, Maud Mousset Hovaere, Messika Messika, Michel Djibré, Nathalie Rolin, Philippe Burtin, Pierre Garcon, Saad Nseir, Xavier Valette, Christian Rabe, Eberhard Barth, Henning Ebelt, Kristina Fuest, Marcus Franz, Michael Horacek, Michael Schuster, Patrick Meybohm, Raphael Romano Bruno, Sebastian Allgäuer, Simon Dubler, Stefan J Schaller, Stefan Schering, Stephan Steiner, Thorben Dieck, Tim Rahmel, Tobias Graf, Anastasia Koutsikou, Aristeidis Vakalos, Bogdan Raitsiou, Elli Niki Flioni, Evangelia Neou, Fotios Tsimpoukas, Georgios Papathanakos, Giorgos Marinakis, Ioannis Koutsodimitropoulos, Kounougeri Aikaterini, Nikoletta Rovina, Stylliani Kourelea, Polychronis Tasioudis, Vasiiios Zidianakis, Vryza Konstantinia, Zoi Aidoni, Brian Marsh, Catherine Motherway, Chris Read, Ignacio Martin-Loeches, Andrea Neville Cracchiolo, Aristide Morigi, Italo Calamai, Stefania Brusa, Ahmed Elhadi, Ahmed Tarek, Ala Khaled, Hazem Ahmed, Wesal Ali Belkhair, Alexander D Cornet, Diederik Gommers, Dylan W De Lange, Eva van Boven, Jasper Haringman, Lenneke Haas, Lettie van den Berg, Oscar Hoiting, Peter de Jager, Rik T Gerritsen, Tom Dormans, Willem Dieperink, Alena Breidablik Alena Breidablik, Anita Slapgard, Anne-Karin Rime, Bente Jannestad, Britt Sjøbøe, Eva Rice, Finn H Andersen, Hans Frank Strietzel, Jan Peter Jensen, Jørund Langørgen, Kirsti Tøien, Kristian Strand, Michael Hahn, Pål Klepstad, Aleksandra Biernacka, Anna Kluzik, Bartosz Kudlinski, Dariusz Maciejewski, Dorota Studzińska, Hubert Hymczak, Jan Stefaniak, Joanna Solek-Pastuszka, Joanna Zorska, Katarzyna Cwyl, Lukasz J Krzych, Maciej Zukowski, Małgorzata Lipińska-Gediga, Marek Pietruszko, Mariusz Piechota, Marta Serwa, Miroslaw Czuczwar, Mirosław Ziętkiewicz, Natalia Kozera, Paweł Nasiłowski, Paweł Sendur, Paweł Zatorski, Piotr Galkin, Ryszard Gawda, Urszula Kościuczuk, Waldemar Cyrankiewicz, Wojciech Gola, Alexandre Fernandes Pinto, Ana Margarida Fernandes, Ana Rita Santos, Cristina Sousa, Inês Barros, Isabel Amorim Ferreira, Jacobo Bacariza Blanco, João Teles Carvalho, Jose Maia, Nuno Candeias, Nuno Catorze, Vladislav Belskiy, Africa Lores, Angela Prado Mira, Catia Cilloniz, David Perez-Torres, Emilio Maseda, Enver Rodriguez, Estefania Prol-Silva, Gaspar Eixarch, Gemma Gomà, Gerardo Aguilar, Gonzalo Navarro Velasco, Marián Irazábal Jaimes, Mercedes Ibarz Villamayor, Noemí Llamas Fernández, Patricia Jimeno Cubero, Sonia López-Cuenca, Teresa Tomasa, Anders Sjöqvist, Camilla Brorsson, Fredrik Schiöler, Henrik Westberg, Jessica Nauska, Joakim Sivik, Johan Berkius, Karin Kleiven Thiringer, Lina De Geer, Sten Walther, Filippo Boroli, Joerg C Schefold, Leila Hergafi, Philippe Eckert, Ismail Yıldız, Ihor Yovenko, Yuriy Nalapko, Richard Pugh, Malbec, Odile, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Mater Misericordiae University Hospital [Dublin] (The Mater Hospital), Jagiellonian University Medical College / Uniwersytet Jagielloński Collegium Medicum [Krakow, Poland], Innsbruck Medical University [Austria] (IMU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), and Intensive Care

Subjects
Aged, 80 and over, Octogenarians, Critical Care, Frailty, Omvårdnad, Research, Critical Illness, [SDV]Life Sciences [q-bio], 610 Medicine & health, Nursing, Cohort Studies, Hospitalization, [SDV] Life Sciences [q-bio], Critical Illness/therapy, Nonagenarians, Humans, Intensive care medicine, Geriatrics and Gerontology, Outcome
Abstract

Funding Information: This study was endorsed by the ESICM. Free support for running the electronic database and was granted from the dep. of Epidemiology, University of Aarhus, Denmark. Financial support for creation of the e-CRF and maintenance of the database was possible from a grant (open project support) by Western Health region in Norway) 2018 who also funded the participating Norwegian ICUs. DRC Ile de France and URC Est helped conducting VIP2 in France. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021, The Author(s). Background: Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients. Methods: We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80–89.9 years) and nonagenarian (> 90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians. Results: The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%; p < 0.001), but lower SOFA scores at admission (6 + 5 vs. 7 + 6; p < 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%; p < 0.001). ICU mortality was comparable (27% vs. 27%; p = 0.973) but a higher 30-day-mortality (45% vs. 40%; p = 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90–1.74; p = 0.19)). Conclusion: After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered– together with illness severity and pre-existing functional capacity - to effectively guide triage decisions. Trial registration: NCT03134807 and NCT03370692. publishersversion published

Published
2021

19. Steroid use in elderly critically ill COVID-19 patients

Author

Wojciech Szczeklik, Hans Flaatten, Michael Joannidis, Mirosław Czuczwar, Christian Jung, Michael Beil, Raphael Romano Bruno, Jesper Fjølner, Tilemachos Zafeiridis, Rui Moreno, Sviri Sigal, Bernardo Bollen Pinto, Bernhard Wernly, Peter Vernon van Heerden, Muhammed Elhadi, Antonio Artigas, David M. Dudzinski, Georg Wolff, Susannah Leaver, Finn H. Andersen, Brian Marsh, Sandra Oeyen, Dylan W. de Lange, Malte Kelm, Joerg C. Schefold, Ariane Boumendil, Maurizio Cecconi, Bertrand Guidet, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Aarhus University Hospital, Massachusetts General Hospital [Boston], Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Geneva University Hospitals and Geneva University, University of Bern, The Hebrew University of Jerusalem (HUJ), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Medical University of Lublin, University of Tripoli - University Al Fateh, Innsbruck Medical University [Austria] (IMU), Ghent University Hospital, University Hospital of Larissa, Mater Misericordiae University Hospital [Dublin] (The Mater Hospital), Aalesund University College, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Humanitas University [Milan] (Hunimed), St George’s University Hospitals, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Utrecht University [Utrecht], University of Bergen (UiB), Haukeland University Hospital, NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), HAL-SU, Gestionnaire, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Mater Misericordiae University Hospital (The Mater Hospital), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, Critical Illness, MEDLINE, 610 Medicine & health, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Secondary analysis, Medicine and Health Sciences, medicine, Research Letter, Humans, MESH: COVID-19, MESH: SARS-CoV-2, 030212 general & internal medicine, Intensive care medicine, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Aged, MESH: Aged, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, business.industry, Critically ill, SARS-CoV-2, fungi, COVID-19, MESH: Steroids, 3. Good health, respiratory tract diseases, body regions, 030228 respiratory system, Steroid use, MESH: Critical Illness, Steroids, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

More than a year after the onset of the SARS-Cov-2 pandemic, treating patients with COVID-19 remains a challenge. By contrast to the rapid development of effective vaccines against SARS-Cov-2, the development of specific and effective therapeutics against COVID-19 remains largely unresolved., This secondary analysis of the COVIP study shows a higher 30-day-mortality in critically ill elderly COVID-19 patients who received steroids as part of their treatment.

Published
2021

20. Quality of life of survivors 1 year after the diagnosis of diffuse large B-cell lymphoma: a LYSA study

Author

Fabrice Jardin, Krimo Bouabdallah, Sandra Malak, Corinne Haioun, Alexandra-Cristina Paunescu, Vincent Ribrag, Gerhard Rumpold, Christiane Copie, Nicolas Mounier, David Sibon, Caroline Besson, Marie Preau, Steven Le Gouill, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), CHU Henri Mondor, Institut Curie - Saint Cloud (ICSC), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'hématologie [Gustave Roussy], CHU Bordeaux [Bordeaux], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Groupe de Recherche en Psychologie Sociale (GRePS), Université Lumière - Lyon 2 (UL2), Institut de Psychologie, Hôpital l'Archet, Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier de Versailles André Mignot (CHV), Bernardo, Elizabeth, and Innsbruck Medical University [Austria] (IMU)

Subjects
Adult, Male, medicine.medical_specialty, Lymphoma, Health Status, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Hospital Anxiety and Depression Scale, Comorbidities, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Quality of life, Cancer Survivors, Internal medicine, Bayesian multivariate linear regression, Surveys and Questionnaires, medicine, Chemotherapy, Humans, Survivors, Depression (differential diagnoses), Aged, Aged, 80 and over, Posttraumatic growth, business.industry, Hematology, General Medicine, Middle Aged, medicine.disease, humanities, Quality of Life, Original Article, Female, Lymphoma, Large B-Cell, Diffuse, business, Diffuse large B-cell lymphoma, Psychosocial
Abstract

Health-related quality of life (HRQoL) is a multidimensional concept including physical, emotional, social, and cognitive functions, disease symptoms, and side effects of treatment. Differences in HRQoL due to gender, existence of comorbidities, and number of chemotherapy cycles are little explored in diffuse large B-cell lymphoma (DLBCL) survivors. Our objective was to investigate whether differences in HRQoL in function of these factors exist 1 year after the diagnosis of DLBCL. One hundred and one patients, enrolled in the RT3 (Real-Time Tailored Therapy) Study, answered self-administrated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC High-Grade Non-Hodgkin Lymphoma (NHL-HG29), Hospital Anxiety and Depression Scale (HADS), Post Traumatic Growth Inventory (PTGI), and Multidimensional Fatigue Inventory (MFI) questionnaires. Adjusted means of scores were calculated in multivariate linear regression models. Fifty-seven survivors (mean age of 58.5 years) answered all questionnaires. Women have significantly higher scores of posttraumatic growth and lower physical functioning than men (P < 0.04). Survivors with comorbidities have increased physical fatigue and symptom burden, increased emotional impact, mental fatigue and depression, and reduced physical functioning and global health status (all P < 0.05). A greater number of cycles of chemotherapy increase the level of symptoms (pain, neuropathy, and dyspnoea; P < 0.05). The various aspects related to HRQoL should be discussed with DLBCL patients and investigated, with the aim of developing strategies to ensure appropriate psychosocial and supportive care and to improve the HRQoL in these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04689-4.

Published
2021

21. Characterizing Convection Schemes Using Their Responses to Imposed Tendency Perturbations

Author

Y L Hwong, Steven C. Sherwood, Alison Stirling, Romain Roehrig, Penelope Maher, Robert S. Plant, Ludovic Touzé-Peiffer, Siwon Song, Catherine Rio, David Fuchs, Chimene Laure Daleu, University of New South Wales [Sydney] (UNSW), School of Physics [UNSW Sydney] (UNSW), United Kingdom Met Office [Exeter], Centre national de recherches météorologiques (CNRM), Institut national des sciences de l'Univers (INSU - CNRS)-Météo France-Centre National de la Recherche Scientifique (CNRS), University of Reading (UOR), Innsbruck Medical University [Austria] (IMU), University of Exeter, Laboratoire de Météorologie Dynamique (UMR 8539) (LMD), Institut national des sciences de l'Univers (INSU - CNRS)-École polytechnique (X)-École des Ponts ParisTech (ENPC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département des Géosciences - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
Convection, Physical geography, 010504 meteorology & atmospheric sciences, Parameterized complexity, 3d model, GC1-1581, Classification of discontinuities, [SDU.STU.ME]Sciences of the Universe [physics]/Earth Sciences/Meteorology, Oceanography, 010502 geochemistry & geophysics, 01 natural sciences, radiative‐convective equilibrium, Environmental Chemistry, idealized model, Statistical physics, atmospheric modelling, convection, Physics::Atmospheric and Oceanic Physics, 0105 earth and related environmental sciences, Global and Planetary Change, Forcing (recursion theory), Atmospheric models, linear response function, climate modelling, Linear response function, GB3-5030, SCM, convective parameterization, atmospheric convection, General Circulation Model, General Earth and Planetary Sciences, single-column models, radiative-convective equilibrium
Abstract

This repository contains the data and scripts required to reproduce the results of the paper "Characterizing Convection Schemes Using Their Responses to Imposed Tendency Perturbations" submitted to the Journal of Advances inModeling Earth Systems (JAMES). Brief description of project An SCM intercomparison project based on the Linear Response Function framework of Kuang (2010), where we examine the temperature and moisture responses to small convective tendency perturbations. Participating Single-Column Models (SCMs): WRF, LMDZ, CNRM, UM, SCAM Convection schemes tested: WRF Kain-Fritsch WRF New-Tiedtke WRF New-Simplified-Arakawa-Schubert WRF Betts-Miller-Janjic WRF Zhang-McFarlane CNRM PCMT scheme UM Simplified-Betts-Miller UM Mass-Flux scheme (Gregory & Rowntree) SCAM Zhang-McFarlane LMDZ modified-Emanuel scheme + Cold pool formulation Repository structure /data directory: contains the data from the SCMs, in csv format /data/[model_name]/ directories: contain the data of the individual models. There are four sub-directories (five for WRF) for each model: REF directory: contains data for RCE mean state, including Temperature (T) and Relative Humidity (RH) matrix_X_raw directory: contains raw data for the T and q responses to dT/dt and dq/dt perturbations matrix_M_inv directory: contains the post-processed (normalized and standardized) M-1 matrix data response_profiles directory: contains the post-processed response profiles (vertical column) for perturbation at two levels (850 and 650 hPa) (for WRF only) pbl_mp_sensitivity directory: data for WRF PBL and MP sensitivity tests. There are three sub-directories in this folder: mean_states directory: contains data for the RCE mean state sensitivity to PBL and MP schemes response_profiles directory: contains data for the sensitivity of T and q responses to PBL and MP schemes response_profiles_non_idealized directory: contains data to compare sensitivity of T and q responses to PBL and MP schemes between idealized and non-idealized setups /scripts directory: contains the python scripts to post-process and plot the figures in the paper /scripts/plot_inidividual_matrix/ directory: contains scripts to plot the M-1 matrix and the 2-levels response profiles for individual SCMs plot_matrix.py : script to post-process and plot the matrix and response profiles for selected SCM using the raw data in the matrix_X_raw folders. Option available to save the (post-processed) outputs as csv files in the matrix_M_inv and response_profiles folders of the selected SCM /scripts/plot_figures/ directory: contains scripts to plot the Figures in the paper plot_rce_mean_states_all_models.py : script to plot Figure 1 (RCE mean state T and RH of all SCMs) plot_anomaly_profiles.py : script to plot Figure 2 - 3 (vertical profiles of T and q responses for selected SCMs) plot_matrix_all_models.py : script to plot Figures 4 - 7 (M-1 matrices of all SCMs) plot_rh_q_correlation_matrix.py : script to plot Figure 8 (correlation matrix of RH vs. q') plot_pbl_mp_sensitivity_mean_states.py : script to plot Figures 9 - 10 (sensitivity of RCE mean state to PBL and MP schemes) plot_pbl_mp_sensitivity_responses.py : script to plot Figures 11 - 12 (sensitivity of T and q responses to PBL and MP schemes) plot_pbl_mp_sensitivity_responses_non_idealized.py : script to plot Figures A1 - A2 (sensitivity of T and q responses to PBL and MP schemes comparison between idealized and non-idealized setups) &nbsp

Published
2021

22. Chemotherapy and diffuse low-grade gliomas: a survey within the European Low-Grade Glioma Network

Author

Joachim P. Steinbach, Fabien Almairac, Catarina Pessanha Viegas, Andreas F. Hottinger, Luisa Albuquerque, Martin Voss, Johan Pallud, Geert-Jan Rutten, Marie-Therese Forster, Concetta Di Blasi, Denys Fontaine, Giuseppe Luigi Banna, Gord von Campe, Luc Taillandier, Daniel Pinggera, Marie-Hélène Baron, Nicolas Foroglou, Marie Blonski, John Goodden, Christian F. Freyschlag, Carmel Loughrey, Hugues Duffau, Emmanuel Mandonnet, Tadeja Urbanic-Purkart, Amélie Darlix, Salvy-Córdoba, Nathalie, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Goethe-University Frankfurt am Main, Leeds General Infirmary (LGI), Leeds Teaching Hospitals NHS Trust, Università degli studi di Catania = University of Catania (Unict), Aristotle University of Thessaloniki, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tilburg University [Tilburg], Netspar, Hôpital Pasteur [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hospital Garcia de Orta (EPE), EPE- HOSPITAL GARCIA DE ORTA, Medical University Graz, Service de Neuro-Oncologie [CHRU Nancy], Innsbruck Medical University [Austria] (IMU), Università degli studi di Catania [Catania], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, diffuse low-grade glioma, Medicine (miscellaneous), [SDV.CAN]Life Sciences [q-bio]/Cancer, temozolomide, Procarbazine, chemotherapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Glioma, Medicine, ddc:610, Chemotherapy, Temozolomide, business.industry, Lomustine, Original Articles, medicine.disease, PCV, clinical practice, Chemotherapy regimen, 3. Good health, Radiation therapy, Regimen, 030220 oncology & carcinogenesis, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.

Published
2018

23. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Author

Saharnaz Sarlak, Claude Lalou, Rodrigue Rossignol, Andras T. Meszaros, Helmut Klocker, Christian Frezza, Juan Alberto Pérez-Valencia, Ana Carolina B Sant'Anna-Silva, Erich Gnaiger, Laura Tronci, Efterpi Nikitopoulou, Marco Sciacovelli, Innsbruck Medical University [Austria] (IMU), University of Cambridge [UK] (CAM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Perez-Valencia, Juan A. [0000-0002-8282-1763], Tronci, Laura [0000-0002-1217-4046], Klocker, Helmut [0000-0001-7732-9443], Apollo - University of Cambridge Repository, Perez-Valencia, Juan A [0000-0002-8282-1763], Admin, Oskar, and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
0301 basic medicine, Cancer Research, Cell signaling, cancer metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oxidative phosphorylation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biosynthesis, Downregulation and upregulation, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Extracellular, medicine.disease, prostate cancer, succinate, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Citric acid cycle, mitochondria, anaplerosis, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research
Abstract

Simple Summary Depending on the availability of nutrients and increased metabolic demands, tumor cells rearrange their metabolism to survive and, ultimately, proliferate. Here, the authors investigated the effect of succinate, a metabolite of the mitochondrial citric acid cycle, on malignant and non-malignant prostate cells. They analyzed uptake through membrane transporters and intracellular accumulation, which subsequently fuels metabolism and enhances oncogenic properties of the tumor cells. The findings shed light to the metabolic adaptations that prostate tumor cells undergo, providing a better understanding of metabolic rewiring and strategies for therapeutic intervention. Abstract Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.

Published
2021

24. Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Author

Natan Gadoth, Birgit Högl, Rosa Hasan, G. Plazzi, Andrea N. Goldstein-Piekarski, Makrina Daniilidou, Thomas J Rico, Smaranda Leu-Semenescu, Ryan P. Hillary, Neal M. Farber, Guy D. Leschziner, Emmanuel Mignot, Yakov Sivan, Michel Lecendreux, José L. Vicario, Hanna Ollila, Juliette Faraco, Sona Nevsimalova, Isabelle Arnulf, Fang Han, Francesca Canellas, Pauline Dodet, Patrice Bourgin, Geert Mayer, Fabio Pizza, Makoto Honda, Yu-Shu Huang, Kazuhiko Kume, Rosa Peraita-Adrados, Ling Lin, David B. Rye, Takashi Kanbayashi, Eileen B. Leary, Seung Chul Hong, Emmanuel H. During, Anne-Marie Landtblom, Yves Dauvilliers, Aditya Ambati, Ambati A., Hillary R., Leu-Semenescu S., Ollila H.M., Lin L., During E.H., Farber N., Rico T.J., Faraco J., Leary E., Goldstein-Piekarski A.N., Huang Y.-S., Han F., Sivan Y., Lecendreux M., Dodet P., Honda M., Gadoth N., Nevsimalova S., Pizza F., Kanbayashi T., Peraita-Adrados R., Leschziner G.D., Hasan R., Canellas F., Kume K., Daniilidou M., Bourgin P., Rye D., Vicario J.L., Hogl B., Hong S.C., Plazzi G., Mayer G., Landtblom A.M., Dauvilliers Y., Arnulf I., Mignot E.J.-M., Retiveau, Nolwenn, Stanford University, Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence pour les Maladies Rares : narcolepsie, hypersomnie idiopathique et syndrome de Kleine-Levin [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Veterans Affairs Palo Alto Healthcare System, Chang Gung Memorial Hospital [Taipei] (CGMH), Peking University [Beijing], Sackler Faculty of Medicine, Tel Aviv University (TAU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Tokyo Metropolitan Institute of Medical Science (TMIMS), Tel Aviv Sourasky Medical Center [Te Aviv], Charles University [Prague] (CU), University of Bologna/Università di Bologna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université de Tsukuba = University of Tsukuba, Hospital General Universitario 'Gregorio Marañón' [Madrid], Guy's Hospital [London], King‘s College London, Universidade de São Paulo = University of São Paulo (USP), Nagoya City University [Nagoya, Japan], Uppsala University Hospital, Linköping university hospital, CHU Strasbourg, Emory University [Atlanta, GA], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Catholic University of Korea, Philipps Universität Marburg = Philipps University of Marburg, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Pediatrics, Bipolar Disorder, [SDV]Life Sciences [q-bio], Genome-wide association study, MESH: Risk Assessment, MESH: Pregnancy, MESH: Risk Factors, Pregnancy, MESH: Bipolar Disorder, Birth difficultie, Odds Ratio, GWAS, Apathy, MESH: Genetic Variation, Obstetric Labor Complication, MESH: Genetic Association Studies, MESH: Cytokines, Hypersomnia, Multidisciplinary, MESH: Genetic Predisposition to Disease, Pathophysiology, [SDV] Life Sciences [q-bio], Schizophrenia, Female, Disease Susceptibility, medicine.symptom, MESH: Kleine-Levin Syndrome, Human, medicine.medical_specialty, MESH: Obstetric Labor Complications, MESH: Disease Susceptibility, Birth difficulties, Disorders of Excessive Somnolence, Genetic Association Studie, Kleine-Levin Syndrome, Risk Assessment, MESH: Polymorphism, Genetic, medicine, Genetic Predisposition to Disease, Bipolar disorder, Cytokine, MESH: Humans, Polymorphism, Genetic, business.industry, Risk Factor, Genetic Variation, Odds ratio, medicine.disease, MESH: Male, MESH: Odds Ratio, Kleine–Levin syndrome, Kleine-Levin syndrome, bipolar disorder, birth difficulties, hypersomnia, Disinhibition, business, MESH: Female, MESH: Disorders of Excessive Somnolence
Abstract

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case.control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2= 0.15; P < 2.0 ∼ 10-22at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Published
2021

25. The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in Streptomyces lividans

Author

Catherine Esnault, Delin Xu, Noriyasu Shikura, Sebastiaan Werten, Ariane Deniset-Besseau, David Cornu, Eric Jacquet, Marie-Joelle Virolle, Naïma Nhiri, Clara Lejeune, Laila Sago, Cécile Martel, Emmanuelle Darbon, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Physique (ICP), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Jinan University [Guangzhou], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), ANR-17-ASTR-0018,INNOVANTIBIO,MISE EN OEUVRE D UNE STRATEGIE INNOVANTE POUR LA DECOUVERTE DE NOUVEAUX ANTIBIOTIQUES A PARTIR DES BACTERIES STREPTOMYCES(2017), Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Innsbruck Medical University [Austria] (IMU)

Subjects
0301 basic medicine, Microbiology (medical), Operon, [SDV]Life Sciences [q-bio], 030106 microbiology, Mutant, Phosphatase, Biochemistry, Microbiology, Nudix hydrolase, Streptomyces, Actinorhodin, 03 medical and health sciences, Polyphosphate kinase, chemistry.chemical_compound, antibiotic, pho regulon, CHAD domain, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, phosphate, biology, lcsh:RM1-950, biology.organism_classification, Cell biology, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Infectious Diseases, Regulon, polyphosphates, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry
Abstract

In Streptomyces, antibiotic biosynthesis is triggered in phosphate limitation that is usually correlated with energetic stress. Polyphosphates constitute an important reservoir of phosphate and energy and a better understanding of their role in the regulation of antibiotic biosynthesis is of crucial importance. We previously characterized a gene, SLI_4384/ppk, encoding a polyphosphate kinase, whose disruption greatly enhanced the weak antibiotic production of Streptomyces lividans. In the condition of energetic stress, Ppk utilizes polyP as phosphate and energy donor, to generate ATP from ADP. In this paper, we established that ppk is co-transcribed with its two downstream genes, SLI_4383, encoding a phosin called PptA possessing a CHAD domain constituting a polyphosphate binding module and SLI_4382 encoding a nudix hydrolase. The expression of the ppk/pptA/SLI_4382 operon was shown to be under the positive control of the two-component system PhoR/PhoP and thus mainly expressed in condition of phosphate limitation. However, pptA and SLI_4382 can also be transcribed alone from their own promoter. The deletion of pptA resulted into earlier and stronger actinorhodin production and lower lipid content than the disruption of ppk, whereas the deletion of SLI_4382 had no obvious phenotypical consequences. The disruption of ppk was shown to have a polar effect on the expression of pptA, suggesting that the phenotype of the ppk mutant might be linked, at least in part, to the weak expression of pptA in this strain. Interestingly, the expression of phoR/phoP and that of the genes of the pho regulon involved in phosphate supply or saving were strongly up-regulated in pptA and ppk mutants, revealing that both mutants suffer from phosphate stress. Considering the presence of a polyphosphate binding module in PptA, but absence of similarities between PptA and known exo-polyphosphatases, we proposed that PptA constitutes an accessory factor for exopolyphosphatases or general phosphatases involved in the degradation of polyphosphates into phosphate.

Published
2021

26. Impact of Phosphate Availability on Membrane Lipid Content of the Model Strains, Streptomyces lividans and Streptomyces coelicolor

Author

Clara Lejeune, Sonia Abreu, Pierre Chaminade, Thierry Dulermo, Michelle David, Sebastiaan Werten, Marie-Joelle Virolle, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Lipides : systèmes analytiques et biologiques (Lip(Sys)²), Université Paris-Saclay, Lesaffre International, Innsbruck Medical University [Austria] (IMU), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), ANR-11-BTBR-0003,PROBIO3,Production biocatalytique de bioproduits lipidiques à partir de matières premières renouvelables et(2011), and ANR-17-ASTR-0018,INNOVANTIBIO,MISE EN OEUVRE D UNE STRATEGIE INNOVANTE POUR LA DECOUVERTE DE NOUVEAUX ANTIBIOTIQUES A PARTIR DES BACTERIES STREPTOMYCES(2017)

Subjects
Microbiology (medical), phosphatidylinositol, Operon, lcsh:QR1-502, Phospholipid, ornithine lipids, Microbiology, lcsh:Microbiology, phosphate limitation, 03 medical and health sciences, chemistry.chemical_compound, Biosynthesis, acyltransferase, Phosphatidylinositol, phospholipase C, phospholipids, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Chemistry, Streptomyces coelicolor, Wild type, Ornithine, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, hemolysin, Complementation, Biochemistry, bacteria, lipids (amino acids, peptides, and proteins), triacylglycerol
Abstract

In this issue we demonstrated that the phospholipid content of Streptomyces lividans varies greatly with Pi availability being was much lower in Pi limitation than in Pi proficiency whereas that of Streptomyces coelicolor varied little with Pi availability. In contrast the content in phosphate free ornithine lipids was enhanced in both strains in condition of phosphate limitation. Ornithine lipids biosynthesis starts with the N-acylation of ornithine to form lyso-ornithine that is then O-acylated to yield ornithine lipid. The operon sco1222-23 was proposed to be involved in the conversion of specific amino acids into ornithine in condition of phosphate limitation whereas the sco0921-20 operon encoding N- and O-acyltransferase, respectively, was shown to be involved in the biosynthesis of these lipids. The expression of these two operons was shown to be under the positive control of the two components system PhoR/PhoP and thus induced in phosphate limitation. The expression of phoR/phoP being weak in S. coelicolor, the poor expression of these operons resulted into a fivefold lower ornithine lipids content in this strain compared to S. lividans. In the deletion mutant of the sco0921-20 operon of S. lividans, lyso-ornithine and ornithine lipids were barely detectable and TAG content was enhanced. The complementation of this mutant by the sco0921-20 operon or by sco0920 alone restored ornithine lipids and TAG content to wild type level and was correlated with a twofold increase in the cardiolipin content. This suggested that SCO0920 bears, besides its broad O-acyltransferase activity, an N-acyltransferase activity and this was confirmed by the detection of lyso-ornithine in this strain. In contrast, the complementation of the mutant by sco0921 alone had no impact on ornithine lipids, TAG nor cardiolipin content but was correlated with a high lyso-ornithine content. This confirmed that SCO0921 is a strict N-acyltransferase. However, interestingly, the over-expression of the sco0921-20 operon or of sco0921 alone in S. coelicolor, led to an almost total disappearance of phosphatidylinositol that was correlated with an enhanced DAG and TAG content. This suggested that SCO0921 also acts as a phospholipase C, degrading phosphatidylinositol to indirectly supply of phosphate in condition of phosphate limitation.

Published
2021

27. Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group

Author

Rocchi, S, Scherer, E, Mengoli, C, Alanio, A, Botterel, F, Bougnoux, M, Bretagne, S, Cogliati, M, Cornu, M, Dalle, Frédéric, Damiani, Céline, Denis, J, Fuchs, S, Gits-Muselli, M, Hagen, F, Halliday, C, Hare, R, Iriart, Xavier, Klaassen, C, Lackner, M, Lengerova, M, Letscher-Bru, V, Morio, F, Nourrisson, C, Posch, W, Sendid, B, Springer, J, Willinger, B, White, P, Barnes, R, Cruciani, M, Donnelly, J, Loeffler, J, Millon, L, Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Università degli Studi di Padova = University of Padua (Unipd), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Université Paris Cité (UPCité), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École nationale vétérinaire - Alfort (ENVA), CHU Henri Mondor [Créteil], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Università degli Studi di Milano = University of Milan (UNIMI), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de parasitologie mycologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Vin Aliment Microbiologie et Stress (VAlMiS), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Parasitologie et de Mycologie Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Leopold Franzens Universität Innsbruck - University of Innsbruck, UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Univ Utrecht, Westerdijk Fungal Biodivers Inst, Fungal Physiol, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands, Partenaires INRAE, University Medical Center [Utrecht], Shanghai Key Laboratory of Molecular Medical Mycology, Changzheng Hospital, Second Military Medical University, Statens Serum Institut [Copenhagen], Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Brno, CHU Strasbourg, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, University Hospital Wuerzburg / Universitäts­klinikum Würzburg, Medizinische Universität Wien = Medical University of Vienna, Public Health Wales [Cardiff, Royaume uni], University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], This work was supported by a grant from the French Ministry of Health PHRC (Projet Hospitalier de Recherche Clinique) national-ModiMucor 2014-A00580-47., Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Génomique évolutive, modélisation et santé (CNRS-UMR2000), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), CHU Henri Mondor, Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris]-Université Paris Cité (UPCité), University of Innsbruck, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris]-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Padova Medical School, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Université Paris Cité - UFR Médecine Paris Centre [Santé] (UPC Médecine Paris Centre), Université Paris Cité (UPC), Institut Pasteur [Paris]-Université Paris Cité (UPC), and Università degli Studi di Milano [Milano] (UNIMI)

Subjects
standardization, MESH: Clinical Laboratory Techniques / instrumentation, MESH: Humans, MESH: Mucorales / genetics, Mucorales PCR, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, circulating DNA, MESH: Molecular Diagnostic Techniques / standards, MESH: Observer Variation, MESH: Mucormycosis / blood, MESH: Reproducibility of Results, MESH: France, interlaboratory assay, MESH: Real-Time Polymerase Chain Reaction / standards, MESH: Hospitals, University / statistics & numerical data, MESH: Clinical Laboratory Techniques / standards, MESH: DNA, Fungal / genetics, MESH: Clinical Laboratory Techniques / methods, MESH: Mucormycosis / diagnosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

Published
2021

28. Reliability of the Clinical Frailty Scale in very elderly ICU patients: a prospective European study

Author

Flaatten, Hans, the VIP2 Study Group, [missing], Guidet, Bertrand, Andersen, Finn H., Artigas, Antonio, Cecconi, Maurizio, Boumendil, Ariane, Elhadi, Muhammed, Fjølner, Jesper, Joannidis, Michael, Jung, Christian, Leaver, Susannah, Marsh, Brian, Moreno, Rui, Oeyen, Sandra, Nalapko, Yuriy, Schefold, Joerg C., Szczeklik, Wojciech, Walther, Sten, Watson, Ximena, Zafeiridis, Tilemachos, de Lange, Dylan W., Gestionnaire, HAL Sorbonne Université 5, University of Bergen (UiB), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Service de Réanimation Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Tripoli - University Al Fateh, Aarhus University Hospital, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Düsseldorf, St George's, University of London, University of Dublin, Instituto Universitário de Lisboa (ISCTE-IUL), Ghent University Hospital, European Wellness, University of Bern, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Linköping university hospital, University Hospital of Larissa, University Medical Center [Utrecht], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Innsbruck Medical University [Austria] (IMU)

Subjects
Icu patients, medicine.medical_specialty, Anestesi och intensivvård, Octogenarians, health care facilities, manpower, and services, 610 Medicine & health, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Clinical frailty scale, Inter-rater variability, Intensive care, Anesthesiology, medicine, Medicine and Health Sciences, 030212 general & internal medicine, Reliability (statistics), Anesthesiology and Intensive Care, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, 3. Good health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Scale (social sciences), Cohort, Physical therapy, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Kappa
Abstract

Purpose Frailty is a valuable predictor for outcome in elderly ICU patients, and has been suggested to be used in various decision-making processes prior to and during an ICU admission. There are many instruments developed to assess frailty, but few of them can be used in emergency situations. In this setting the clinical frailty scale (CFS) is frequently used. The present study is a sub-study within a larger outcome study of elderly ICU patients in Europe (the VIP-2 study) in order to document the reliability of the CFS. Materials and methods From the VIP-2 study, 129 ICUs in 20 countries participated in this sub-study. The patients were acute admissions ≥ 80 years of age and frailty was assessed at admission by two independent observers using the CFS. Information was obtained from the patient, if not feasible, from the family/caregivers or from hospital files. The profession of the rater and source of data were recorded along with the score. Interrater variability was calculated using linear weighted kappa analysis. Results 1923 pairs of assessors were included and background data of patients were similar to the whole cohort (n = 3920). We found a very high inter-rater agreement (weighted kappa 0.86), also in subgroup analyses. The agreement when comparing information from family or hospital records was better than using only direct patient information, and pairs of raters from same profession performed better than from different professions. Conclusions Overall, we documented a high reliability using CFS in this setting. This frailty score could be used more frequently in elderly ICU patients in order to create a more holistic and realistic impression of the patient´s condition prior to ICU admission.

Published
2021

29. EAN consensus statement for management of patients with neurological diseases during the COVID-19 pandemic

Author

Marialuisa Zedde, S Oztuk, Claudio L. Bassetti, Michael Crean, T. J. von Oertzen, Antonella Macerollo, Raimund Helbok, Johann Sellner, Ettore Beghi, L. Campiglio, Luis F. Maia, Alex Twardzik, Martin Rakusa, Antonio Pisani, Riccardo Soffietti, Celia Oreja-Guevara, Elisa Bianchi, Thomas M Jenkins, Pille Taba, Elena Moro, G. Di Liberto, Francesco Cavallieri, Daniel Bereczki, Anna Sauerbier, Maurizio Leone, Benedetta Bodini, Johannes Kepler Universität Linz (JKU), The Walton Centre NHS Foundation Trust, University of Liverpool, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), European Academy of Neurology [Vienna, Austria] (Head Office), Selcuk University [Konya, Turkey] (Faculty of Medicine), University of Bern, Semmelweis University of Medicine [Budapest], Faculté de médecine [Genève], Innsbruck Medical University [Austria] (IMU), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Università degli Studi di Roma Tor Vergata [Roma], University Hospital of Cologne [Cologne], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University of Turin, Università degli Studi di Modena e Reggio Emilia, Service de neurologie [Saint-Antoine], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Università degli Studi di Milano [Milano] (UNIMI), Centro Hospitalar do Porto, University of Maribor, University of Tartu, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), University of Sheffield [Sheffield], Gestionnaire, Hal Sorbonne Université, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Service de Neurologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Università degli Studi di Milano = University of Milan (UNIMI)

Subjects
medicine.medical_specialty, Neurology, Consensus, Delphi Technique, Statement (logic), [SDV]Life Sciences [q-bio], education, Clinical Neurology, Delphi method, 610 Medicine & health, Guidelines as Topic, Disease, Guidelines, Likert scale, 03 medical and health sciences, 0302 clinical medicine, COVID‐19, Pandemic, Medicine, Humans, 030212 general & internal medicine, human, Pandemics, chronic disease, COVID-19, neurology, practice guideline, business.industry, Subject (documents), ddc, 3. Good health, Patient Care Management, [SDV] Life Sciences [q-bio], Nervous System Diseases, Family medicine, Good clinical practice, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background and purpose\ud \ud The recent SARS‐CoV‐2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast‐evolving pandemic, evidence‐based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID‐19.\ud \ud \ud Methods\ud \ud A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co‐chairs rated importance on a five‐point Likert scale. Results were graded by importance and reported as consensus statements.\ud \ud \ud Results\ud \ud In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty‐nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co‐chairs of 29 SPs. Whilst general recommendations related to prevention of COVID‐19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy.\ud \ud \ud Conclusion\ud \ud This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID‐19 pandemic that provides immediate guidance for neurologists. In this fast‐evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

Published
2021

30. Baseline Levels of C-Reactive Protein and Proinflammatory Cytokines Are Not Associated with Early Response to Amisulpride in Patients with First Episode Psychosis

Author

W. Wolfgang Fleischhacker, René S. Kahn, Robert H. Yolken, El Chérif Ibrahim, Celso Arango, Olfa Khalfallah, Susana Barbosa, Richard Drake, Laetitia Davidovic, Philip McGuire, Shôn Lewis, Inge Winter van Rossum, Dan Rujescu, Cyprien Gilet, Paola Dazzan, Emanuela Martinuzzi, Raoul Belzeaux, Marion Leboyer, Birte Glenthøj, Nicolas Glaichenhaus, Covadonga M. Díaz-Caneja, Stefan Leucht, Iris E. C. Sommer, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), University Medical Center Groningen [Groningen] (UMCG), University of Bergen (UiB), King‘s College London, Hospital General Universitario 'Gregorio Marañón' [Madrid], Innsbruck Medical University [Austria] (IMU), University of Halle, Partenaires INRAE, Glostrup Hospital, IT University of Copenhagen, University Medical Center [Utrecht], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Johns Hopkins University School of Medicine [Baltimore], University of Manchester [Manchester], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Movement Disorder (MD), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Université Nice Sophia Antipolis (1965 - 2019) (UNS), IT University of Copenhagen (ITU), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Technische Universität München [München] (TUM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), and CHU Henri Mondor [Créteil]

Subjects
0301 basic medicine, Psychosis, medicine.medical_specialty, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, remission, Internal medicine, medicine, Amisulpride, psychosis, Adverse effect, Positive and Negative Syndrome Scale, biology, business.industry, C-reactive protein, longitudinal study, medicine.disease, 3. Good health, Clinical trial, Psychiatry and Mental health, 030104 developmental biology, inflammation, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, proinflammatory cytokines, biology.protein, business, 030217 neurology & neurosurgery, medicine.drug, Cohort study
Abstract

Background Patients with a First-Episode of Psychosis (FEP) exhibit low-grade inflammation as demonstrated by elevated levels of C reactive protein (CRP) and pro-inflammatory cytokines. Aims The primary goal of this study was to investigate the association between pro-inflammatory biomarkers and clinical outcomes in unmedicated FEP patients. Method We used clinical data and biological samples from 289 FEP patients participating to the Optimization of Treatment and Management of Schizophrenia in Europe (OPTIMISE) clinical trial. Patients were assessed at baseline and 4-5 weeks after treatment with amisulpride. Baseline serum levels of interleukin (IL)-6, IL-8, Tumor Necrosis Factor (TNF)-α and CRP were measured. We first used multivariable regression to investigate the association between each of the four tested biomarkers and the following clinical outcomes: Positive And Negative Syndrome Scale (PANSS), Calgary Depression Score for Schizophrenia (CDSS), remission according to Andreasen’s criteria and Serious Adverse Events (SAEs). As a complementary approach, we used an unsupervised clustering method to stratify patients into an “inflamed” or a “non-inflamed” biotype based on baseline levels of IL-6, IL-8 and TNF-α. We then used linear and logistic regressions to investigate the association between the patient biotype and clinical outcomes. Results After adjusting for covariates and confounders, we did not find any association between IL-6, IL-8, TNF-α, CRP or the patient biotype and clinical outcomes. Implications Our results do not support the existence of an association between baseline levels of CRP and proinflammatory cytokines and early response to amisulpride in unmedicated FEP patients.

Published
2021

31. The Role of Complement in Microbial Infections

Author

Iara Taborda de Messias Reason, Nicole M. Thielens, Heribert Stoiber, Reinhard Würzner, Innsbruck Medical University [Austria] (IMU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratório de Imunopatologia Molecular, Universidade Tecnológica Federal do Paraná [Curitiba] (UTFPR), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)

Subjects
lcsh:Immunologic diseases. Allergy, Immunology, Biology, parasites, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Microbiology, 03 medical and health sciences, 0404 agricultural biotechnology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Humans, complement, viruses, bacteria, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, pathogens, 04 agricultural and veterinary sciences, Bacterial Infections, Complement System Proteins, 040401 food science, Complement (complexity), Editorial, Mycoses, Virus Diseases, fungi, lcsh:RC581-607
Abstract

International audience

Published
2021

32. ELIXIR and Toxicology : a community in development

Author

Noelia Ramirez, Iseult Lynch, Nikolaos S. Thomaidis, Ralf J. M. Weber, Hilda Witters, Evan E Bolton, Antony Williams, Pavel Babica, Susanna-Assunta Sansone, Kasia Arturi, Anže Županič, Gerard J.P. van Westen, Karine Audouze, Sergio Martinez Cuesta, Tobias Schulze, Jos Bessems, Dimitrios Damalas, Montserrat Cases, Penny Nymark, Ferran Sanz, Uko Maran, Haralambos Sarimveis, Ludek Blaha, Jaroslav Slobodnik, Jos C. S. Kleinjans, Todor Kondic, Hristo Aladjov, Egon Willighagen, Hervé Ménager, Brett Sallach, Danyel Jennen, Sirarat Sarntivijai, Roland C. Grafström, Rob Stierum, Jonathan Tedds, John M. Hancock, Reza M. Salek, Boï Kone, Karel Berka, Herbert Oberacher, Craig E. Wheelock, Steffen Neumann, Alasdair J. G. Gray, Pascal Kahlem, Sylvie Remy, Emma L. Schymanski, Marco Dilger, Ola Spjuth, Barbara Zdrazil, Marvin Martens, Kirtan Dave, Jana Klánová, Henner Hollert, Daan P. Geerke, Philippe Rocca-Serra, Nina Jeliazkova, Thomas Exner, Chris T. Evelo, Fabien Jourdan, Reza Aalizadeh, Department of Bioinformatics, Maastricht University Medical Center (BiGCaT), The Netherlands Organisation for Applied Scientific Research (TNO), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Maastricht Centre for Systems Biology, Maastricht University Medical Center (MaCSBio), National and Kapodistrian University of Athens (NKUA), Bulgarian Academy of Sciences (BAS), Swiss Federal Institute of Aquatic Science & Technology (EAWA), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Research Centre for Toxic Compounds in the Environment [Brno] (RECETOX / MUNI), Faculty of Science [Brno] (SCI / MUNI), Masaryk University [Brno] (MUNI)-Masaryk University [Brno] (MUNI), Palacky University Olomouc, Flemish Institute for Technological Research (VITO), National Center for Biotechnology Information (NCBI), Chemotargets SL, GSFC University, Forschungs- und Beratungsinstitut Gefahrstoffe GmbH (FoBiG), Seven Past Nine, Vrije Universiteit Amsterdam [Amsterdam] (VU), Karolinska Institutet [Stockholm], Misvik Biology, Heriot-Watt University [Edinburgh] (HWU), ELIXIR Hub [Cambridge], Goethe-University Frankfurt am Main, Ideaconsult, Maastricht University [Maastricht], ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Faculté de Médecine, de pharmacie et d’Odonto-Stomatologie [Bamako, Mali] (FMPOS), Université de Bamako, University of Birmingham [Birmingham], University of Tartu, AstraZeneca [Cambridge, UK], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Français de Bioinformatique (IFB-CORE), Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Leibniz Institute of Plant Biochemistry (IPB), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Universitat Rovira i Virgili, University of Oxford, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of York [York, UK], Universitat Pompeu Fabra [Barcelona] (UPF), National Technical University of Athens [Athens] (NTUA), Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Environmental Institute Kos, Uppsala University, Leiden Academic Center for Drug Research, United States Environmental Protection Agency [Cincinnati], University of Vienna [Vienna], National Institute of Biology [Ljubljana] (NIB), This work received funding from the European Union’s Horizon 2020 research infrastrcuture programme via the OpenRiskNet project under grant agreement No. 731075.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 681002 (EU-ToxRisk).This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 814572.SN acknowledges BMBF funding under grant number 031L0107.This work was supported by OBERON (https://oberon-4eu.com), a project funded by the European Union's Horizon 2020 research and innovation program under the grant agreement No. 825712.This work was supported by the European Union,'s Horizon 2020 research and innovation program HBM4EU, grant agreement No. 733032 (https://www.hbm4eu.eu).Supported by the European Union’s Horizon 2020 programme under the Marie Skłodowska-Curie grant agreement No. 859891.Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.This work was supported by the European Union,'s Horizon 2020 research and innovation program HARMLESS, grant agreement No. 953183.This work was supported by the European Union,'s Horizon 2020 research and innovation program Gov4Nano, grant agreement No. 814401.This work was supported by the Swedish Fund for Research Without Animal Experiments under grant number N2020-0005.This work was supported by the European Union,'s Horizon 2020 research and innovation program NTS-EXPOSURE, Grant agreement ID: 896141.This work was supported by the European Union,'s LIFE program LIFE-APEX, Grant agreement ID: LIFE17 ENV/SK/000355.This study was funded by the German Environment Agency within the PHION project (grant number 3718 674150).The Data Readiness Group is supported, in this ELIXIR Community, by the H2020 Precision Toxicology project (H2020-EU 965406).The Data Readiness Group is supported, in this ELIXIR Community, by the Wellcome ISA-InterMine project (208381/A/17/Z).The Data Readiness Group is supported, in this ELIXIR Community, by the Wellcome FAIRsharing project (212930/Z/18/Z).This work received funding from the European Union’s Horizon 2020 research and innovation programme RiskGONE Project under grant agreement No. 814425.NR's research is funded by a Miguel Servet contract (CO19/00060) from Instituto de Salud Carlos III, cofinanced by the European Union.UM (Uni. of Tartu) is grateful for support to Ministry of Education and Research, Republic of Estonia through Estonian Research Council (grant number IUT34-14) and to European Union European Regional Development Fund through Foundation Archimedes (grant number TK143, Centre of Excellence in Molecular Cell Engineering).Development and Implementation of a Sustainable Modelling Platform for NanoInformatics.Linking LRI Ambit chemoinformatic system with the IUCLID substance database to support read-across of substance endpoint data and category formation.This work was supported by the French Ministry of Research and National Research Agency as part of the French MetaboHUB, the national metabolomics and fluxomics infrastructure (Grant ANR-INBS-0010).This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement GOLIATH No. 825489., ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), European Project: 681002,H2020,H2020-PHC-2015-single-stage_RTD,EU-ToxRisk(2016), European Project: 825712,H2020-EU.3.1.1. - Understanding health, wellbeing and disease,H2020-SC1-2018-Single-Stage-RTD,OBERON(2019), European Project: 733032,H2020,HBM4EU(2017), European Project: 814425,RiskGONE, European Project: 825489,H2020,GOLIATH(2019), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ménager, Hervé, Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation - - METABOHUB2011 - ANR-11-INBS-0010 - INBS - VALID, An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century - EU-ToxRisk - - H20202016-01-01 - 2021-12-31 - 681002 - VALID, An integrative strategy of testing systems for identification of EDs related to metabolic disorders - OBERON - - H2020-EU.3.1.1. - Understanding health, wellbeing and disease2019-01-01 - 2019-12-31 - 825712 - VALID, European Human Biomonitoring Initiative - HBM4EU - - H20202017-01-01 - 2021-12-31 - 733032 - VALID, Risk Governance of Nanotechnology - RiskGONE - 814425 - INCOMING, and Beating Goliath: Generation Of NoveL, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Compounds - GOLIATH - - H20202019-01-19 - 2023-12-31 - 825489 - VALID

Subjects
Interoperability, Context (language use), interoperability, Predictive toxicology, Multidisciplinary, general & others [F99] [Life sciences], Pharmacology and Toxicology, 010501 environmental sciences, Toxicology, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Multidisciplinaire, généralités & autres [F99] [Sciences du vivant], General Pharmacology, Toxicology and Pharmaceutics, Chemical risk, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, 0105 earth and related environmental sciences, computer.programming_language, FAIR, 0303 health sciences, Government, General Immunology and Microbiology, General Medicine, Farmakologi och toxikologi, Sketch, 3. Good health, ELIXIR, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Elixir (programming language), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer
Abstract

International audience; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

Published
2021

33. Biallelic AOPEP Loss‐of‐Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

Author

Aurélie Méneret, Manju A. Kurian, Michael C. Kruer, Alexander P. Drew, Niccolo E. Mencacci, Jean Madeleine de Sainte Agathe, Juliane Winkelmann, Lisa G. Riley, Sylvia Boesch, Saskia Biskup, Pedro Gonzalez-Alegre, Sheng Chih Jin, Janine Reunert, Sophie Reining, Kishore R. Kumar, Matthias Baumann, Riccardo Berutti, Fabienne Clot, Marie Vidailhet, Victor S.C. Fung, Thorsten Marquardt, Steven J. Lubbe, Robert Adam, Somayeh Bakhtiari, Tanya Bardakjian, Nicolas Derive, Ignacio Juan Keller Sarmiento, Michel Tchan, Michael Zech, Helmholtz Zentrum München = German Research Center for Environmental Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Concord Repatriation General Hospital, The University of Sydney, Garvan Institute of medical research, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Westmead Hospital [Sydney], Royal Brisbane & Women's Hospital, University of Queensland [Brisbane], Centre for Clinical Research [Brisbane], CeGaT GmbH, Barrow Neurological Institute, University of Arizona, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Perelman School of Medicine, University of Pennsylvania, Northwestern University Feinberg School of Medicine, Institute of Child Health [London], University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Gestionnaire, Hal Sorbonne Université, Helmholtz-Zentrum München (HZM), Technische Universität München [München] (TUM), Garvan Institute of Medical Research [Darlinghurst, Australia], University of Pennsylvania [Philadelphia], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University [Austria] (IMU), and Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU)

Subjects
Proband, Movement disorders, AOPEP, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, rare disease, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Compound heterozygosity, loss-of-function variants, Aminopeptidases, Aopep, Genomic Analysis, Loss-of-function Variants, Monogenic Dystonia, Rare Disease, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Loss of Function Mutation, medicine, Humans, Exome, Allele, 030304 developmental biology, Dystonia, Genetics, 0303 health sciences, Parkinsonism, Proteolytic enzymes, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Pedigree, Phenotype, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dystonic Disorders, genomic analysis, Mutation, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, monogenic dystonia
Abstract

BACKGROUND Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging. OBJECTIVE We sought to expand the catalogue of monogenic etiologies for isolated dystonia. METHODS After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles. RESULTS Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism. CONCLUSIONS Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2021

34. Early Evaluation of Organ Failure Using MELD-XI in Critically Ill Elderly COVID-19 Patients

Author

Johanna Hornemann, Christian Jung, Malte Kelm, Sandra Oeyen, Dylan W. de Lange, Michael Joannidis, Brian Marsh, Wojciech Szczeklik, Bernardo Bollen Pinto, Stephan Binneboessel, Finn H. Andersen, Bernhard Wernly, Michael Beil, Philipp Heinrich Baldia, Muhammed Elhadi, Hans Flaatten, Peter Vernon van Heerden, Raphael Romano Bruno, Eumorfia Kondili, Georg Wolff, Ariane Boumendil, Rui Moreno, Jesper Fjølner, Susannah Leaver, Bertrand Guidet, Joerg C. Schefold, Sigal Sviri, Antonio Artigas, Jakob Wollborn, Gestionnaire, Hal Sorbonne Université, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Bergen (UiB), Aarhus University Hospital, CIBER de Epidemiología y Salud Pública (CIBERESP), Geneva University Hospitals and Geneva University, Hadassah Hebrew University Medical Center [Jerusalem], The Hebrew University of Jerusalem (HUJ), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Ghent University Hospital, Mater Misericordiae University Hospital (The Mater Hospital), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), St George’s University Hospitals, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Réanimation Médicale [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Physiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Critical Illness, [SDV]Life Sciences [q-bio], Disease, Logistic regression, Severity of Illness Index, chemistry.chemical_compound, Physiology (medical), Intensive care, Internal medicine, medicine, Humans, 610 Medicine & health, Aged, Creatinine, business.industry, Critically ill, SARS-CoV-2, Confounding, COVID-19, Hematology, Prognosis, body regions, [SDV] Life Sciences [q-bio], chemistry, Cardiology and Cardiovascular Medicine, business
Abstract

International audience; PURPOSE Critically ill elderly patients who suffer from Sars-CoV-2 disease are at high risk for organ failure. The modified MELD-XI score has not been evaluated for outcome prediction in these most vulnerable patients. METHODS The Corona Virus disease (COVID19) in Very Elderly Intensive Care Patients study (COVIP, NCT04321265) prospectively recruited patients on intensive care units (ICU), who were = 70 years. Data were collected from March 2020 to February 2021. The MELD-XI score was calculated using the highest serum bilirubin and creatinine on ICU admission. Univariate and multivariable logistic regression analyses were performed to assess associations between the MELD-XI score and mortality. The primary outcome was 30-day-mortality, the secondary outcomes were ICU- and 3-month-mortality. RESULTS In total, data from 2,993 patients were analyzed. Most patients had a MELD-XI

Published
2021

35. COVID-19 infection in adult patients with hematological malignancies:a European Hematology Association Survey (EPICOVIDEHA)

Author

Pagano, Livio, Salmanton-García, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Víšek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerová, Barbora, Córdoba-Mascuñano, Raúl, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Čerňan, Martin, Jakšić, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valković, Toni, Poulsen, Christian Bjørn, Machado, Marina, Glenthøj, Andreas, Stoma, Igor, Ráčil, Zdeněk, Piukovics, Klára, Navrátil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, García-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Vélez, Irati, Fernández, Noemí, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antić, Darko, Al-Khabori, Murtadha, García-Sanz, Ramón, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Čolović, Natasa, Schönlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Méndez, Gustavo-Adolfo, Petzer, Verena, Novák, Jan, Besson, Caroline, Duléry, Rémy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Žák, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiří, López-García, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Aleš, Herbrecht, Raoul, Núñez-Martín-Buitrago, Lucía, Mancini, Valentina, Shwaylia, Hawraa, Sciumè, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinić, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbényi, Zita, Çolak, Gökçe Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramón-Sánchez, Cristina, Cornely, Oliver A., Finizio, Olimpia, Fazzi, Rita, Sapienza, Giuseppe, Chauchet, Adrien, Van Praet, Jens, Prattes, Juergen, Dargenio, Michelina, Rossi, Cédric, Shirinova, Ayten, Malak, Sandra, Tafuri, Agostino, Ommen, Hans-Beier, Bologna, Serge, Khedr, Reham Abdelaziz, Choquet, Sylvain, Joly, Bertrand, Ceesay, M. Mansour, Philippe, Laure, Kho, Chi Shan, Desole, Maximilian, Tsirigotis, Panagiotis, Otašević, Vladimir, Borducchi, Davimar M. M., Antoniadou, Anastasia, Gaziev, Javid, Almaslamani, Muna A., García-Poutón, Nicole, Paterno, Giovangiacinto, Torres-López, Andrea, Tarantini, Giuseppe, Mellinghoff, Sibylle, Gräfe, Stefanie, Börschel, Niklas, Passweg, Jakob, Merelli, Maria, Barać, Aleksandra, Wolf, Dominik, Shaikh, Mohammad Usman, Thiéblemont, Catherine, Bernard, Sophie, Funke, Vaneuza Araújo Moreira, Daguindau, Etienne, Khostelidi, Sofya, Nucci, Fabio Moore, Martín-González, Juan-Alberto, Landau, Marianne, Soussain, Carole, Laureana, Cécile, Lacombe, Karine, Kohn, Milena, Aliyeva, Gunay, Piedimonte, Monica, Fouquet, Guillemette, Rêgo, Mayara, Hoell-Neugebauer, Baerbel, Cartron, Guillaume, Pinto, Fernando, Alburquerque, Ana Munhoz, Passos, Juliana, Yilmaz, Asu Fergun, Redondo-Izal, Ana-Margarita, Altuntaş, Fevzi, Heath, Christopher, Kolditz, Martin, Schalk, Enrico, Guolo, Fabio, Karthaus, Meinolf, Della Pepa, Roberta, Vinh, Donald, Noël, Nicolas, Deau Fischer, Bénédicte, Drenou, Bernard, Mitra, Maria Enza, Meletiadis, Joseph, Bilgin, Yavuz M., Jindra, Pavel, Espigado, Ildefonso, Drgoňa, Ľuboš, Serris, Alexandra, Di Blasi, Roberta, Ali, Natasha, EPICOVIDEHA working group, [missing], Pagano, Livio, Salmanton-Garcia, Jon, Marchesi, Francesco, Busca, Alessandro, Corradini, Paolo, Hoenigl, Martin, Klimko, Nikolai, Koehler, Philipp, Pagliuca, Antonio, Passamonti, Francesco, Verga, Luisa, Visek, Benjamin, Ilhan, Osman, Nadali, Gianpaolo, Weinbergerova, Barbora, Cordoba-Mascunano, Raul, Marchetti, Monia, Collins, Graham P., Farina, Francesca, Cattaneo, Chiara, Cabirta, Alba, Gomes-Silva, Maria, Itri, Federico, van Doesum, Jaap, Ledoux, Marie-Pierre, Cernan, Martin, Jaksic, Ozren, Duarte, Rafael F., Magliano, Gabriele, Omrani, Ali S., Fracchiolla, Nicola S., Kulasekararaj, Austin, Valkovic, Toni, Poulsen, Christian Bjorn, Machado, Marina, Glenthoj, Andreas, Stoma, Igor, Racil, Zdenek, Piukovics, Klara, Navratil, Milan, Emarah, Ziad, Sili, Uluhan, Maertens, Johan, Blennow, Ola, Bergantim, Rui, Garcia-Vidal, Carolina, Prezioso, Lucia, Guidetti, Anna, del Principe, Maria Ilaria, Popova, Marina, de Jonge, Nick, Ormazabal-Velez, Irati, Fernandez, Noemi, Falces-Romero, Iker, Cuccaro, Annarosa, Meers, Stef, Buquicchio, Caterina, Antic, Darko, Al-Khabori, Murtadha, Garcia-Sanz, Ramon, Biernat, Monika M., Tisi, Maria Chiara, Sal, Ertan, Rahimli, Laman, Colovic, Natasa, Schonlein, Martin, Calbacho, Maria, Tascini, Carlo, Miranda-Castillo, Carolina, Khanna, Nina, Mendez, Gustavo-Adolfo, Petzer, Verena, Novak, Jan, Besson, Caroline, Dulery, Remy, Lamure, Sylvain, Nucci, Marcio, Zambrotta, Giovanni, Zak, Pavel, Seval, Guldane Cengiz, Bonuomo, Valentina, Mayer, Jiri, Lopez-Garcia, Alberto, Sacchi, Maria Vittoria, Booth, Stephen, Ciceri, Fabio, Oberti, Margherita, Salvini, Marco, Izuzquiza, Macarena, Nunes-Rodrigues, Raquel, Ammatuna, Emanuele, Obr, Ales, Herbrecht, Raoul, Nunez-Martin-Buitrago, Lucia, Mancini, Valentina, Shwaylia, Hawraa, Sciume, Mariarita, Essame, Jenna, Nygaard, Marietta, Batinic, Josip, Gonzaga, Yung, Regalado-Artamendi, Isabel, Karlsson, Linda Katharina, Shapetska, Maryia, Hanakova, Michaela, El-Ashwah, Shaimaa, Borbenyi, Zita, Colak, Gokce Melis, Nordlander, Anna, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Rinaldi, Amelia, De Ramon-Sanchez, Cristina, Cornely, Oliver A., Pagano, L., Salmanton-Garcia, J., Marchesi, F., Busca, A., Corradini, P., Hoenigl, M., Klimko, N., Koehler, P., Pagliuca, A., Passamonti, F., Verga, L., Visek, B., Ilhan, O., Nadali, G., Weinbergerova, B., Cordoba-Mascunano, R., Marchetti, M., Collins, G. P., Farina, F., Cattaneo, C., Cabirta, A., Gomes-Silva, M., Itri, F., van Doesum, J., Ledoux, M. -P., Cernan, M., Jaksic, O., Duarte, R. F., Magliano, G., Omrani, A. S., Fracchiolla, N. S., Kulasekararaj, A., Valkovic, T., Poulsen, C. B., Machado, M., Glenthoj, A., Stoma, I., Racil, Z., Piukovics, K., Navratil, M., Emarah, Z., Sili, U., Maertens, J., Blennow, O., Bergantim, R., Garcia-Vidal, C., Prezioso, L., Guidetti, A., del Principe, M. I., Popova, M., de Jonge, N., Ormazabal-Velez, I., Fernandez, N., Falces-Romero, I., Cuccaro, A., Meers, S., Buquicchio, C., Antic, D., Al-Khabori, M., Garcia-Sanz, R., Biernat, M. M., Tisi, M. C., Sal, E., Rahimli, L., Colovic, N., Schonlein, M., Calbacho, M., Tascini, C., Miranda-Castillo, C., Khanna, N., Mendez, G. -A., Petzer, V., Novak, J., Besson, C., Dulery, R., Lamure, S., Nucci, M., Zambrotta, G., Zak, P., Seval, G. C., Bonuomo, V., Mayer, J., Lopez-Garcia, A., Sacchi, M. V., Booth, S., Ciceri, F., Oberti, M., Salvini, M., Izuzquiza, M., Nunes-Rodrigues, R., Ammatuna, E., Obr, A., Herbrecht, R., Nunez-Martin-Buitrago, L., Mancini, V., Shwaylia, H., Sciume, M., Essame, J., Nygaard, M., Batinic, J., Gonzaga, Y., Regalado-Artamendi, I., Karlsson, L. K., Shapetska, M., Hanakova, M., El-Ashwah, S., Borbenyi, Z., Colak, G. M., Nordlander, A., Dragonetti, G., Maraglino, A. M. E., Rinaldi, A., De Ramon-Sanchez, C., Cornely, O. A., Finizio, O., Fazzi, R., Sapienza, G., Chauchet, A., Van Praet, J., Prattes, J., Dargenio, M., Rossi, C., Shirinova, A., Malak, S., Tafuri, A., Ommen, H. -B., Bologna, S., Khedr, R. A., Choquet, S., Joly, B., Ceesay, M. M., Philippe, L., Kho, C. S., Desole, M., Tsirigotis, P., Otasevic, V., Borducchi, D. M. M., Antoniadou, A., Gaziev, J., Almaslamani, M. A., Garcia-Pouton, N., Paterno, G., Torres-Lopez, A., Tarantini, G., Mellinghoff, S., Grafe, S., Borschel, N., Passweg, J., Merelli, M., Barac, A., Wolf, D., Shaikh, M. U., Thieblemont, C., Bernard, S., Funke, V. A. M., Daguindau, E., Khostelidi, S., Nucci, F. M., Martin-Gonzalez, J. -A., Landau, M., Soussain, C., Laureana, C., Lacombe, K., Kohn, M., Aliyeva, G., Piedimonte, M., Fouquet, G., Rego, M., Hoell-Neugebauer, B., Cartron, G., Pinto, F., Alburquerque, A. M., Passos, J., Yilmaz, A. F., Redondo-Izal, A. -M., Altuntas, F., Heath, C., Kolditz, M., Schalk, E., Guolo, F., Karthaus, M., Della Pepa, R., Vinh, D., Noel, N., Deau Fischer, B., Drenou, B., Mitra, M. E., Meletiadis, J., Bilgin, Y. M., Jindra, P., Espigado, I., Drgona, L., Serris, A., Di Blasi, R., Ali, N., Stem Cell Aging Leukemia and Lymphoma (SALL), Salvy-Córdoba, Nathalie, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University Hospital of Cologne [Cologne], Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), Città della Salute e della Scienza University-Hospital, IRCCS Istituto Nazionale dei Tumori [Milano], University of California [San Diego] (UC San Diego), University of California (UC), Medical University of Graz, Odessa National I.I.Mechnikov University, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, King's College Hospital (KCH), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Dipartimento di Medicina e Chirurgia = School of Medicine and Surgery [Monza], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Faculty of Medicine in Hradec Kralove [Republique Tchèque], Charles University [Prague] (CU), Ankara University School of Medicine [Turkey], Azienda Ospedaliera Universitaria Integrata of Verona, Masaryk University [Brno] (MUNI), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Ospedale SS Antonio e Biagio e Cesare Arrigo, Churchill Hospital Oxford Centre for Haematology, IRCCS San Raffaele Scientific Institute [Milan, Italie], ASST Spedali Civili of Brescia, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Universitat Autònoma de Barcelona (UAB), Instituto Português de Oncologia de Lisboa Francisco Gentil, Ospedale San Luigi Gonzaga, University Medical Center Groningen [Groningen] (UMCG), Institut de Cancérologie de Strasbourg Europe (ICANS), Palacky University Olomouc, Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Hamad Medical Corporation [Doha, Qatar], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Rijeka, Croatian Cooperative Group for Hematological Diseases (CROHEM), Zealand University Hospital [Roskilde, Denmark], Hospital General Universitario 'Gregorio Marañón' [Madrid], Department of Clinical Microbiology [Rigshospitalet], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Homieĺ State Medical University (GSMU), Institute of Hematology and Blood Transfusion [Prague, Czech Republic], University of Szeged [Szeged], University Hospital Ostrava, Mansoura University [Egypt], Marmara University [Kadıköy - İstanbul], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Karolinska University Hospital [Stockholm], Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Hospital de São João [Porto], Faculdade de Medicina da Universidade do Porto (FMUP), Clinic Barcelona Hospital Universitari, Department of Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Pavlov First Saint Petersburg State Medical University [St. Petersburg], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Complejo Hospitalario de Navarra, Hospital Universitario Marqués de Valdecilla [Santander], La Paz University Hospital, Azienda Usl Toscana centro [Firenze], AZ Klina, Clinical Center of Serbia (KCS), University of Belgrade [Belgrade], Sultan Qaboos University Hospital, Partenaires INRAE, Hospital Universitario de Salamanca, Servicio de Haematologia, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), University of Wrocław [Poland] (UWr), San Bortolo Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospital Universitario 12 de Octubre [Madrid], Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Universidad Rey Juan Carlos [Madrid] (URJC), University of Basel (Unibas), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Kralovské Vinohrady, Centre Hospitalier de Versailles André Mignot (CHV), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département Hématologie biologique [CHRU Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universidade Federal do Estado do Rio de Janeiro (UNIRIO), San Gerardo Hospital of Monza, Oxford NIHR Biomedical Research Centre, IRCCS Ospedale San Raffaele [Milan, Italy], Assi Sette Llaghi Varese, Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), University Hospital Olomouc [Czech Republic], ASST Grande Ospedale Metropolitano Niguarda, University Hospital Centre Zagreb, Instituto Nacional do Câncer, Copenhagen University Hospital, Republican Scientific and Practical Center (RSPC) for organ and Tissue Transplantation, Minsk, Republican Scientific and Practical Center (RSPC) for Organ and Transplantation, German Centre for Infection Research (DZIF), Gilead Sciences, Pagano, Livio [0000-0001-8287-928X], Salmanton-García, Jon [0000-0002-6766-8297], Marchesi, Francesco [0000-0001-6353-2272], Busca, Alessandro [0000-0001-5361-5613], Corradini, Paolo [0000-0002-9186-1353], Hoenigl, Martin [0000-0002-1653-2824], Klimko, Nikolay [0000-0001-6095-7531], Koehler, Philipp [0000-0002-7386-7495], Pagliuca, Antonio [0000-0003-2519-0333], Passamonti, Francesco [0000-0001-8068-5289], Verga, Luisa [0000-0003-1142-8435], Víšek, Benjamin [0000-0001-8268-452X], Ilhan, Osman [0000-0003-1665-372X], Weinbergerová, Barbora [0000-0001-6460-2471], Córdoba, Raúl [0000-0002-7654-8836], Marchetti, Monia [0000-0001-7615-0572], Farina, Francesca [0000-0002-5124-6970], Cattaneo, Chiara [0000-0003-0031-3237], Cabirta, Alba [0000-0001-7198-8894], Gomes-Silva, Maria [0000-0002-6993-2450], Itri, Federico [0000-0002-3532-5281], Doesum, Jaap van [0000-0003-0214-3219], Ledoux, Marie-Pierre [0000-0002-3261-3616], Čerňan, Martin [0000-0003-2345-1229], Jakšić, Ozren [0000-0003-4026-285X], Magliano, Gabriel [0000-0002-9129-1530], Omrani, Ali S. [0000-0001-5309-6358], Fracchiolla, Nicola S. [0000-0002-8982-8079], Kulasekararaj, Austin G. [0000-0003-3180-3570], Valković, Toni [0000-0001-6083-8815], Poulsen, Christian Bjørn [0000-0001-9785-1378], Machado, Marina [0000-0002-8370-2248], Glenthøj, Andrea [0000-0003-2082-0738], Stoma, Igor [0000-0003-0483-7329], Ráčil, Zdeněk [0000-0003-3511-4596], Piukovics, Klára [0000-0003-4480-3131], Emarah, Ziad [0000-0003-0622-2598], Sili, Uluhan [0000-0002-9939-9298], Maertens, Johan [0000-0003-4257-5980], Bergantim, Rui [0000-0002-7811-9509], García-Vidal, Carolina [0000-0002-8915-0683], Prezioso, Lucia [0000-0003-1660-4960], Principe, Maria Ilaria del [0000-0002-3958-0669], Popova, Marina [0000-0001-8536-5495], Jonge, Nick de [0000-0002-9901-0887], Ormazabal-Vélez, Irati [0000-0003-1141-5546], Falces-Romero, Iker [0000-0001-5888-7706], Cuccaro, Annarosa [0000-0002-0237-1839], Meers, Stef [0000-0003-1754-2175], Buquicchio, Caterina [0000-0002-3683-5953], Antić, Darko [0000-0002-2608-1342], Al-Khabori, Murtadha [0000-0002-2937-8838], García-Sanz, Ramón [0000-0003-4120-2787], Biernat, Monika [0000-0003-3161-3398], Tisi, Maria Chiara [0000-0001-8231-6700], Sal, Ertan [0000-0003-2761-2675], Rahimli, Laman [0000-0003-2266-445X], Schönlein, Martin [0000-0002-1010-0975], Calbacho, María [0000-0001-8106-4863], Tascini, Carlo [0000-0001-9625-6024], Miranda-Castillo, Carolina [0000-0001-8763-9576], Khanna, Nina [0000-0002-2642-419X], Méndez, Gustavo-Adolfo [0000-0003-0514-7004], Petzer, Verena [0000-0002-9205-1440], Besson, Caroline [0000-0003-4364-7173], Duléry, Rémy [0000-0002-5024-1713], Lamure, Sylvain [0000-0001-5980-305X], Nucci, Marcio [0000-0003-4867-0014], Zambrotta, Giovanni [0000-0002-8612-2994], Žák, Pavel [0000-0003-4465-5343], Cengiz Seval, Guldane [0000-0001-9433-2054], Bonuomo, Valentina [0000-0001-6491-8337], Mayer, Jiří [0000-0003-0567-9887], López-García, Alberto [0000-0002-5354-5261], Sacchi, Maria Vittoria [0000-0001-8133-3357], Booth, Stephen [0000-0003-2687-0234], Ciceri, Fabio [0000-0003-0873-0123], Nunes-Rodrigues, Raquel [0000-0002-8347-4281], Ammatuna, Emanuele [0000-0001-8247-4901], Obr, Aleš [0000-0002-6758-3074], Herbrecht, Raoul [0000-0002-9381-4876], Shwaylia, Hawraa [0000-0002-4098-6092], Sciumè, Mariarita [0000-0001-7958-4966], Essame, Jenna [0000-0003-0926-5577], Batinić, Josip [0000-0001-5595-9911], Gonzaga, Yung [0000-0003-1416-2118], Regalado-Artamendi, Isabel [0000-0002-9673-9015], Karlsson, Linda Katharina [0000-0003-3317-7550], Shapetska, Maryia [0000-0002-1223-9161], El-Ashwah, Shaimaa [0000-0003-2210-1534], Çolak, Gökçe Melis [0000-0002-7662-7454], Dragonetti, Giulia [0000-0003-1775-6333], Rinaldi, Amelia [0000-0002-8211-5076], Ramón, Cristina de [0000-0002-8167-6410], Cornely, Oliver A. [0000-0001-9599-3137], Institut Català de la Salut, [Pagano L] Hematology, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy. Università Cattolica del Sacro Cuore, Rome, Italy. [Salmanton-García J] Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Excellence Center for Medical Mycology (ECMM), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. Cologne Excellence Cluster On Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [Marchesi F] Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. [Busca A] Stem Cell Transplant Center, AOU Citta’ Della Salute E Della Scienza, Turin, Italy. [Corradini P] University of Milan and Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. [Hoenigl M] Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA, USA. Clinical and Translational Fungal Working Group, University of California San Diego, La Jolla, CA, USA. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Graz, Austria. [Cabirta A, Izuzquiza M] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Hematology, Salmanton-García, Jon, Klimko, Nikolay, Víšek, Benjamin, Weinbergerová, Barbora, Córdoba, Raúl, Doesum, Jaap van, Čerňan, Martin, Jakšić, Ozren, Magliano, Gabriel, Kulasekararaj, Austin G., Valković, Toni, Poulsen, Christian Bjørn, Glenthøj, Andrea, Ráčil, Zdeněk, Piukovics, Klára, García-Vidal, Carolina, Principe, Maria Ilaria del, Jonge, Nick de, Ormazabal-Vélez, Irati, Antić, Darko, García-Sanz, Ramón, Biernat, Monika, Schönlein, Martin, Calbacho, María, Méndez, Gustavo-Adolfo, Duléry, Rémy, Žák, Pavel, Cengiz Seval, Guldane, Mayer, Jiří, López-García, Alberto, Obr, Aleš, Sciumè, Mariarita, Batinić, Josip, Çolak, Gökçe Melis, Ramón, Cristina de, and Universidad de Sevilla. Departamento de Medicina

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Cancer Research, MESH: Registries, Epidemiology, MESH: Hospitalization, Hematological malignancies, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], MESH: Aged, 80 and over, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Malalties - Factors de risc, Risk of mortality, Medicine and Health Sciences, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Medicine, MESH: COVID-19, Registries, Sang - Malalties - Complicacions, RC254-282, Cause of death, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, MESH: Aged, Aged, 80 and over, Hematology, MESH: Middle Aged, Mortality rate, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, CANCER, Europe, Hospitalization, Intensive Care Units, Oncology, MESH: Young Adult, Hematologic Neoplasms, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Infektologija, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, COVID-19, EHA, Pandemic, Aged, Humans, SARS-CoV-2, Young Adult, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], [SDV.CAN] Life Sciences [q-bio]/Cancer, Intensive care, Internal medicine, Diseases of the blood and blood-forming organs, MESH: SARS-CoV-2, neoplasias::neoplasias por localización::neoplasias hematológicas [ENFERMEDADES], Molecular Biology, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, pandemic, hematological malignancies, epidemiology, MESH: Humans, Science & Technology, business.industry, Myelodysplastic syndromes, Research, MESH: Adult, Neoplasms::Neoplasms by Site::Hematologic Neoplasms [DISEASES], medicine.disease, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Infectology, Settore MED/15, MESH: Male, Settore MED/15 - MALATTIE DEL SANGUE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19 (Malaltia) - Diagnòstic, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], MESH: Europe, RC633-647.5, business, MESH: Female, Other subheadings::Other subheadings::/complications [Other subheadings], MESH: Hematologic Neoplasms
Abstract

Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value, EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Published
2021

36. Assessing the effect of genetic markers on drug immunogenicity from a mechanistic model-based approach

Author

Marc Pallardy, Aude Gleizes, Xavier Mariette, Julianne Duhazé, Florian Deisenhammer, Salima Hacein-Bey-Abina, Anna Fogdell-Hahn, Delphine Bachelet, Philippe Broët, Signe Hässler, Matthieu Allez, Miguel Caubet, CHU Sainte Justine [Montréal], Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Innsbruck Medical University [Austria] (IMU), Karolinska Institutet [Stockholm], Inflammation, microbiome, immunosurveillance (MI2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de rhumatologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP]

Subjects
Genetic Markers, Drug, Semi-parametric, Epidemiology, Computer science, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Population, Health Informatics, Computational biology, 030226 pharmacology & pharmacy, 01 natural sciences, Antibodies, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Genetic, Test statistic, Humans, Computer Simulation, Two-part improper survival model, 0101 mathematics, education, Semi-continuous data, Survival analysis, Statistic, media_common, Drug immunogenicity, lcsh:R5-920, [SDV.GEN]Life Sciences [q-bio]/Genetics, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Immunogenicity, 3. Good health, Semiparametric model, [SDV] Life Sciences [q-bio], [STAT]Statistics [stat], Log-rank test, Pharmaceutical Preparations, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Medicine (General), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Background With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue. This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. Identifying genetic markers associated with the immunogenicity of biotherapeutic drugs may provide new opportunities for risk stratification before the introduction of the drug. However, real-world investigations should take into account that the population under study is a mixture of pre-immune, immune-reactive and immune-tolerant subjects. Method In this work, we propose a novel test for assessing the effect of genetic markers on drug immunogenicity taking into account that the population under study is a mixed one. This test statistic is derived from a novel two-part semiparametric improper survival model which relies on immunological mechanistic considerations. Results Simulation results show the good behavior of the proposed statistic as compared to a two-part logrank test. In a study on drug immunogenicity, our results highlighted findings that would have been discarded when considering classical tests. Conclusion We propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares. This test is also applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups.

Published
2020

37. Definitions of Computer-Assisted Surgery and Intervention, Image-Guided Surgery and Intervention, Hybrid Operating Room, and Guidance Systems

Author

Guido Costamagna, Martin Smith, Michele Diana, Sven Jonas, Go Wakabayashi, Lee L. Swanström, Luc Soler, Juan M. Verde, Christiaan G. Overduin, Didier Mutter, Toby Collins, Reto Bale, Mårten Falkenberg, Amilcar Alzaga, Carina Riediger, Silvana Perretta, Jurgen J. Fütterer, Niklas Kvarnström, Stéphane Cotin, Michael Moche, Alain Garcia Vazquez, David A. Geller, Patrick Pessaux, Mariano E Giménez, Bernard Dallemagne, Mariano Palermo, Beat P. Müller-Stich, Jacques Marescaux, Ivo Boškoski, Alexandre Hostettler, Michael Kostrzewa, Edgardo Serra, Bruno C. Odisio, Jean Nicolas Vauthey, Nicolas Golse, Benoit Gallix, l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, McGill University = Université McGill [Montréal, Canada], Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), The University of Texas M.D. Anderson Cancer Center [Houston], Universitätsklinikum Leipzig [Germany] (UKL), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Radboud University Medical Center [Nijmegen], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Heidelberg University Hospital [Heidelberg], Sahlgrenska University Hospital [Gothenburg], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut National de Recherche en Informatique et en Automatique (Inria), Siemens AG [Germany], and University of the Witwatersrand [Johannesburg] (WITS)

Subjects
Computer-assisted surgery, medicine.medical_specialty, guidance systems, RD1-811, Process (engineering), Computer science, hybrid operating room, medicine.medical_treatment, Settore MED/18 - CHIRURGIA GENERALE, minimal invasion, Terminology, Image-guided surgery, Multidisciplinary approach, medicine, General Earth and Planetary Sciences, Hybrid operating room, Original Study, Systematic process, Medical physics, Surgery, image guidance, computer assistance, Knowledge transfer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, General Environmental Science
Abstract

Objective: To develop consensus definitions of image-guided surgery, computer-assisted surgery, hybrid operating room, and surgical navigation systems. Summary Background Data: The use of minimally invasive procedures has increased tremendously over the past 2 decades, but terminology related to image-guided minimally invasive procedures has not been standardized, which is a barrier to clear communication. Methods: Experts in image-guided techniques and specialized engineers were invited to engage in a systematic process to develop consensus definitions of the key terms listed above. The process was designed following review of common consensus-development methodologies and included participation in 4 online surveys and a post-surveys face-to-face panel meeting held in Strasbourg, France. Results: The experts settled on the terms computer-assisted surgery and intervention, image-guided surgery and intervention, hybrid operating room, and guidance systems and agreed-upon definitions of these terms, with rates of consensus of more than 80% for each term. The methodology used proved to be a compelling strategy to overcome the current difficulties related to data growth rates and technological convergence in this field. Conclusions: Our multidisciplinary collaborative approach resulted in consensus definitions that may improve communication, knowledge transfer, collaboration, and research in the rapidly changing field of image-guided minimally invasive techniques., This study gathered experts with multiple backgrounds and used common consensus-development methodologies in 2 phases (online and panel meeting). It resulted in definitions that may improve communication, knowledge transfer, collaboration, and research in the field of image-guided minimally invasive techniques.

Published
2020

38. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

Author

Caroline Trang, Salima Hacein-Bey Abina, Malin Ryner, Florian Deisenhammer, Manuel Comabella, Abiba Doukani, Philippe Broët, Anna Fogdell-Hahn, Julianne Duhaze, Hans-Peter Hartung, Clemens Warnke, Natacha Szely, Delphine Bachelet, Alessandra Vultaggio, Bernd C. Kieseier, Sebastian Spindeldreher, Olivier Brocq, Poul Erik Hyldgaard-Jensen, Michael Auer, Marc Pallardy, Matthieu Allez, Mary Birchler, Tom W J Huizinga, Yehuda Chowers, Yoram Bouhnik, Dorothea Buck-Martin, Elizabeth C. Jury, Amy Loercher, Dan Sikkema, Aude Gleizes, Tobias Derfuss, Jessica J Manson, Guillaume Cadiot, Claudia Sievers, Michael Khalil, Naoimh Donnellan, Raija L.P. Lindberg, Agnès Hincelin Mery, Badreddine Mohand Oumoussa, Enrico Maggi, Martin Soubrier, Kathleen Ingenhoven, Orhan Aktas, Sophie Tourdot, Xavier Montalban, Maria Nachury, Niek de Vries, Timothy P. Hickling, Christophe Richez, Bernhard Hemmer, Franck Carbonnel, Finn Sellebjerg, Jérôme Avouac, Petra Nytrova, Xavier Mariette, Anna Lauren, Signe Hässler, Pierre Dönnes, Eva Havrdova, Michael Guger, Claudia Mauri, BRUNEL, Nadège, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Sainte Justine [Montréal], Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), GlaxoSmithKline, Glaxo Smith Kline, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Princesse Grace [Monaco], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Hôpital universitaire Robert Debré [Reims], University of Haifa [Haifa], Universitat Autònoma de Barcelona (UAB), University Hospital Basel [Basel], VU University Medical Center [Amsterdam], Royal Berkshire Hospital, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Kepler University Hospital, University Hospital Düsseldorf, Charles University [Prague] (CU), Leiden University Medical Center (LUMC), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University College of London [London] (UCL), Karl-Franzens-Universität Graz, Malmö Högskola = Malmö University, University of Basel (Unibas), Università degli Studi di Firenze = University of Florence (UniFI), University College London Hospitals (UCLH), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU de Bordeaux Pellegrin [Bordeaux], Karolinska Institutet [Stockholm], CHU Clermont-Ferrand, Université de Florence, Fachhochschule Köln, University of Skövde [Sweden], Pfizer, SANOFI Recherche, Hopital Saint-Louis [AP-HP] (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Dusseldorf, Innsbruck Medical University [Austria] (IMU), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karl-Franzens-Universität [Graz, Autriche], Malmø University, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Graz, AII - Inflammatory diseases, and Clinical Immunology and Rheumatology

Subjects
Male, Physiology, [SDV]Life Sciences [q-bio], Single Nucleotide Polymorphisms, Autoimmune Diseases/drug therapy, Biological Therapy/methods, Arthritis, 030204 cardiovascular system & hematology, Biochemistry, Inflammatory bowel disease, Etanercept, Arthritis, Rheumatoid, Cohort Studies, chemistry.chemical_compound, Medical Conditions, 0302 clinical medicine, Crohn Disease, Antibiotics, Immune Physiology, Medicine and Health Sciences, Prospective Studies, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Immune System Proteins, Antimicrobials, Drugs, Neurodegenerative Diseases, General Medicine, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Biological Therapy, Antibodies, Monoclonal, Humanized/therapeutic use, Neurology, Arthritis, Rheumatoid/drug therapy, Rheumatoid arthritis, Genome-Wide Association Study/methods, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Rituximab, Immunosuppressive Agents, Interferon beta-1a, Research Article, medicine.drug, Adult, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Rheumatoid Arthritis, Gastroenterology and Hepatology, Antibodies, Monoclonal, Humanized, Microbiology, Antibodies, HLA-DQ alpha-Chains, Autoimmune Diseases, 03 medical and health sciences, Tocilizumab, Rheumatology, Adalimumab/therapeutic use, Microbial Control, HLA-DQ alpha-Chains/genetics, Rituximab/therapeutic use, Genetics, medicine, Adalimumab, Humans, Antigens, Biological Products/immunology, Pharmacology, Biological Products, Interferon beta-1a/therapeutic use, business.industry, Inflammatory Bowel Disease, Biology and Life Sciences, Proteins, medicine.disease, Demyelinating Disorders, Infliximab, Minor allele frequency, Infliximab/therapeutic use, chemistry, Crohn Disease/drug therapy, Immunosuppressive Agents/therapeutic use, Multiple Sclerosis/drug therapy, Clinical Immunology, Colitis, Ulcerative, Clinical Medicine, Colitis, Ulcerative/drug therapy, business, Genome-Wide Association Study
Abstract

Background Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. Methods and findings The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn’s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253–0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437–0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616–4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319–3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923–5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139–6.764], p < 1 × 10−5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106–4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. Conclusion In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies., In a multicohort prospective study of patients from 12 countries, Signe Hässler and colleagues investigate clinical and genetic factors associated with development of anti-biopharmaceutical drug antibodies in patients with autoimmune diseases., Author summary Why was this study done? Biopharmaceutical products such as monoclonal antibodies are widely used to treat autoimmune diseases. Biopharmaceutical products may induce the development of antidrug antibodies, which often lead to therapy failure. Patient-related factors that influence the development of antidrug antibodies need to be characterized. What did the researchers do and find? We set up a European multicohort prospective study on 4 autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis) treated with 8 different biopharmaceutical products. We collected demographic and clinical data and tested antidrug antibodies in longitudinal serum samples from 560 patients. For 457 patients who gave consent, we also collected genetic data. We identified antibiotics and immunosuppressants as negatively associated risk factors and heavy smoking, infections during the study, the HLA-DQA1*05 allele and a minor variant in the CXCL12 chemokine gene associated with increased protein expression as risk factors of antidrug antibody development. What do these findings mean? Our findings suggest that the combination of immunosuppressant and biopharmaceutical therapy could be associated with decreased risk of antidrug antibody occurrence, which has implications for rheumatoid arthritis and inflammatory bowel diseases, for which immunosuppressants are often, but not always, given together with biopharmaceuticals. Patients heterozygotes or homozygotes for the HLA-DQA1*05 allele may have an increased risk of antidrug antibody occurrence associated with biopharmaceutical therapy. The small study size warrants a validation through independent studies, in particular for the genetic findings.

Published
2020

39. Treatment of MOG-IgG-associated disorder with rituximab

Author

Jonathan Ciron, Kimihiko Kaneko, Ilijas Jelcic, Bruno Brochet, Mikael Cohen, Elisabeth Maillart, Sven Jarius, David M. Hunt, Dagoberto Callegaro, Sean J. Pittock, Daniel Whittam, Tanuja Chitnis, Stewart Webb, Rob Forsyth, Silvia Tenembaum, Thomas Berger, Alvaro Cobo-Calvo, Anu Jacob, Brian G. Weinshenker, Rinze F. Neuteboom, Alexander U. Brandt, Luana Micheli Oliveira, Venkatraman Karthikeayan, Ichiro Nakashima, David Laplaud, Douglas Kazutoshi Sato, Ayman Tourbah, Emily Gibbons, Lekha Pandit, Romain Deschamps, Grace Y. Gombolay, Su Hyun Kim, A. Sebastian Lopez-Chiriboga, Tom Solomon, Santiago Pardo, Andreas Lutterotti, Ming K. Lim, Saif Huda, M. Isabel Leite, Michael J. Levy, Klaus Berek, Damien Biotti, Romain Marignier, Eric Thouvenot, Markus Reindl, Katy Murray, Ho Jin Kim, Jeffrey Bennett, Kevin Rostasy, Guillaume Mathey, Jacqueline Palace, Matthew Gornall, Yael Hacohen, Marco Capobianco, Silvia Cicconi, Cheryl Hemingway, Kazuo Fujihara, Marcelo Matiello, Bertrand Audoin, Tatsuro Misu, Brigitte Wildemann, Friedemann Paul, The Walton Centre NHS Foundation Trust, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mayo Clinic [Rochester], Massachusetts General Hospital [Boston], University of Liverpool, Max Delbrueck Center for Molecular Medicine, Helmholtz-Gemeinschaft = Helmholtz Association, Innsbruck Medical University [Austria] (IMU), Medizinische Universität Wien = Medical University of Vienna, Universitätsspital Zürich (USZ), Emory Global Health Institute [Atlanta] (EGHI), Emory University [Atlanta, GA], Hospital das Clinicas, University of Sao Paulo School of Medicine, Tohoku University [Sendai], Azienda Ospedaliera Universitaria San Luigi di Orbassano, Institute of Infection and Global Health [University of Liverpool, UK], Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Psychopathologie et Neuropsychologie (LPN), Université Paris 8 Vincennes-Saint-Denis (UP8), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Universität Witten Herdecke, Children's Hospital of Datteln, Erasmus MC-Sophia Hospital [Rotterdam, Netherlands], Great Ormond Street Hospital for Children [London] (GOSH), Newcastle University [Newcastle], Queen Elizabeth University Hospital (Glasgow), Anne Rowling Clinic [Edinburgh, UK], University of Edinburgh, Institute of Neurology, Queen Square, London, Tourettes Clinic-Evelina Childrens Hospital at Guys and St. Thomas', Kings Health Partners AHSC, Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford [Oxford], University of Colorado Anschutz [Aurora], Department of Pharmaceutics, NGSM Institute of Pharmaceutical Science, NITTE Deemed to be University, Mangalore 575018, India, Heidelberg University Hospital [Heidelberg], Pontifícia Universidade Católica do Rio Grande do Sul [Porto Alegre] (PUCRS), Hospital of National Cancer Center [Goyang], Hospital Nacional de Pediatría Prof. Dr Juan P. Garrahan [Buenos Aires], Cleveland Clinic Abu Dhabi [Abou Dabi, Émirats arabes unis], Salvy-Córdoba, Nathalie, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Oxford, Pontifical Catholic University of Rio Grande do Sul (PUC-RS), and Neurology

Subjects
medicine.medical_specialty, Optic neuritis, Controlled studies, Gastroenterology, Article, Myelin oligodendrocyte glycoprotein, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Internal medicine, medicine, Humans, MOG, 030212 general & internal medicine, Poisson regression, Prospective Studies, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Autoantibodies, Retrospective Studies, Retrospective review, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Neuromyelitis optica, biology, business.industry, Multiple sclerosis, General Medicine, medicine.disease, 3. Good health, Neurology, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Immunoglobulin G, biology.protein, symbols, Rituximab, Myelin-Oligodendrocyte Glycoprotein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3–14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3–24.9) months. In this ‘relapsing group’, relapse rate declined by 37% (95%CI=19–52%, p Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.

Published
2020

40. Suspect and non-targeted screening of chemicals of emerging concern for human biomonitoring, environmental health studies and support to risk assessment: From promises to challenges and harmonisation issues

Author

Noelia Caballero-Casero, Martin Krauss, Robert Barouki, Jana Klánová, Jeroen Meijer, Marja H. Lamoree, Annelaure Damont, François Fenaille, Herbert Oberacher, Jean-Philippe Antignac, Bruno Le Bizec, Jelle Vlaanderen, Denis Sarigiannis, Mariane Pourchet, Elliott J. Price, Laurent Debrauwer, Adrian Covaci, Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Masaryk University [Brno] (MUNI), Toxicological Center, University of Antwerp (UA)-Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institute of Legal Medicine, Innsbruck Medical University [Austria] (IMU), Vrije Universiteit Amsterdam [Amsterdam] (VU), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Institute for Risk Assessment Sciences [Utrecht, The Netherlands] (IRAS), Utrecht University [Utrecht], Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Aristotle University of Thessaloniki, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors thank the European Union's Horizon 2020 research and innovation programme HBM4EU under Grant Agreement No. 733032 for its financial support, as well as the Region pays de la Loire, France for its co-funding of the M.P. E.P. acknowledges support from the Czech Operational Programme Research, Development and Education - Project, European Project: 733032, E&H: Environmental Chemistry and Toxicology, AIMMS, LESUR, Hélène, European Union's Horizon 2020 research and innovation programme - 733032 - INCOMING, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Metatoul AXIOM (E20 ), MetaboHUB-MetaToul, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Non targeted, 010504 meteorology & atmospheric sciences, Computer science, [SDV]Life Sciences [q-bio], 010501 environmental sciences, 01 natural sciences, High resolution mass spectrometry, SDG 3 - Good Health and Well-being, Environmental health, Biomonitoring, Chemical of emerging concern, Metabolites, Humans, Profiling (information science), [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Biology, lcsh:Environmental sciences, 0105 earth and related environmental sciences, General Environmental Science, lcsh:GE1-350, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Warning system, business.industry, Non-targeted screening, Environmental Exposure, Suspect screening, Food safety, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, Chemistry, Workflow, 13. Climate action, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Environmental Pollutants, Suspect, business, Risk assessment, Environmental Health, Biological Monitoring, Chromatography, Liquid, Environmental Monitoring
Abstract

Large-scale suspect and non-targeted screening approaches based on high-resolution mass spectrometry (HRMS) are today available for chemical profiling and holistic characterisation of biological samples. These advanced techniques allow the simultaneous detection of a large number of chemical features, including markers of human chemical exposure. Such markers are of interest for biomonitoring, environmental health studies and support to risk assessment. Furthermore, these screening approaches have the promising capability to detect chemicals of emerging concern (CECs), document the extent of human chemical exposure, generate new research hypotheses and provide early warning support to policy. Whilst of growing importance in the environment and food safety areas, respectively, CECs remain poorly addressed in the field of human biomonitoring. This shortfall is due to several scientific and methodological reasons, including a global lack of harmonisation. In this context, the main aim of this paper is to present an overview of the basic principles, promises and challenges of suspect and non-targeted screening approaches applied to human samples as this specific field introduce major specificities compared to other fields. Focused on liquid chromatography coupled to HRMS-based data acquisition methods, this overview addresses all steps of these new analytical workflows. Beyond this general picture, the main activities carried out on this topic within the particular framework of the European Human Biomonitoring initiative (project HBM4EU, 2017-2021) are described, with an emphasis on harmonisation measures.

Published
2020

41. Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel

Author

Siew C. Ng, Herbert Tilg, Harry Sokol, Colleen R. Kelly, Faming Zhang, Giovanni Cammarota, Antonio Gasbarrini, Gianluca Ianiro, Samuel P Costello, Benjamin H. Mullish, Monika Fischer, Luca Masucci, Jessica R. Allegretti, Zain Kassam, Josbert J. Keller, Maurizio Sanguinetti, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Imperial College London, Warren Alpert Medical School of Brown University, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), French Group of Faecal microbiota Transplantation [Paris] (FGFT), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Finch Therapeutics Group, The Chinese University of Hong Kong [Hong Kong], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Harvard Medical School [Boston] (HMS), Nanjing Medical University, Haaglanden Medical Center [La Haye, Pays-Bas] (HMC), Leiden University Medical Center (LUMC), University of Adelaide, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Bodescot, Myriam, Università cattolica del Sacro Cuore [Roma] (Unicatt), and Innsbruck Medical University [Austria] (IMU)

Subjects
medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Settore MED/12 - GASTROENTEROLOGIA, Pneumonia, Viral, MEDLINE, Transplant Donors, Betacoronavirus, Feces, 03 medical and health sciences, 0302 clinical medicine, Pandemic, Living Donors, medicine, Humans, Mass Screening, Intensive care medicine, Pandemics, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Hepatology, SARS-CoV-2, business.industry, Viral Epidemiology, Settore MED/09 - MEDICINA INTERNA, Gastroenterology, COVID-19, Outbreak, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fecal Microbiota Transplantation, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pneumonia, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030211 gastroenterology & hepatology, Coronavirus Infections, business
Abstract

International audience

Published
2020

42. Practical guide to quantification of hepatic iron with MRI

Author

Benjamin Henninger, Maciej W Garbowski, Y. Gandon, Jose M. Alústiza, Department of Radiology [Innsbruck, Austria], Innsbruck Medical University [Austria] (IMU), Osatek [Donostia/San Sebastian, Spain], Donostia Universitary Hospital [Spain], Department of Haematology [London], King's College Hospital (KCH)-King‘s College London, Laboratoire Traitement du Signal et de l'Image (LTSI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Open access funding provided by University of Innsbruck and Medical University of Innsbruck. The authors state that this work has not received any funding., Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
Background information, Liver Iron Concentration, medicine.medical_specialty, Iron Overload, Iron, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Magnetic resonance imaging, Clinical Protocols, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Medical physics, Magnetic Resonance, Hepatic iron, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, General Medicine, 3. Good health, Review article, Liver, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Radiology, business
Abstract

International audience; Our intention is to demystify the MR quantification of hepatic iron (i.e., the liver iron concentration) and give you a step-by-step approach by answering the most pertinent questions. The following article should be more of a manual or guide for every radiologist than a classic review article, which just summarizes the literature. Furthermore, we provide important background information for professional communication with clinicians. The information regarding the physical background is reduced to a minimum. After reading this article, you should be able to perform adequate MR measurements of the LIC with 1.5-T or 3.0-T scanners. KEY POINTS • MRI is widely accepted as the primary approach to non-invasively determine liver iron concentration (LIC). • This article is a guide for every radiologist to perform adequate MR measurements of the LIC. • When using R2* relaxometry, some points have to be considered to obtain correct measurements-all explained in this article.

Published
2020

43. Human Immunodeficiency Virus Continuum of Care in 11 European Union Countries at the End of 2016 Overall and by Key Population: Have We Made Progress?

Author

Vourli, G., Noori, T., Pharris, A., Porter, K., Axelsson, M., Begovac, J., Cazein, F., Costagliola, D., Cowan, S., Croxford, S., Monforte, A. D., Delpech, V., Diaz, A., Girardi, E., Gunsenheimer-Bartmeyer, B., Hernando, V., Leierer, G., Lot, F., Nunez, O., Obel, N., Op de Coul, E., Paraskeva, D., Patrinos, S., Reiss, P., Schmid, D., Sonnerborg, A., Suligoi, B., Supervie, V., van Sighem, A., Zangerle, R., Touloumi, G., Egle, A., Kanatschnig, M., Ollinger, A., Rieger, A., Schmied, B., Wallner, E., Dewasurendra, D., Gisinger, M., Kitchen, M., Plattner, A., Rieser, E., Sarcletti, M., Greil, R., Schachner, M., Skocic, M., Muller, M., Aichwalder, R., Chromy, D., Grabmeier-Pfstershammer, K., Skoll, M., Touzeau, V., Cichon, P., Wolf-Nussmuller, S., Laferl, H., Zoufaly, A., Genger-Hackl, C., Kapper, A., Schneeberger, T., Trattner, E., Schober, G., Atzl, M., Hartmann, B., Puchhammer-Stockl, E., Berg, J., Appoyer, H., Rappold, M., Strickner, S., Schindelwig, K., Ledergerber, B., Fatkenheuer, G., Gerstof, J., Kronborg, G., Pedersen, C., Larsen, C. 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E., Gorgolas, M., Svedhem-Johansson, V., Flamholc, L., Gisslen, M., Hejdeman, B., Norgren, H., Wendahl, S., European Centre for Disease Prevention and Control (ECDC), Esser, Stefan (Beitragende*r), Schenk-Westkamp, Pia (Herausgeber*in), Vourli G., Noori T., Pharris A., Porter K., Axelsson M., Begovac J., Cazein F., Costagliola D., Cowan S., Croxford S., Monforte A.D., Delpech V., Diaz A., Girardi E., Gunsenheimer-Bartmeyer B., Hernando V., Leierer G., Lot F., Nunez O., Obel N., Op de Coul E., Paraskeva D., Patrinos S., Reiss P., Schmid D., Sonnerborg A., Suligoi B., Supervie V., van Sighem A., Zangerle R., Touloumi G., Egle A., Kanatschnig M., Ollinger A., Rieger A., Schmied B., Wallner E., Dewasurendra D., Gisinger M., Kitchen M., Plattner A., Rieser E., Sarcletti M., Greil R., Schachner M., Skocic M., Muller M., Aichwalder R., Chromy D., Grabmeier-Pfstershammer K., Skoll M., Touzeau V., Cichon P., Wolf-Nussmuller S., Laferl H., Zoufaly A., Genger-Hackl C., Kapper A., Schneeberger T., Trattner E., Schober G., Atzl M., Hartmann B., Puchhammer-Stockl E., Berg J., Appoyer H., Rappold M., Strickner S., Schindelwig K., Ledergerber B., Fatkenheuer G., Gerstof J., Kronborg G., Pedersen C., Larsen C.S., Pedersen G., Mohey R., Nielsen L., Weise L., Kvinesdal B., Jensen J., Abgrall S., Bernard L., Billaud E., Boue F., Boyer L., Cabie A., Caby F., Canestri A., Cotte L., de Truchis P., Duval X., Duvivier C., Enel P., Fischer H., Gasnault J., Gaud C., Grabar S., Khuong-Josses M.A., Launay O., Marchand L., Mary-Krause M., Matheron S., Melica-Gregoire G., Melliez H., Meynard J.L., Nacher M., Pavie J., Piroth L., Poizot-Martin I., Pradier C., Reynes J., Rouveix E., Simon A., Slama L., Tattevin P., Tissot-Dupont H., Biga J., Kurth T., Jacquemet N., Guiguet M., Leclercq S., Lievre L., Marshall E., Roul H., Selinger-Leneman H., Potard V., Benveniste O., Breton G., Lupin C., Bourzam E., Girard P.M., Fonquernie L., Valin N., Lefebvre B., Sebire M., Pialoux G., Lebrette M.G., Tibaut P., Adda A., Hamidi M., Cadranel J., Lavole A., Parrot A., Bouchaud O., Vignier N., Mechai F., Makhlouf S., Honore P., Bergmann J.F., Delcey V., Lopes A., Sellier P., Parrinello M., Oksenhendler E., Gerard L., Molina J.M., Rozenbaum W., Denis B., De Castro N., Lascoux C., Yazdanpanah Y., Lariven S., Joly V., Rioux C., Poupard M., Taverne B., Sutton L., Masse V., Genet P., Wifaq B., Gerbe J., Grefe S., Dupont C., Freire Maresca A., Reimann E., Bloch M., Meier F., Mortier E., Zeng F., Montoya B., Perronne C., Mathez D., Marigot-Outtandy D., Berthe H., Greder Belan A., Terby A., Godin Collet C., Marque Juillet S., Ruquet M., Roussin-Bretagne S., Colardelle P., Granier F., Laurichesse J.J., Perronne V., Akpan T., Marcou M., Daneluzzi V., Veyssier-Belot C., Masson H., Welker Y., Brazille P., Kahn J.E., Zucman D., Majerholc C., Fourn E., Bornarel D., Chambrin V., Kansau I., Raho-Moussa M., Lelievre J.D., Saidani M., Chesnel C., Dumont C., Vittecoq D., Derradji O., Bolliot C., Goujard C., Teicher E., Mole M., Bourdic K., Salmon D., Le Jeunne C., Guet P., Pietri M.P., Pannier Metzger E., Marcou V., Loulergue P., Dupin N., Morini J.P., Deleuze J., Gerhardt P., Chanal J., Weiss L., Lucas M.L., Jung C., Ptak M., Viard J.P., Ghosn J., Gazalet P., Cros A., Maignan A., Lortholary O., Rouzaud C., Touam F., Benhadj K., Consigny P.H., Bossi P., Gergely A., Cessot G., Durand F., Beck-Wirth G., Michel C., Benomar M., Rey D., Partisani M., Cheneau C., Batard M.L., Fischer P., Leclercq P., Blanc M., Morand P., Epaulard O., Signori-Schmuck A., Laurichesse H., Jacomet C., Vidal M., Coban D., Casanova S., Fresard A., Guglielminotti C., Botelho-Nevers E., Brunon-Gagneux A., Ronat V., Verdon R., Dargere S., Haustraete E., Feret P., Goubin P., Chavanet P., Fillion A., Croisier D., Gohier S., Arvieux C., Souala F., Chapplain J.M., Ratajczak M., Rohan J., Faller J.P., Ruyer O., Gendrin V., Toko L., Chirouze C., Hustache-Mathieu L., Faucher J.F., Proust A., Magy-Bertrand N., Gil H., Meaux-Ruault N., Sotto A., Rouanet I., Mauboussin J.M., Doncesco R., Jacques G., May T., Rabaud C., Andre M., Delestan M., Bouillon M.P., Bani-Sadr F., Rouger C., Berger J.L., Nguyen Y., Marchou B., Delobel P., Martin Blondel G., Cuzin L., Biezunski N., Alric L., Bonnet D., Guivarch M., Palacin A., Payssan V., Ajana F., Meybeck A., Viget N., Pugliese P., Roger P.M., Rosenthal E., Durant J., Cua E., Naqvi A., Perbost I., Risso K., Quinsat D., Raphael St., Del Giudice P., Dides P.Y., Sambuc R., Antolini-Bouvenot M.S., Druart P., Meddeb L., Ravaux I., Menard A., Tomei C., Dhiver C., Moreau J., Mokhtari S., Soavi M.J., Tomas V., Bregigeon S., Faucher O., Obry-Roguet V., Ritleng A.S., Petit N., Bartoli C., Ruiz J.M., Blanc D., Allegre T., Sordage M., Riou J.M., Faudon C., Slama B., Zerazhi H., Boulat O., Chebrek S., Beyrne M., Granet Brunello P., Pellissier L., Bonnabel D., Cohen Valensi R., Mouchet B., Mboungou G., Lafeuillade A., Hope-Rapp E., Hittinger G., Philip G., Lambry V., Raf F., Allavena C., Hall N., Reliquet V., Chidiac C., Ferry T., Perpoint T., Miailhes P., Boibieux A., Livrozet J.M., Makhlouf D., Brunel F., Chiarello P., Hoen B., Lamaury I., Fabre I., Samar K., Duvallon E., Clavel C., Stegmann S., Walter V., Adriouch L., Huber F., Vanticlke V., Couppie P., Abel S., Pierre-Francois S., Ricaud C., Rodet R., Wartel G., Sautron C., Poubeau P., Borgherini G., Camuset G., Arasteh K., Kowohl Vivantes S., Schurmann D., Warncke Charite M., Rockstroh J., Wasmuth J., Hass S., Jensen B.O., Feind C., Esser S., Schenk-Westkamp P., Haberl A., Stephan C., Plettenberg A., Kuhlendahl F., Adam A., Weitner L., Schewe K., Goey H., Fenske S., Buhk T., Stellbrink H.J., Hofmann C., Hansen S., Degen O., Heuer M., Stoll M., Gerschmann S., Horst H., Trautmann S., Gillor D., Bogner J., Sonntag B., Salzberger B., Fritzsche C., Adamis G., Antoniadou A., Chini M., Chrysos G., Gikas A., Gogos H.A., Katsarou O., Lazanas M., Metallidis S., Panagopoulos P., Paparizos V., Papastamopoulos V., Paraskevis D., Psychogiou M., Sambatakou H., Sipsas N.V., Pantazis N., Papadopoulos A., Nitsotolis T., Xylomenos G., Marangos M.N., Kouramba A., Kontos A., Lioni A., Tsachouridou O., Kourkounti S., Ganitis A., Barbounakis E., d'Arminio Monforte A., Antinori A., Andreoni M., Castagna A., Castelli F., Cauda R., Di Perri G., Galli M., Iardino R., Ippolito G., Lazzarin A., Marchetti G.C., Rezza G., von Schloesser F., Viale P., Ceccherini-Silberstein F., Cozzi-Lepri A., Lo Caputo S., Mussini C., Puoti M., Perno C.F., Bai F., Balotta C., Bandera A., Bonora S., Borderi M., Calcagno A., Capetti A., Capobianchi M.R., Cicalini S., Cingolani A., Cinque P., Di Biagio A., Gianotti N., Gori A., Guaraldi G., Lapadula G., Lichtner M., Madeddu G., Maggiolo F., Marchetti G., Monno L., Nozza S., Pinnetti C., Quiros Roldan E., Rossotti R., Rusconi S., Santoro M.M., Saracino A., Sarmati L., Fanti I., Galli L., Lorenzini P., Rodano A., Macchia M., Tavelli A., Carletti F., Carrara S., Di Caro A., Graziano S., Petroni F., Prota G., Trufa S., Giacometti A., Costantini A., Barocci V., Angarano G., Milano E., Suardi C., Donati V., Verucchi G., Castelnuovo F., Minardi C., Menzaghi B., Abeli C., Cacopardo B., Celesia B., Vecchiet J., Falasca K., Pan A., Lorenzotti S., Sighinolf L., Segala D., Blanc P., Vichi F., Cassola G., Viscoli C., Alessandrini A., Bobbio N., Mazzarello G., Fondaco L., Bonfanti P., Molteni C., Chiodera A., Milini P., Nunnari G., Pellicano G., Rizzardini G., Cannizzo E.S., Moioli M.C., Piolini R., Bernacchia D., Salpietro S., Tincati C., Puzzolante C., Migliorino C., Sangiovanni V., Borgia G., Esposito V., Di Flumeri G., Gentile I., Rizzo V., Cattelan A.M., Marinello S., Cascio A., Trizzino M., Francisci D., Schiaroli E., Parruti G., Sozio F., Magnani G., Ursitti M.A., Cristaudo A., Vullo V., Acinapura R., Moschese D., Capozzi M., Mondi A., Rivano Capparuccia M., Iaiani G., Latini A., Gagliardini R., Plazzi M.M., De Girolamo G., Vergori A., Cecchetto M., Viviani F., De Vito A., Rossetti B., Montagnani F., Franco A., Fontana Del Vecchio R., Di Giuli C., Caramello P., Orofno G.C., Sciandra M., Bassetti M., Londero A., Manfrin V., Battagin G., Starnini G., Ialungo A., van der Valk M., Geerlings S.E., Goorhuis A., Hovius J.W., Lempkes B., Nellen F.J.B., van der Poll T., Prins J.M., van Vugt M., Wiersinga W.J., Wit F.W.M.N., van Duinen M., van Eden J., Hazenberg A., van Hes A.M.H., Pijnappel F.J.J., Smalhout S.Y., Weijsenfeld A.M., Jurriaans S., Back N.K.T., Zaaijer H.L., Berkhout B., Cornelissen M.T.E., Schinkel C.J., Wolthers K.C., Peters E.J.G., van Agtmael M.A., Bomers M., Sigalof K.C.E., Heitmuller M., Laan L.M., Ang C.W., van Houdt R., Jonges M., van Prehn J., Kuijpers T.W., Pajkrt D., Scherpbier H.J., de Boer C., van der Plas A., van den Berge M., Stegeman A., Baas S., Hage de Loof L., Wintermans B., Veenemans J., Pronk M.J.H., Ammerlaan H.S.M., de Munnik E.S., Jansz A.R., Tjhie J., Wegdam M.C.A., Deiman B., Scharnhorst V., van Eeden A., Brokking W., Elsenburg L.J.M., Nobel H., Damen M., van Kasteren M.E.E., Berrevoets M.A.H., Brouwer A.E., Adams A., de Kruijf-Van de Wiel B.A.F.M., Keelan-Pfaf S., van der Ven B., Buiting A.G.M., Murck J.L., Versteeg D., de Vries-Sluijs T.E.M.S., Bax H.I., van Gorp E.C.M., Nouwen J.L., Rijnders B.J.A., Schurink C.A.M., Verbon A., de Jong-Peltenburg N.C., Bassant N., van Beek J.E.A., Vriesde M., van Zonneveld L.M., van den Berg-Cameron H.J., de Groot J., Boucher C.A.B., Koopmans M.P.G., van Kampen J.J.A., Fraaij P.L.A., van Rossum A.M.C., Vermont C.L., van der Knaap L.C., Visser E., Branger J., Douma R.A., Duijf-Van de Ven C.J.H.M., Schippers E.F., van Nieuwkoop C., van IJperen J.M., Geilings J., van der Hut G., van Burgel N.D., Leyten E.M.S., Gelinck L.B.S., Mollema F., Davids-Veldhuis S., Wildenbeest G.S., Heikens E., Groeneveld P.H.P., Bouwhuis J.W., Lammers A.J.J., Kraan S., van Hulzen A.G.W., Kruiper M.S.M., van der Bliek G.L., Bor P.C.J., Bloembergen P., Wolfagen M.J.H.M., Ruijs G.J.H.M., Kroon F.P., de Boer M.G.J., Scheper H., Jolink H., Dorama W., van Holten N., Claas E.C.J., Wessels E., den Hollander J.G., El Moussaoui R., Pogany K., Kastelijns M., Smit J.V., Smit E., Struik-Kalkman D., Tearno C., van Niekerk T., Pontesilli O., Lowe S.H., Oude Lashof A.M.L., Posthouwer D., Ackens R.P., Burgers K., Schippers J., Weijenberg-Maes B., van Loo I.H.M., Havenith T.R.A., Weijer S., van Vonderen M.G.A., Kampschreur L.M., Faber S., Steeman-Bouma R., Weel J., Kootstra G.J., Delsing C.E., van der Burg-Van de Plas M., Heins H., Kortmann W., van Twillert G., Renckens R., Ruiter-Pronk D., van Truijen-Oud F.A., Cohen Stuart J.W.T., Jansen E.R., Hoogewerf M., Rozemeijer W., van der Reijden W.A., Sinnige J.C., Brinkman K., van den Berk G.E.L., Blok W.L., Frissen P.H.J., Lettinga K.D., Schouten W.E.M., Veenstra J., Vrouenraets S.M.E., Brouwer C.J., Geerders G.F., Hoeksema K., Kleene M.J., Knapen M., van der Meche I.B., Mulder-Seeleman E., Toonen A.J.M., Wijnands S., Kwa D., van Crevel R., van Aerde 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Pedreira J.D., Galera C., Albendin H., Iborra A., Campillo M.A., Vidal A., Amador C., Pasquau F., Ena J., Benito C., Fenoll V., Mohamed-Balghata M.O., Gomez M.A., Alberto de Zarraga M., Rivas M.E., Gorgolas M., Svedhem-Johansson V., Flamholc L., Gisslen M., Hejdeman B., Norgren H., Wendahl S., Global Health, Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, ANS - Neuroinfection & -inflammation, Internal medicine, Medical Microbiology and Infection Prevention, AMS - Rehabilitation & Development, VU University medical center, Amsterdam Gastroenterology Endocrinology Metabolism, Pediatric surgery, Neurology, Amsterdam Neuroscience - Neurodegeneration, Pulmonary medicine, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Ethics, Law & Medical humanities, APH - Quality of Care, ACS - Pulmonary hypertension & thrombosis, Amsterdam Neuroscience - Neuroinfection & -inflammation, Amsterdam Reproduction & Development (AR&D), APH - Societal Participation & Health, Pediatrics, HAL-SU, Gestionnaire, National and Kapodistrian University of Athens (NKUA), University College of London [London] (UCL), Public Health Agency of Sweden, University of Zagreb, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Statens Serum Institut [Copenhagen], Public Health England [London], Università degli Studi di Milano = University of Milan (UNIMI), Instituto de Salud Carlos III [Madrid] (ISC), Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Robert Koch Institute [Berlin] (RKI), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University of Copenhagen = Københavns Universitet (UCPH), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Hellenic Center for Disease Control and Prevention, Amsterdam UMC - Amsterdam University Medical Center, Austrian Agency for Health and Food Safety (AGES), Department of Infectious Diseases, Institution of Medicine, Karolinska University Hospital and Karolinska Institutet, Istituto Superiore di Sanita [Rome], Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), University of Athens Medical School [Athens], Vourli, G, Noori, T, Pharris, A, Porter, K, Axelsson, M, Begovac, J, Cazein, F, Costagliola, D, Cowan, S, Croxford, S, Monforte, A, Delpech, V, Diaz, A, Girardi, E, Gunsenheimer-Bartmeyer, B, Hernando, V, Leierer, G, Lot, F, Nunez, O, Obel, N, Op de Coul, E, Paraskeva, D, Patrinos, S, Reiss, P, Schmid, D, Sonnerborg, A, Suligoi, B, Supervie, V, van Sighem, A, Zangerle, R, Touloumi, G, Egle, A, Kanatschnig, M, Ollinger, A, Rieger, A, Schmied, B, Wallner, E, Dewasurendra, D, Gisinger, M, Kitchen, M, Plattner, A, Rieser, E, Sarcletti, M, Greil, R, Schachner, M, Skocic, M, Muller, M, Aichwalder, R, Chromy, D, Grabmeier-Pfstershammer, K, Skoll, M, Touzeau, V, Cichon, P, Wolf-Nussmuller, S, Laferl, H, Zoufaly, A, Genger-Hackl, C, Kapper, A, Schneeberger, T, Trattner, E, Schober, G, Atzl, M, Hartmann, B, Puchhammer-Stockl, E, Berg, J, Appoyer, H, Rappold, M, Strickner, S, Schindelwig, K, Ledergerber, B, Fatkenheuer, G, Gerstof, J, Kronborg, G, Pedersen, C, Larsen, C, Pedersen, G, Mohey, R, Nielsen, L, Weise, L, Kvinesdal, B, Jensen, J, Abgrall, S, Bernard, L, Billaud, E, Boue, F, Boyer, L, Cabie, A, Caby, F, Canestri, A, Cotte, L, de Truchis, P, Duval, X, Duvivier, C, Enel, P, Fischer, H, Gasnault, J, Gaud, C, Grabar, S, Khuong-Josses, M, Launay, O, Marchand, L, Mary-Krause, M, Matheron, S, Melica-Gregoire, G, Melliez, H, Meynard, J, Nacher, M, Pavie, J, Piroth, L, Poizot-Martin, I, Pradier, C, Reynes, J, Rouveix, E, Simon, A, Slama, L, Tattevin, P, Tissot-Dupont, H, Biga, J, Kurth, T, Jacquemet, N, Guiguet, M, Leclercq, S, Lievre, L, Marshall, E, Roul, H, Selinger-Leneman, H, Potard, V, Benveniste, O, Breton, G, Lupin, C, Bourzam, E, Girard, P, Fonquernie, L, Valin, N, Lefebvre, B, Sebire, M, Pialoux, G, Lebrette, M, Tibaut, P, Adda, A, Hamidi, M, Cadranel, J, Lavole, A, Parrot, A, Bouchaud, O, Vignier, N, Mechai, F, Makhlouf, S, Honore, P, Bergmann, J, Delcey, V, Lopes, A, Sellier, P, Parrinello, M, Oksenhendler, E, Gerard, L, Molina, J, Rozenbaum, W, Denis, B, De Castro, N, Lascoux, C, Yazdanpanah, Y, Lariven, S, Joly, V, Rioux, C, Poupard, M, Taverne, B, Sutton, L, Masse, V, Genet, P, Wifaq, B, Gerbe, J, Grefe, S, Dupont, C, Freire Maresca, A, Reimann, E, Bloch, M, Meier, F, Mortier, E, Zeng, F, Montoya, B, Perronne, C, Mathez, D, Marigot-Outtandy, D, Berthe, H, Greder Belan, A, Terby, A, Godin Collet, C, Marque Juillet, S, Ruquet, M, Roussin-Bretagne, S, Colardelle, P, Granier, F, Laurichesse, J, Perronne, V, Akpan, T, Marcou, M, Daneluzzi, V, Veyssier-Belot, C, Masson, H, Welker, Y, Brazille, P, Kahn, J, Zucman, D, Majerholc, C, Fourn, E, Bornarel, D, Chambrin, V, Kansau, I, Raho-Moussa, M, Lelievre, J, Saidani, M, Chesnel, C, Dumont, C, Vittecoq, D, Derradji, O, Bolliot, C, Goujard, C, Teicher, E, Mole, M, Bourdic, K, Salmon, D, Le Jeunne, C, Guet, P, Pietri, M, Pannier Metzger, E, Marcou, V, Loulergue, P, Dupin, N, Morini, J, Deleuze, J, Gerhardt, P, Chanal, J, Weiss, L, Lucas, M, Jung, C, Ptak, M, Viard, J, Ghosn, J, Gazalet, P, Cros, A, Maignan, A, Lortholary, O, Rouzaud, C, Touam, F, Benhadj, K, Consigny, P, Bossi, P, Gergely, A, Cessot, G, Durand, F, Beck-Wirth, G, Michel, C, Benomar, M, Rey, D, Partisani, M, Cheneau, C, Batard, M, Fischer, P, Leclercq, P, Blanc, M, Morand, P, Epaulard, O, Signori-Schmuck, A, Laurichesse, H, Jacomet, C, Vidal, M, Coban, D, Casanova, S, Fresard, A, Guglielminotti, C, Botelho-Nevers, E, Brunon-Gagneux, A, Ronat, V, Verdon, R, Dargere, S, Haustraete, E, Feret, P, Goubin, P, Chavanet, P, Fillion, A, Croisier, D, Gohier, S, Arvieux, C, Souala, F, Chapplain, J, Ratajczak, M, Rohan, J, Faller, J, Ruyer, O, Gendrin, V, Toko, L, Chirouze, C, Hustache-Mathieu, L, Faucher, J, Proust, A, Magy-Bertrand, N, Gil, H, Meaux-Ruault, N, Sotto, A, Rouanet, I, Mauboussin, J, Doncesco, R, Jacques, G, May, T, Rabaud, C, Andre, M, Delestan, M, Bouillon, M, Bani-Sadr, F, Rouger, C, Berger, J, Nguyen, Y, Marchou, B, Delobel, P, Martin Blondel, G, Cuzin, L, Biezunski, N, Alric, L, Bonnet, D, Guivarch, M, Palacin, A, Payssan, V, Ajana, F, Meybeck, A, Viget, N, Pugliese, P, Roger, P, Rosenthal, E, Durant, J, Cua, E, Naqvi, A, Perbost, I, Risso, K, Quinsat, D, Raphael, S, Del Giudice, P, Dides, P, Sambuc, R, Antolini-Bouvenot, M, Druart, P, Meddeb, L, Ravaux, I, Menard, A, Tomei, C, Dhiver, C, Moreau, J, Mokhtari, S, Soavi, M, Tomas, V, Bregigeon, S, Faucher, O, Obry-Roguet, V, Ritleng, A, Petit, N, Bartoli, C, Ruiz, J, Blanc, D, Allegre, T, Sordage, M, Riou, J, Faudon, C, Slama, B, Zerazhi, H, Boulat, O, Chebrek, S, Beyrne, M, Granet Brunello, P, Pellissier, L, Bonnabel, D, Cohen Valensi, R, Mouchet, B, Mboungou, G, Lafeuillade, A, Hope-Rapp, E, Hittinger, G, Philip, G, Lambry, V, Raf, F, Allavena, C, Hall, N, Reliquet, V, Chidiac, C, Ferry, T, Perpoint, T, Miailhes, P, Boibieux, A, Livrozet, J, Makhlouf, D, Brunel, F, Chiarello, P, Hoen, B, Lamaury, I, Fabre, I, Samar, K, Duvallon, E, Clavel, C, Stegmann, S, Walter, V, Adriouch, L, Huber, F, Vanticlke, V, Couppie, P, Abel, S, Pierre-Francois, S, Ricaud, C, Rodet, R, Wartel, G, Sautron, C, Poubeau, P, Borgherini, G, Camuset, G, Arasteh, K, Kowohl Vivantes, S, Schurmann, D, Warncke Charite, M, Rockstroh, J, Wasmuth, J, Hass, S, Jensen, B, Feind, C, Esser, S, Schenk-Westkamp, P, Haberl, A, Stephan, C, Plettenberg, A, Kuhlendahl, F, Adam, A, Weitner, L, Schewe, K, Goey, H, Fenske, S, Buhk, T, Stellbrink, H, Hofmann, C, Hansen, S, Degen, O, Heuer, M, Stoll, M, Gerschmann, S, Horst, H, Trautmann, S, Gillor, D, Bogner, J, Sonntag, B, Salzberger, B, Fritzsche, C, Adamis, G, Antoniadou, A, Chini, M, Chrysos, G, Gikas, A, Gogos, H, Katsarou, O, Lazanas, M, Metallidis, S, Panagopoulos, P, Paparizos, V, Papastamopoulos, V, Paraskevis, D, Psychogiou, M, Sambatakou, H, Sipsas, N, Pantazis, N, Papadopoulos, A, Nitsotolis, T, Xylomenos, G, Marangos, M, Kouramba, A, Kontos, A, Lioni, A, Tsachouridou, O, Kourkounti, S, Ganitis, A, Barbounakis, E, d'Arminio Monforte, A, Antinori, A, Andreoni, M, Castagna, A, Castelli, F, Cauda, R, Di Perri, G, Galli, M, Iardino, R, Ippolito, G, Lazzarin, A, Marchetti, G, Rezza, G, von Schloesser, F, Viale, P, Ceccherini-Silberstein, F, Cozzi-Lepri, A, Lo Caputo, S, Mussini, C, Puoti, M, Perno, C, Bai, F, Balotta, C, Bandera, A, Bonora, S, Borderi, M, Calcagno, A, Capetti, A, Capobianchi, M, Cicalini, S, Cingolani, A, Cinque, P, Di Biagio, A, Gianotti, N, Gori, A, Guaraldi, G, Lapadula, G, Lichtner, M, Madeddu, G, Maggiolo, F, Monno, L, Nozza, S, Pinnetti, C, Quiros Roldan, E, Rossotti, R, Rusconi, S, Santoro, M, Saracino, A, Sarmati, L, Fanti, I, Galli, L, Lorenzini, P, Rodano, A, Macchia, M, Tavelli, A, Carletti, F, Carrara, S, Di Caro, A, Graziano, S, Petroni, F, Prota, G, Trufa, S, Giacometti, A, Costantini, A, Barocci, V, Angarano, G, Milano, E, Suardi, C, Donati, V, Verucchi, G, Castelnuovo, F, Minardi, C, Menzaghi, B, Abeli, C, Cacopardo, B, Celesia, B, Vecchiet, J, Falasca, K, Pan, A, Lorenzotti, S, Sighinolf, L, Segala, D, Blanc, P, Vichi, F, Cassola, G, Viscoli, C, Alessandrini, A, Bobbio, N, Mazzarello, G, Fondaco, L, Bonfanti, P, Molteni, C, Chiodera, A, Milini, P, Nunnari, G, Pellicano, G, Rizzardini, G, Cannizzo, E, Moioli, M, Piolini, R, Bernacchia, D, Salpietro, S, Tincati, C, Puzzolante, C, Migliorino, C, Sangiovanni, V, Borgia, G, Esposito, V, Di Flumeri, G, Gentile, I, Rizzo, V, Cattelan, A, Marinello, S, Cascio, A, Trizzino, M, Francisci, D, Schiaroli, E, Parruti, G, Sozio, F, Magnani, G, Ursitti, M, Cristaudo, A, Vullo, V, Acinapura, R, Moschese, D, Capozzi, M, Mondi, A, Rivano Capparuccia, M, Iaiani, G, Latini, A, Gagliardini, R, Plazzi, M, De Girolamo, G, Vergori, A, Cecchetto, M, Viviani, F, De Vito, A, Rossetti, B, Montagnani, F, Franco, A, Fontana Del Vecchio, R, Di Giuli, C, Caramello, P, Orofno, G, Sciandra, M, Bassetti, M, Londero, A, Manfrin, V, Battagin, G, Starnini, G, Ialungo, A, van der Valk, M, Geerlings, S, Goorhuis, A, Hovius, J, Lempkes, B, Nellen, F, van der Poll, T, Prins, J, van Vugt, M, Wiersinga, W, Wit, F, van Duinen, M, van Eden, J, Hazenberg, A, van Hes, A, Pijnappel, F, Smalhout, S, Weijsenfeld, A, Jurriaans, S, Back, N, Zaaijer, H, Berkhout, B, Cornelissen, M, Schinkel, C, Wolthers, K, Peters, E, van Agtmael, M, Bomers, M, Sigalof, K, Heitmuller, M, Laan, L, Ang, C, van Houdt, R, Jonges, M, van Prehn, J, Kuijpers, T, Pajkrt, D, Scherpbier, H, de Boer, C, van der Plas, A, van den Berge, M, Stegeman, A, Baas, S, Hage de Loof, L, Wintermans, B, Veenemans, J, Pronk, M, Ammerlaan, H, de Munnik, E, Jansz, A, Tjhie, J, Wegdam, M, Deiman, B, Scharnhorst, V, van Eeden, A, Brokking, W, Elsenburg, L, Nobel, H, Damen, M, van Kasteren, M, Berrevoets, M, Brouwer, A, Adams, A, de Kruijf-Van de Wiel, B, Keelan-Pfaf, S, van der Ven, B, Buiting, A, Murck, J, Versteeg, D, de Vries-Sluijs, T, Bax, H, van Gorp, E, Nouwen, J, Rijnders, B, Schurink, C, Verbon, A, de Jong-Peltenburg, N, Bassant, N, van Beek, J, Vriesde, M, van Zonneveld, L, van den Berg-Cameron, H, de Groot, J, Boucher, C, Koopmans, M, van Kampen, J, Fraaij, P, van Rossum, A, Vermont, C, van der Knaap, L, Visser, E, Branger, J, Douma, R, Duijf-Van de Ven, C, Schippers, E, van Nieuwkoop, C, van IJperen, J, Geilings, J, van der Hut, G, van Burgel, N, Leyten, E, Gelinck, L, Mollema, F, Davids-Veldhuis, S, Wildenbeest, G, Heikens, E, Groeneveld, P, Bouwhuis, J, Lammers, A, Kraan, S, van Hulzen, A, Kruiper, M, van der Bliek, G, Bor, P, Bloembergen, P, Wolfagen, M, Ruijs, G, Kroon, F, de Boer, M, Scheper, H, Jolink, H, Dorama, W, van Holten, N, Claas, E, Wessels, E, den Hollander, J, El Moussaoui, R, Pogany, K, Kastelijns, M, Smit, J, Smit, E, Struik-Kalkman, D, Tearno, C, van Niekerk, T, Pontesilli, O, Lowe, S, Oude Lashof, A, Posthouwer, D, Ackens, R, Burgers, K, Schippers, J, Weijenberg-Maes, B, van Loo, I, Havenith, T, Weijer, S, van Vonderen, M, Kampschreur, L, Faber, S, Steeman-Bouma, R, Weel, J, Kootstra, G, Delsing, C, van der Burg-Van de Plas, M, Heins, H, Kortmann, W, van Twillert, G, Renckens, R, Ruiter-Pronk, D, van Truijen-Oud, F, Cohen Stuart, J, Jansen, E, Hoogewerf, M, Rozemeijer, W, van der Reijden, W, Sinnige, J, Brinkman, K, van den Berk, G, Blok, W, Frissen, P, Lettinga, K, Schouten, W, Veenstra, J, Vrouenraets, S, Brouwer, C, Geerders, G, Hoeksema, K, Kleene, M, Knapen, M, van der Meche, I, Mulder-Seeleman, E, Toonen, A, Wijnands, S, Kwa, D, van Crevel, R, van Aerde, K, Doferhof, A, Henriet, S, ter Hofstede, H, Hoogerwerf, J, Keuter, M, Richel, O, Albers, M, Grintjes-Huisman, K, de Haan, M, Marneef, M, Strik-Albers, R, Rahamat-Langendoen, J, Stelma, F, Burger, D, Gisolf, E, Hassing, R, Claassen, M, ter Beest, G, van Bentum, P, Langebeek, N, Tiemessen, R, Swanink, C, van Lelyveld, S, Soetekouw, R, van der Prijt, L, van der Swaluw, J, Bermon, N, Jansen, R, Herpers, B, Veenendaal, D, Verhagen, D, Lauw, F, van Broekhuizen, M, van Wijk, M, Bierman, W, Bakker, M, Kleinnijenhuis, J, Kloeze, E, Middel, A, Scholvinck, E, Stienstra, Y, Verhage, A, Wouthuyzen-Bakker, K, Boonstra, A, de Groot-De Jonge, H, van der Meulen, P, de Weerd, D, Niesters, H, van Leer-Buter, C, Knoester, M, Hoepelman, A, Arends, J, Barth, R, Bruns, A, Ellerbroek, P, Mudrikova, T, Oosterheert, J, de Regt, M, Schadd, E, van Zoelen, M, Aarsman, K, Grifoen-Van Santen, B, de Kroon, I, van Rooijen, C, van Berkel, M, Schuurman, R, Verduyn-Lunel, F, Wensing, A, Bont, L, Geelen, S, Loefen, Y, Wolfs, T, Nauta, N, Zaheri, S, Boyd, A, Bezemer, D, Smit, C, Hillebregt, M, de Jong, A, Woudstra, T, Bergsma, D, Meijering, R, van de Sande, L, Rutkens, T, van der Vliet, S, de Groot, L, van den Akker, M, Bakker, Y, El Berkaoui, A, Bezemer, M, Bretin, N, Djoechro, E, Geerlinks, J, Kruijne, E, Lodewijk, C, Lucas, E, van der Meer, R, Munjishvili, L, Paling, F, Peeck, B, Ree, C, Regtop, R, Ruijs, Y, Schoorl, M, Schnorr, P, Tuijn, E, Veenenberg, L, Witte, E, Tuk, B, Moreno, S, del Amo, J, Dalmau, D, Navarro, M, Gonzalez, M, Blanco, J, Garcia, F, Rubio, R, Iribarren, J, Gutierrez, F, Vidal, F, Berenguer, J, Gonzalez, J, Sobrino, P, Alejos, B, Alvarez, D, Jarrin, I, Moreno, C, Munoz-Fernandez, M, Garcia-Merino, I, Rico, C, de la Fuente, J, Torre, A, Portilla, J, Merino, E, Reus, S, Boix, V, Giner, L, Gadea, C, Portilla, I, Pampliega, M, Diez, M, Rodriguez, J, Sanchez-Paya, J, Podzamczer, D, Imaz, E, Van Den Eyncle, E, Di Yacovo, S, Sumoy, M, Gomez, J, Hernandez, J, Aleman, M, Alonso, M, Hernandez, M, Diaz-Flores, F, Garcia, D, Pelazas, R, Asensi, V, Valle, E, Carton, J, Perez, V, Molina, M, Garcia, J, Carrera, E, Pulido, F, Bisbal, O, Matarranz, M, Lagarde, M, Rubio-Martin, R, Hernando, A, Bermejo, L, Dominguez, L, Arrizabalaga, J, Aramburu, M, Camino, X, Rodriguez-Arrondo, F, von Wichmann, M, Tome, L, Goenaga, M, Bustinduy, M, Galparsoro, H, Ibarguren, M, Aguado, M, Umerez, M, Masia, M, Lopez, C, Padilla, S, Navarro, A, Montolio, F, Robledano, C, Colome, J, Adsuar, A, Pascual, R, Carlos, F, Martinez, M, Fernandez, M, Garcia, E, Muga, R, Tor, J, Sanvisens, A, Bernaldo de Quiros Lopez, J, Miralles, P, Gutierrez, I, Ramirez, M, Padilla, B, Gijon, P, Carrero, A, Aldamiz-Echevarria, T, Tejerina, F, Parras, F, Balsalobre, P, Diez, C, Peraire, J, Vilades, C, Veloso, S, Vargas, M, Lopez-Dupla, M, Olona, M, Aguilar, A, Sirvent, J, Alba, V, Calavia, O, Montero, M, Lacruz, J, Blanes, M, Calabuig, E, Cuellar, S, Lopez, J, Salavert, M, de la Serna, I, Arribas, J, Montes, M, Pena, J, Arribas, B, Castro, J, Zamora, J, Perez, I, Estebanez, M, Garcia, S, Diaz, M, Alcariz, N, Mingorance, J, Montero, D, Gonzalez, A, Isabel de Jose, M, de los Santos, I, Sanz, J, Salas, A, Sarria, C, Berrocal, A, Garcia-Fraile, L, Oteo, J, Ibarra, V, Metola, L, Sanz, M, Perez-Martinez, L, Pascual, A, Ramos, C, Arazo, P, Gil, D, Jaen, A, Cairo, M, Irigoyen, D, Jordano, Q, Xercavins, M, Martinez-Lacasa, J, Velli, P, Font, R, Sanmarti, M, Ibanez, L, Rivero, M, Casado, M, Diaz, J, Uriz, J, Reparaz, J, Irigoyen, C, Arraiza, M, Segura, F, Amengual, M, Navarro, G, Sala, M, Cervantes, M, Pineda, V, Segura, V, Anton, E, Nogueras, M, Casado, J, Dronda, F, Moreno, A, Elias, M, Lopez, D, Gutierrez, C, Madrid, N, Lamas, A, Marti, P, de Diaz, A, Serrrano, S, Donat, L, Cano, A, Bernal, E, Munoz, A, Pena, A, Munoz, L, Parra, J, Alvarez, M, Chueca, N, Guillot, V, Vinuesa, D, Fernandez, J, Del Romero, J, Rodriguez, C, Puerta, T, Carrio, J, Vera, M, Ballesteros, J, Domingo, P, Sambeat, M, Lamarca, K, Mateo, G, Gutierrez, M, Fernandez, I, Antela, A, Losada, E, Riera, M, Penaranda, M, Leyes, M, Ribas, M, Campins, A, Vidal, C, Gil, L, Fanjul, F, Marinescu, C, Ribera, E, Santos, J, Marquez, M, Viciana, I, Palacios, R, Gonzalez, C, Viciana, P, Leal, M, Lopez-Cortes, L, Espinosa, N, Munoz, J, Zubero, M, Baraia-Etxaburu, J, Ibarra, S, Ferrero, O, Lopez de Munain, J, Camara, M, Lopez, I, de la Pena, M, Suarez-Garcia, I, Malmierca, E, Olalla, J, del Arco, A, de la Torre, J, Prada, J, Caracuel, Z, Lopez-Lirola, A, Lozano, A, Fernandez, E, Martinez, O, Vera, F, Martinez, L, Alcaraz, B, Jimeno, A, Poveda, E, Pernas, B, Mena, A, Grandal, M, Castro, A, Pedreira, J, Galera, C, Albendin, H, Iborra, A, Campillo, M, Vidal, A, Amador, C, Pasquau, F, Ena, J, Benito, C, Fenoll, V, Mohamed-Balghata, M, Gomez, M, Alberto de Zarraga, M, Rivas, M, Gorgolas, M, Svedhem-Johansson, V, Flamholc, L, Gisslen, M, Hejdeman, B, Norgren, H, and Wendahl, S

Subjects
Male, 0301 basic medicine, Psychological intervention, Human immunodeficiency virus (HIV), Medizin, Continuum of care, Europe, HIV infection, Key population, Sex, Anti-Retroviral Agents, Continuity of Patient Care, European Union, HIV, Humans, HIV Infections, medicine.disease_cause, key population, 0302 clinical medicine, HIV Infection, 030212 general & internal medicine, Men having sex with men, media_common, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Transmission (medicine), Infectious Diseases, AcademicSubjects/MED00290, HIV infection, continuum of care, sex, key population, Europe, Microbiology (medical), Population, Socio-culturale, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), SDG 3 - Good Health and Well-being, medicine, media_common.cataloged_instance, European union, education, Pandemics, continuum of care, sex, business.industry, SARS-CoV-2, COVID-19, medicine.disease, 030112 virology, Major Articles and Commentaries, Anti-Retroviral Agent, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Demography
Abstract

Background High uptake of antiretroviral treatment (ART) is essential to reduce human immunodeficiency virus (HIV) transmission and related mortality; however, gaps in care exist. We aimed to construct the continuum of HIV care (CoC) in 2016 in 11 European Union (EU) countries, overall and by key population and sex. To estimate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, we compared 2016 to 2013 estimates for the same countries, representing 73% of the population in the region. Methods A CoC with the following 4 stages was constructed: number of people living with HIV (PLHIV); proportion of PLHIV diagnosed; proportion of those diagnosed who ever initiated ART; and proportion of those ever treated who achieved viral suppression at their last visit. Results We estimated that 87% of PLHIV were diagnosed; 92% of those diagnosed had ever initiated ART; and 91% of those ever on ART, or 73% of all PLHIV, were virally suppressed. Corresponding figures for men having sex with men were: 86%, 93%, 93%, 74%; for people who inject drugs: 94%, 88%, 85%, 70%; and for heterosexuals: 86%, 92%, 91%, 72%. The proportion suppressed of all PLHIV ranged from 59% to 86% across countries. Conclusions The EU is close to the 90-90-90 target and achieved the UNAIDS target of 73% of all PLHIV virally suppressed, significant progress since 2013 when 60% of all PLHIV were virally suppressed. Strengthening of testing programs and treatment support, along with prevention interventions, are needed to achieve HIV epidemic control., Standardized definitions were used to estimate a 4-stage continuum of human immunodeficiency virus (HIV) care in 11 European Union (EU) countries in 2016. The EU is close to the 90-90-90 target, with the main challenge being the percentage of undiagnosed infections.

Published
2020

44. National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio : a pooled analysis of 458 population-based studies in Asian and Western countries

Author

NCD Risk Factor Collaboration (NCD-RisC), [missing], Taddei, Cristina, Jackson, Rod, Zhou, Bin, Bixby, Honor, Danaei, Goodarz, Di Cesare, Mariachiara, Kuulasmaa, Kari, Hajifathalian, Kaveh, Bentham, James, Bennett, James E, Aekplakorn, Wichai, Cifkova, Renata, Dallongeville, Jean, DeBacquer, Dirk, Giampaoli, Simona, Gudnason, Vilmundur, Khang, Young-Ho, Laatikainen, Tiina, Mann, JimI, Marques-Vidal, Pedro, Mensah, George A, Müller-Nurasyid, Martina, Ninomiya, Toshiharu, Petkeviciene, Janina, Rodríguez-Artalejo, Fernando, Servais, Jennifer, Söderberg, Stefan, Stavreski, Bill, Wilsgaard, Tom, Zdrojewski, Tomasz, Zhao, Dong, Stevens, Gretchen A, Savin, Stefan, Cowan, Melanie J, Riley, Leanne M, Ezzati, Majid, Adams, Robert J, Ahrens, Wolfgang, Amouyel, Philippe, Amuzu, Antoinette, Anderssen, Sigmund A, Ariansen, Inger, Arveiler, Dominique, Aspelund, Thor, Auvinen, Juha, Avdicová, Mária, Banach, Maciej, Bandosz, Piotr, Banegas, José R, Barbagallo, Carlo M, Bata, Iqbal, Baur, Louise A, Beaglehole, Robert, Bernotiene, Gailute, Bi, Yufang, Bienek, Asako, Björkelund, Cecilia, Bo, Simona, Boehm, Bernhard O, Bonaccio, Marialaura, Bongard, Vanina, Borchini, Rossana, Borghs, Herman, Breckenkamp, Juergen, Brenner, Hermann, Bruno, Graziella, Busch, Markus A, Cabrera de León, Antonio, Capuano, Vincenzo, Casanueva, Felipe F, Casas, Juan-Pablo, Caserta, Carmelo A, Censi, Laura, Chen, Fangfang, Chen, Shuohua, Chirlaque, María-Dolores, Cho, Belong, Cho, Yumi, Chudek, Jerzy, Claessens, Frank, Clarke, Janine, Clays, Els, Cooper, Cyrus, Costanzo, Simona, Cottel, Dominique, Cowell, Chris, Crujeiras, Ana B, Cui, Liufu, D'Arrigo, Graziella, Dauchet, Luc, De Backer, Guy, De Bacquer, Dirk, de Gaetano, Giovanni, De Henauw, Stefaan, De Smedt, Delphine, Dennison, Elaine, Deschamps, Valérie, DiCastelnuovo, Augusto, Dobson, Annette J, Donfrancesco, Chiara, Döring, Angela, Drygas, Wojciech, Du, Yong, Dziankowska-Zaborszczyk, Elzbieta, Eggertsen, Robert, Ekelund, Ulf, Elosua, Roberto, Eriksson, Johan G, Evans, Alun, Faeh, David, Felix-Redondo, Francisco J, Fernández-Bergés, Daniel, Ferrari, Marika, Ferrieres, Jean, Finn, Joseph D, Forslund, Ann-Sofie, Forsner, Maria, Frontera, Guillermo, Fujita, Yuki, Gaciong, Zbigniew, Galvano, Fabio, Gao, Jingli, Garcia-de-la-Hera, Manoli, Garnett, Sarah P, Gaspoz, Jean-Michel, Gasull, Magda, Gates, Louise, Gianfagna, Francesco, Gill, Tiffany K, Giovannelli, Jonathan, Goltzman, David, GonzalezGross, Marcela, Gottrand, Frederic, Graff-Iversen, Sidsel, Grafnetter, Dušan, Gregor, Ronald D, Grodzicki, Tomasz, Grosso, Giuseppe, Gruden, Grabriella, Gu, Dongfeng, Guallar-Castillón, Pilar, Gudmundsson, Elias F, Guessous, Idris, Gunnlaugsdottir, Johanna, Gutzwiller, Felix, Hardy, Rebecca, Hata, Jun, Haugsgjerd, Teresa, Hayes, Alison J, He, Jiang, He, Yuna, Herrala, Sauli, TapaniHihtaniemi, Ilpo, Hobbs, Michael, Hopman, Wilma M, MaríaHuerta, José, Huybrechts, Inge, Iacoviello, Licia, Iannone, Anna G, Ikeda, Nayu, Iwasaki, Masanori, Jamrozik, Konrad, Janszky, Imre, Jarvelin, Marjo-Riitta, Jasienska, Grazyna, Jennings, Garry, Jeong, Seung-lyeal, QiangJiang, Chao, Joffres, Michel, Jokelainen, Jari J, Jonas, Jost B, Jóźwiak, Jacek, Kajantie, Eero O, Kauhanen, Jussi, Keil, Ulrich, Keinänen-Kiukaanniemi, Sirkka, Kersting, Mathilde, Kiechl-Kohlendorfer, Ursula, Kiechl, Stefan, Kim, Jeongseon, Kim, Yeon-Yong, Klumbiene, Jurate, Knoflach, Michael, Ko, Stephanie, Kolle, Elin, Korpelainen, Raija, Koskinen, Seppo, Kouda, Katsuyasu, Kratzer, Wolfgang, Kriemler, Susi, Krokstad, Steinar, Kujala, Urho M, Kurjata, Pawel, HingLam, Tai, Lanska, Vera, Lappas, Georg, Laugsand, Lars E, Lee, Jeonghee, Lehtimäki, Terho, Li, Yanping, Lilly, Christa L, Lin, Xu, Lind, Lars, Lissner, Lauren, Liu, Jing, Lopez-Garcia, Esther, Lorbeer, Roberto, EugenioLozano, José, Luksiene, Dalia, Lundqvist, Annamari, Lundqvist, Robert, Lytsy, Per, Ma, Guansheng, Machi, Suka, Maggi, Stefania, Magliano, Dianna J, Manzato, Enzo, Mathiesen, Ellisiv B, McLachlan, Stela, McLean, Rachael M, McLean, Scott B, Meirhaeghe, Aline, Meisinger, Christa, Metcalf, Patricia, Mi, Jie, Miller, Jody C, Moreno, Luis A, Morin, Suzanne, Mossakowska, Malgorzata, Muiesan, Maria L, Mursu, Jaakko, Nakamura, Harunobu, Námešná, Jana, Nauck, Matthias, MariaNavarrete-Muñoz, Eva, Neal, William A, Nenko, Ilona, Niiranen, Teemu J, Ning, Guang, Noale, Marianna, Norie, Sawada, Noto, Davide, O'Neill, Terence, O'Reilly, Dermot, Oh, Kyungwon, Olafsson, Örn, MichelPaccaud, Fred, Pajak, Andrzej, Palmieri, Luigi, Panza, Francesco, Parnell, Winsome R, Peltonen, Markku, Peters, Annette, Petersmann, Astrid, Pigeot, Iris, Pilotto, Lorenza, Piwonska, Aleksandra, Plans-Rubió, Pedro, Porta, Miquel, Price, Jacqueline F, Puder, Jardena J, Puhakka, Soile E, Radisauskas, Ricardas, Raitakari, Olli, Ramos, Rafel, Redon, Josep, Rigo, Fernando, Rodriguez-Perez, MaríadelCristo, Romaguera, Dora, Ronkainen, Kimmo, Rosengren, Annika, Roy, Joel G R, Ruidavets, Jean-Bernard, Rutkowski, Marcin, Salanave, Benoit, Salmerón, Diego, Salomaa, Veikko, Salonen, Jukka T, Salvetti, Massimo, Sans, Susana, Saramies, Jouko L, Saum, Kai-Uwe, Scheidt-Nave, Christa, Schienkiewitz, Anja, Schipf, Sabine, Schmidt, Carsten O, Schöttker, Ben, Sebert, Sylvain, Sen, Abhijit, Shaw, Jonathan E, Shibuya, Kenji, WookShin, Dong, Shiri, Rahman, Simons, Judith, Simons, Leon A, Sjöström, Michael, Slowikowska-Hilczer, Jolanta, Slusarczyk, Przemyslaw, Solfrizzi, Vincenzo, Sonestedt, Emily, Soumare, Aicha, Staessen, Jan A, Stathopoulou, Maria G, Steene-Johannessen, Jostein, Stehle, Peter, Stieber, Jutta, Stöckl, Doris, Stokwiszewski, Jakub, Sundström, Johan, Suriyawongpaisal, Paibul, Tamosiunas, Abdonas, JooTan, Eng, Taylor, Anne, Tell, Grethe, Thijs, Lutgarde, Tolonen, HannaK, Topór-Madry, Roman, JoséTormo, María, Torrent, Maties, Tsugane, Shoichiro, Tuomainen, Tomi-Pekka, Tuomilehto, Jaakko, Tzourio, Christophe, Uusitalo, Hannu M T, Van Herck, Koen, Vanderschueren, Dirk, Vanuzzo, Diego, Vatten, Lars, Vega, Tomas, Veronesi, Giovanni, Vioque, Jesus, Virtanen, JyrkiK, Visvikis-Siest, Sophie, Vollenweider, Peter, Voutilainen, Sari, Vrijheid, Martine, Wagner, Aline, Wagner, Anne, Wang, Ming-Dong, Wang, Qian, XingWang, Ya, Wannamethee, S Goya, Wei, Wenbin, Whincup, Peter H, Wiecek, Andrzej, Willeit, Johann, Willeit, Peter, Wojtyniak, Bogdan, Wong, Andrew, Woodward, Mark, GiwercmanWu, Aleksander, Wu, Frederick C, Wu, Shouling, Xu, Haiquan, Xu, Liang, Yan, Weili, Yang, Xiaoguang, Ye, Xingwang, Yoshihara, Akihiro, Zambon, Sabina, Zhao, Wenhua, Imperial College London, University of Auckland [Auckland], Harvard T.H. Chan School of Public Health, Middlesex University, National Institute for Health and Welfare [Helsinki], Weill Medical College of Cornell University [New York], University of Kent [Canterbury], Mahidol University [Bangkok], Charles University [Prague] (CU), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Universiteit Gent = Ghent University [Belgium] (UGENT), Istituto Superiore di Sanita [Rome], Icelandic Heart Association [Kopavogur, Iceland] (IHA), Seoul National University [Seoul] (SNU), University of Otago [Dunedin, Nouvelle-Zélande], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Helmholtz-Zentrum München (HZM), Kyushu University [Fukuoka], Universidad Autonoma de Madrid (UAM), CIBER de Epidemiología y Salud Pública (CIBERESP), Umeå University, The Arctic University of Norway (UiT), Medical University of Gdańsk, Capital University of Medical Sciences [Beijing] (CUMS), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Adelaide, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), London School of Hygiene and Tropical Medicine (LSHTM), Norwegian School of Sport Sciences = Norges idrettshøgskole [Oslo] (NIH), Norwegian Institute of Public Health [Oslo] (NIPH), Université de Strasbourg (UNISTRA), University of Iceland [Reykjavik], University of Oulu, Regional Authority of Public Health [Slovaquia] (RAPH), Ministry of Health of the Slovak Republic [Slovaquia], Medical University of Łódź (MUL), Università degli studi di Palermo - University of Palermo, Dalhousie University [Halifax], The University of Sydney, Public Health Agency of Canada, University of Gothenburg (GU), University of Turin, Nanyang Technological University [Singapour], Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Universität Bielefeld = Bielefeld University, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Robert Koch Institute [Berlin] (RKI), Universidad de La Laguna [Tenerife - SP] (ULL), Universidade de Santiago de Compostela [Spain] (USC ), University College of London [London] (UCL), University of Silesia in Katowice, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Southampton, Biomolécules et inflammation pulmonaire, Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Santé publique France - French National Public Health Agency [Saint-Maurice, France], University of Queensland [Brisbane], IMIM-Hospital del Mar, Generalitat de Catalunya, Queen's University [Belfast] (QUB), Universität Zürich [Zürich] = University of Zurich (UZH), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Manchester [Manchester], Kindai University, Medical University of Warsaw - Poland, Università degli studi di Catania [Catania], Geneva University Hospital (HUG), Universitá degli Studi dell’Insubria, McGill University = Université McGill [Montréal, Canada], Universidad Politécnica de Madrid (UPM), Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institute for Clinical and Experimental Medicine (IKEM), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Bergen (UiB), Tulane University, Chinese Center for Disease Control and Prevention, Oulu University Hospital [Oulu], The University of Western Australia (UWA), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Niigata University, Norwegian University of Science and Technology (NTNU), Simon Fraser University (SFU.ca), University of Eastern Finland, Westfälische Wilhelms-Universität Münster (WWU), Innsbruck Medical University [Austria] (IMU), Universitätsklinikum Ulm - University Hospital of Ulm, University of Jyväskylä (JYU), The University of Hong Kong (HKU), Sahlgrenska Academy at University of Gothenburg [Göteborg], Tampere University Hospital, University of Tampere [Finland], West Virginia University [Morgantown], University of Chinese Academy of Sciences [Beijing] (UCAS), Uppsala Universitet [Uppsala], Universität Greifswald - University of Greifswald, Peking University [Shenzhen], The Jikei University School of Medicine, Baker Heart and Diabetes Institute (AUSTRALIA), Universita degli Studi di Padova, University of Edinburgh, University of Zaragoza - Universidad de Zaragoza [Zaragoza], International Institute of Molecular and Cell Biology [Warsaw] (IIMCB), Università degli Studi di Brescia [Brescia], Konan University [Kobe, Japan], University of Turku, Shanghai Jiao Tong University School of Medicine, Department of Epidemiology and Biostatistics, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, Department of Epidemiology, Health Economics and Public Health, UMR 558 INSERM, Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Unité de Surveillance et d'Epidémiologie Nutritionnelle (USEN), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut de Veille Sanitaire (INVS)-Université Paris 13 (UP13), Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain, parent, Department of Chronic Disease Prevention, Institute for plasma research, Institute for Plasma Research, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Department of Reproductive Endocrinology, University of Bari Aldo Moro (UNIBA), Nutritional Epidemiology, Department of Clinical Sciences, Clinical Research Center, Lund University [Lund]-Lund University [Lund], Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Applied Food Science, Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Research Unit Hypertension and Cardiovascular Epidemiology [Louvain, Belgique], Studies Coordinating Centre [Louvain, Belgique], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), National Cancer Center, University of Kuopio, Epidémiologie cardiovasculaire et métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Tampere University, Department of Andrology and Endocrinology, Katholieke Universiteit Leuven, Norwegian University of Science and Technology [Trondheim] (NTNU), Departamento de Salud Pública, Universidad Miguel Hernández [Elche] (UMH), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Department of Internal Medicine, School of Public Health and Clinical Nutrition, Epidemiologia Ambiental, Centre for Research in Environmental Epidemiology (CREAL)-Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP) of Pamplona-Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Department of Epidemiology and Public Health, EA 3430, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Medical University of Silesia (SUM), University of Innsbruck, National Institute of Hygiene Warsaw, The Georges Institute for International Health, Naval Research Laboratory (NRL), Grant numbers 101506/Z/13/Z and Research Training Fellowship 203616/Z/16/Z, Ministry of Health of the Czech Republic (grant number 15-27109A), UAM. Departamento de Medicina Preventiva y Salud Pública y Microbiología, HUS Children and Adolescents, Department of Public Health, Universidad Autónoma de Madrid (UAM), Università degli studi di Torino = University of Turin (UNITO), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), CHU Toulouse [Toulouse], Université Paris 13 (UP13)-Institut de Veille Sanitaire (INVS)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM), Taddei, C, Zhou, B, Bixby, H, Danaei, G, Di Cesare, M, Kuulasmaa, K, Hajifathalian, K, Bentham, J, Bennett, JE, Aekplakorn, W, Cifkova, R, Dallongeville, J, DeBacquer, D, Giampaoli, S, Gudnason, V, Khang, Y-O, Laatikainen, T, Mann, JI, Marques-Vidal, P, Mensah, GA, Müller-Nurasyid, M, Ninomiya, T, Petkeviciene, J, Rodríguez-Artalejo, F, Servais, J, Söderberg, S, Stavreski, B, Wilsgaard, T, Zdrojewski, T, Zhao, D, Stevens, GA, Savin, S, Cowan, Mj, Riley, LM, Ezzati, M, Adams, R, Ahrens, W, Amouyel, P, Amuzu, A, Anderssen, SA, Ariansen, I, Arveiler, D, Aspelund, T, Auvinen, A, Avdicová, M, Banach, M, Bandosz, P, Banegas. JR, Barbagallo, CM, Bata, I, Baur, LA, Beaglehole, R, Bennet, JE, Bernotiene, G, Bi, Y, Bienek, A, Björkelund, C, Bo, S, Boehm, BO, Bonaccio, M, Bongard, V, Borchini, R, Borghs, H, Breckenkamp, J, Brenner, H, Bruno, G, Busch, MA, CabreradeLeón, A, Capuano, V, Casanueva, FF, Casas, J-P, Caserta, CA, Censi, L, Chen, F, Chen, S, Chirlaque, M-D, Cho, B, Cho, Y, Chudek, J, Claessens, F, Clarke, J, Clays, E, Cooper, C, Costanzo, S, Cottel, D, Cowell C, Crujeiras, AB, Cui, L, D'Arrigo, G, Dauchet, L, De Backer, G, De Bacquer, D, de Gaetano, G, De Henauw, S, De Smedt, D, Dennison, E, Desschamps, V, Di Castelnuovo, A, Dobson, AJ, Donfrancesco, C, Döring, A, Doua, K, Drygas, W, Du, Y, Dziankowska-Zaborszczyk, E, Eggertsen, R, Ekelund, U, Elousa, R, Eriksson, JG, Evans, A, Faeh, D, Felix-Redondo, FJ, Fernández-Bergés, D, Ferrari, M, Ferrieres, J, Finn, JD, Forslund, A-S, Forsner, M, Frontera, G, Fujita, Y, Gaciong, Z, Galvano, F, Gao, J, Garcia-de-la-Hera, M, Garnett, SP, Gaspoz, J-M, Gasul, L, Gates, L, Gianfagna, F, Gill, TK, Giovannelli, J, Goltzman, D, GonzalezGross, M, Gottrand, F, Graff-Iversen, S, Grafnetter, D, Gregor, RD, Grodzicki, T, Grosso, G, Gruden, G, Gu, D, Guallar-Castillón, P, Gudmundsson, EF, Guessous, I, Gunnlaugsdottir J, Gutzwiller, F, Hardy, R, Hata, J, Haugsgjerd, T, Hayes, AJ, He, H, He, Y, Herrala, S, Hihtaniemi, IP, Hobbs, M, Hopman, WM, Huerta, JM, Huybrechts, I, Iacoviello, L, Iannone, AG, Ikeda, N, Iwasaki, M, Jackson, R, Jamrozi, K, Janszky, I, Jarvelin, M-R, Jasienska, G, Jennings, G, Jeong, S-L, Jiang, CQ, Joffres, M, Jokelainen, JJ, Jonas, JB, Jóźwiak, J, Kajantie, EO, Kauhanen, K, Keil, U, Keinänen-Kiukaanniemi, S, Kersting, M, Khang, Y-H, Kiechl-Kohlendorfer, U, Kiechl, S, Kim, J, Kim, Y-Y, Klumbiene, J, Knoflach, M, Ko, S, Kolle, E, Korpelainen, R, Koskinen, S, Kouda, K, Kratzer, W, Kriemler, S, Krokstad, S, Kujala,UM, Kurjata, P, Lam, TH, Lanska, V, Lappas , G, Laugsand, LE, Lee, J, Lehtimäki, T, Li, Y, Lilly, C, Lin, X, Lind, L, Lissner, L, Liu, J, Lopez-Garcia, E, Lorbeer, R, Lozano, JE, Luksiene, D, Lundqvist, A, Lundqvist, R, Lytsy, P, Ma, G, Machi, S, Maggi, S, Magliano, DJ, Manzato, E, Mathiesen, EB, McLachlan, S, McLean, RM, Meirhaeghe, A, Metcalf, P, Mi, JM, Miller, JC, Moreno, LA, Morin, S, Mossakowska, M, Muiesan, ML, Mursu, J, Nakamura, H, Námešná, J, Navarrete-Muñoz, EM, Neal, WA, Nenko, I, Niiranen, T, Ning, G, Noale, M, Norie, S, Noto, Davide, O’Neill, T, O'Reilly, D, Oh, K, Olafsson, O, Paccaud, F, Pajak, A, Palmieri, L, Panza, F, Parnell, WR, Peltonen, M, Peters, A, Petersmann, A, P Pigeot, I, Pilotto, L, Piwonska, A, Pedro Plans-Rubió, P, Porta, M, Price, JF, Puder, JJ, Puhakka, SE, Radisauskas, R, Raitakari, O, Ramos, R, Redon, J, Rigo, F, Rodriguez-Perez, MdC, Romaguera, D, Ronkainen, K, Rosengren, A, Roy, JGR, Ruidavets, JB, Rutkowski, M, Salanave, B, Salmeron, D, Salomaa, V, Salonen, JT, Salvetti, M, Sans, S, Saramies, JL, Saum, K-U, Scheidt-Nave, C, Schienkiewitz, A, Schipf, S, Schmidt, CO, Schottker, B, Sebert S, Sen, A, Shaw, JE, Shibuya, K, Shin, DO, Shiri, R, Simons, J, Simons, LA, Sjostrom, M, Slowikowska-Hilczer, J, Slusarczyk, P, Solfrizzi, V, Sonestedt, E, Soumare, A, Staessen, JA, Stathopoulou, MG, Steene-Johannessen, J, Stehle, P, Stieber, J, Stöckl, D, Stokwiszewski, J, Sundström, J, Suriyawongpaisal, P, Tamosiunas, A, Tan, E, Taylor, A, Tell, G, Thijs, L, Tolonen, HK, Topór-Madry, R, Tormo, MJ, Torrent, M, Tsugane, S, Tuomainen, T-P, Tuomilehto, J, Tzourio, C, Uusitalo, HMT, Van Herck, K, Vanderschueren, D, Vanuzzo, D, Vatten, L, Vega, T, Veronesi, G, Vioque, P, Virtanen, JK, Visvikis-Siest, S, Vollenweider, P, Voutilainen, S, Vrijheid, M, Wagner, A, Wang, M-D, Wang, Q, Wang YX, Wannamethee, SG, Wei, W, Whincup, PH, Wiecek, A, Willeit, J, Willeit, P, Wojtyniak, B, Wong, A, Woodward, M, Wu, FC, JianFeng Wu, JF, Wu, SL, Xu, H, Xu, L, Yan, W, Yang, X, Ye, X, Yoshihara, A, Zambon, S, Zhao, W, NCD Risk Factor Collaboration (NCD-RisC), Jackson, R., Zhou, B., Bixby, H., Danaei, G., Di Cesare, M., Kuulasmaa, K., Hajifathalian, K., Bentham, J., Bennett, J.E., Aekplakorn, W., Cifkova, R., Dallongeville, J., DeBacquer, D., Giampaoli, S., Gudnason, V., Khang, Y.H., Laatikainen, T., Mann, J., Marques-Vidal, P., Mensah, G.A., Müller-Nurasyid, M., Ninomiya, T., Petkeviciene, J., Rodríguez-Artalejo, F., Servais, J., Söderberg, S., Stavreski, B., Wilsgaard, T., Zdrojewski, T., Zhao, D., Stevens, G.A., Savin, S., Cowan, M.J., Riley, L.M., Ezzati, M., Adams, R.J., Ahrens, W., Amouyel, P., Amuzu, A., Anderssen, S.A., Ariansen, I., Arveiler, D., Aspelund, T., Auvinen, J., Avdicová, M., Banach, M., Bandosz, P., Banegas, J.R., Barbagallo, C.M., Bata, I., Baur, L.A., Beaglehole, R., Bernotiene, G., Bi, Y., Bienek, A., Björkelund, C., Bo, S., Boehm, B.O., Bonaccio, M., Bongard, V., Borchini, R., Borghs, H., Breckenkamp, J., Brenner, H., Bruno, G., Busch, M.A., Cabrera de León, A., Capuano, V., Casanueva, F.F., Casas, J.P., Caserta, C.A., Censi, L., Chen, F., Chen, S., Chirlaque, M.D., Cho, B., Cho, Y., Chudek, J., Claessens, F., Clarke, J., Clays, E., Cooper, C., Costanzo, S., Cottel, D., Cowell, C., Crujeiras, A.B., Cui, L., D'Arrigo, G., Dauchet, L., De Backer, G., De Bacquer, D., de Gaetano, G., De Henauw, S., De Smedt, D., Dennison, E., Deschamps, V., DiCastelnuovo, A., Dobson, A.J., Donfrancesco, C., Döring, A., Drygas, W., Du, Y., Dziankowska-Zaborszczyk, E., Eggertsen, R., Ekelund, U., Elosua, R., Eriksson, J.G., Evans, A., Faeh, D., Felix-Redondo, F.J., Fernández-Bergés, D., Ferrari, M., Ferrieres, J., Finn, J.D., Forslund, A.S., Forsner, M., Frontera, G., Fujita, Y., Gaciong, Z., Galvano, F., Gao, J., Garcia-de-la-Hera, M., Garnett, S.P., Gaspoz, J.M., Gasull, M., Gates, L., Gianfagna, F., Gill, T.K., Giovannelli, J., Goltzman, D., GonzalezGross, M., Gottrand, F., Graff-Iversen, S., Grafnetter, D., Gregor, R.D., Grodzicki, T., Grosso, G., Gruden, G., Gu, D., Guallar-Castillón, P., Gudmundsson, E.F., Guessous, I., Gunnlaugsdottir, J., Gutzwiller, F., Hardy, R., Hata, J., Haugsgjerd, T., Hayes, A.J., He, J., He, Y., Herrala, S., TapaniHihtaniemi, I., Hobbs, M., Hopman, W.M., MaríaHuerta, J., Huybrechts, I., Iacoviello, L., Iannone, A.G., Ikeda, N., Iwasaki, M., Jamrozik, K., Janszky, I., Jarvelin, M.R., Jasienska, G., Jennings, G., Jeong, S.L., QiangJiang, C., Joffres, M., Jokelainen, J.J., Jonas, J.B., Jóźwiak, J., Kajantie, E.O., Kauhanen, J., Keil, U., Keinänen-Kiukaanniemi, S., Kersting, M., Kiechl-Kohlendorfer, U., Kiechl, S., Kim, J., Kim, Y.Y., Klumbiene, J., Knoflach, M., Ko, S., Kolle, E., Korpelainen, R., Koskinen, S., Kouda, K., Kratzer, W., Kriemler, S., Krokstad, S., Kujala, U.M., Kurjata, P., HingLam, T., Lanska, V., Lappas, G., Laugsand, L.E., Lee, J., Lehtimäki, T., Li, Y., Lilly, C.L., Lin, X., Lind, L., Lissner, L., Liu, J., Lopez-Garcia, E., Lorbeer, R., EugenioLozano, J., Luksiene, D., Lundqvist, A., Lundqvist, R., Lytsy, P., Ma, G., Machi, S., Maggi, S., Magliano, D.J., Manzato, E., Mathiesen, E.B., McLachlan, S., McLean, R.M., McLean, S.B., Meirhaeghe, A., Meisinger, C., Metcalf, P., Mi, J., Miller, J.C., Moreno, L.A., Morin, S., Mossakowska, M., Muiesan, M.L., Mursu, J., Nakamura, H., Námešná, J., Nauck, M., MariaNavarrete-Muñoz, E., Neal, W.A., Nenko, I., Niiranen, T.J., Ning, G., Noale, M., Norie, S., Noto, D., O'Neill, T., O'Reilly, D., Oh, K., Olafsson, Ö., MichelPaccaud, F., Pajak, A., Palmieri, L., Panza, F., Parnell, W.R., Peltonen, M., Peters, A., Petersmann, A., Pigeot, I., Pilotto, L., Piwonska, A., Plans-Rubió, P., Porta, M., Price, J.F., Puder, J.J., Puhakka, S.E., Radisauskas, R., Raitakari, O., Ramos, R., Redon, J., Rigo, F., Rodriguez-Perez, M., Romaguera, D., Ronkainen, K., Rosengren, A., Ruidavets, J.B., Rutkowski, M., Salanave, B., Salmerón, D., Salomaa, V., Salonen, J.T., Salvetti, M., Sans, S., Saramies, J.L., Saum, K.U., Scheidt-Nave, C., Schienkiewitz, A., Schipf, S., Schmidt, C.O., Schöttker, B., Sebert, S., Sen, A., Shaw, J.E., Shibuya, K., WookShin, D., Shiri, R., Simons, J., Simons, L.A., Sjöström, M., Slowikowska-Hilczer, J., Slusarczyk, P., Solfrizzi, V., Sonestedt, E., Soumare, A., Staessen, J.A., Stathopoulou, M.G., Steene-Johannessen, J., Stehle, P., Stieber, J., Stöckl, D., Stokwiszewski, J., Sundström, J., Suriyawongpaisal, P., Tamosiunas, A., JooTan, E., Taylor, A., Tell, G., Thijs, L., Tolonen, H., Topór-Madry, R., JoséTormo, M., Torrent, M., Tsugane, S., Tuomainen, T.P., Tuomilehto, J., Tzourio, C., Van Herck, K., Vanderschueren, D., Vanuzzo, D., Vatten, L., Vega, T., Veronesi, G., Vioque, J., Virtanen, J., Visvikis-Siest, S., Vollenweider, P., Voutilainen, S., Vrijheid, M., Wagner, A., Wang, M.D., Wang, Q., XingWang, Y., Wannamethee, S.G., Wei, W., Whincup, P.H., Wiecek, A., Willeit, J., Willeit, P., Wojtyniak, B., Wong, A., Woodward, M., GiwercmanWu, A., Wu, F.C., Wu, S., Xu, H., Xu, L., Yan, W., Yang, X., Ye, X., Yoshihara, A., Zambon, S., Zhao, W., Universiteit Gent = Ghent University (UGENT), Istituto Superiore di Sanità (ISS), Helmholtz Zentrum München = German Research Center for Environmental Health, Kyushu University, The Arctic University of Norway [Tromsø, Norway] (UiT), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Catania = University of Catania (Unict), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Università degli Studi di Padova = University of Padua (Unipd), Università degli Studi di Brescia = University of Brescia (UniBs), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Laboratoire Chrono-environnement (UMR 6249) (LCE), Leopold Franzens Universität Innsbruck - University of Innsbruck, National Institute of Public Health - National Institute of Hygiene [Poland], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Medical University of Silesia, Katowice, University of Helsinki, National Institute for Health and Welfare, University of Helsinki, University of Helsinki, and University of Helsinki, Finnish Institute of Occupational Health

Subjects
Male, gupo de ascendencia continental asiática, Settore MED/09 - Medicina Interna, Total Cholesterol, Ldl Cholesterol, Hdl Cholesterol, Blood Lipids, Multi-country Study, Epidemiology, kolesteroli, humanos, Blood lipids, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, triglicéridos, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, HDL cholesterol, Medicine and Health Sciences, CARDIOVASCULAR RISK-FACTORS, Medicine, 030212 general & internal medicine, mediana edad, lípidos, Public, Environmental & Occupational Health, 2. Zero hunger, anciano, education.field_of_study, Age Factors, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Middle Aged, colesterol, adulto, kansainvälinen vertailu, Lipids, 3142 Public health care science, environmental and occupational health, 3. Good health, Europe, Cholesterol, Population Surveillance, LDL cholesterol, SERUM-LIPIDS, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Adult, Asian Continental Ancestry Group, Canada, Total cholesterol, blood lipids, multi-country study, medicine.medical_specialty, Asia, Medicina, European Continental Ancestry Group, Population, Nursing, HDL-kolesteroli, White People, DIETARY-FAT, 03 medical and health sciences, Sex Factors, Asian People, kansanterveys, vigilancia de la población, Humans, CORONARY-HEART-DISEASE, ddc:610, LDL-kolesteroli, education, Triglycerides, METAANALYSIS, Aged, INDIVIDUAL DATA, Science & Technology, business.industry, Omvårdnad, blood lipid, Cholesterol, HDL, Ecological study, nutritional and metabolic diseases, Cholesterol, LDL, United States, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Cholesterol/blood, Lipids/blood, Population Surveillance/methods, Triglycerides/blood, chemistry, WORLDWIDE TRENDS, Multi-country study, grupo de ascendencia continental europea, business, HIGH-DENSITY-LIPOPROTEIN, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Demography, Lipoprotein
Abstract

Artículo con numerosos autores. Sólo quedan reflejados el primero, los pertenecientes a la UAM y el colectivo, Background: Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease, multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and non-HDL cholesterol and the total-to-HDL cholesterol ratio in Asian and Western countries. Methods: We pooled 458 population-based studies with 82.1 million participants in 23 Asian and Western countries. We estimated changes in mean total, HDL and non-HDL cholesterol and mean total-to-HDL cholesterol ratio by country, sex and age group. Results: Since ∼1980, mean TC increased in Asian countries. In Japan and South Korea, the TC rise was due to rising HDL cholesterol, which increased by up to 0.17 mmol/L per decade in Japanese women; in China, it was due to rising non-HDL cholesterol. TC declined in Western countries, except in Polish men. The decline was largest in Finland and Norway, at ∼0.4 mmol/L per decade. The decline in TC in most Western countries was the net effect of an increase in HDL cholesterol and a decline in non-HDL cholesterol, with the HDL cholesterol increase largest in New Zealand and Switzerland. Mean total-to-HDL cholesterol ratio declined in Japan, South Korea and most Western countries, by as much as ∼0.7 per decade in Swiss men (equivalent to ∼26% decline in coronary heart disease risk per decade). The ratio increased in China. Conclusions: HDL cholesterol has risen and the total-to-HDL cholesterol ratio has declined in many Western countries, Japan and South Korea, with only a weak correlation with changes in TC or non-HDL cholesterol., This work was supported by the Wellcome Trust (grant numbers 101506/Z/13/Z and Research Training Fellowship 203616/Z/16/Z). R.C. acknowledges funding from the Ministry of Health of the Czech Republic (grant number 15-27109A)

Published
2020

45. A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group

Author

Zain Kassam, Alexander Link, Eero Mattila, Chris J. J. Mulder, Josbert J. Keller, Christoph Högenauer, Ed J. Kuijper, Maurizio Sanguinetti, Gianluca Laniro, Maria J G T Vehreschild, Elisabeth M. Terveer, Ajit Sood, Patrizia Kump, Simon D. Goldenberg, Oleksiy Gridnyev, Simon Mark Dahl Baunwall, Olena Gubska, Giovanni Cammarota, Simone C. Lieberknecht, Cyriel Y. Ponsioen, Francis Mégraud, Andrey Dorofeev, Shiv Kumar Sarin, Antonio Gasbarrini, Reetta Satokari, Herbert Tilg, Christian Lodberg Hvas, Horace R T Williams, Rogier E. Ooijevaar, Laurent Alric, Radislav Nakov, Hein W. Verspaget, Abraham Goorhuis, Ramesh P. Arasaradnam, Georgina L. Hold, Lorenza Putignani, Perttu Arkkila, Sergiy Tkatch, Juozas Kupcinskas, Harry Sokol, Megraud, Francis, Haaglanden Medical Center [La Haye, Pays-Bas] (HMC), Leiden University Medical Center (LUMC), University of Amsterdam [Amsterdam] (UvA), Aarhus University Hospital, Frankfurt University Hospital, Medical University Graz, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French Group of Fecal Microbiota Transplantation [Paris] (GFTF), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Tsaritsa Yoanna University Hospital = Queen Giovanna University Hospital [Sofia], King‘s College London, Guy's and St Thomas NHS Foundation Trust [London], Ukranian Scientific and Practical Center of Endocrine Surgery [Kyiv], Fondazione Policlinico Universitario Agostino Gemelli IRCCS, National Medical Academy of Postgraduate Education n.a. P.L. Shupic [Kiev], Bogomolets national medical university, University Hospital Coventry Warwickshire (UHCW), University Hospital Coventry, Institute of Liver and Biliary Sciences [New Delhi], Dayanand Medical College and Hospital [Ludhiana], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), VU University Medical Center [Amsterdam], Lithuanian University of health Sciences [Kaunas], Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Leids Universitair Medisch Centrum [Leiden], University of New South Wales [Sydney] (UNSW), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Finch Therapeutics Group, ESCMID Study Group for Host and Microbiota Interaction [Basel] (ESGHAMI), Imperial College London, University of Cologne, German Centre for Infection Research (DZIF), University of Helsinki, Tsaritsa Yoanna University Hospital [Sofia], Fondazione Policlinico Universitario Agostino Gemelli IRCCS [Rome], Fondazione Policlinico Universitario Agostino Gemelli [Rome], CHU Toulouse [Toulouse], Otto-von-Guericke University [Magdeburg] (OVGU), Innsbruck Medical University [Austria] (IMU), Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Reetta Maria Satokari / Principal Investigator, HUMI - Human Microbiome Research, Research Programs Unit, Faculty of Medicine, and HUS Internal Medicine and Rehabilitation

Subjects
Quality Assurance, Health Care, Small Bowel, Fecal microbiota transplantation, Feces, 0302 clinical medicine, fluids and secretions, Recurrence, Procedure, Multidisciplinary approach, stool bank, Medicine, 030212 general & internal medicine, faecal microbiota transplantation, Biological Specimen Banks, Informed Consent, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Microbiota, Clostridium infections, microbiology, therapy, Clostridium difficile, isolation&purification, Donor selection, Consensus, digestive, oral, and skin physiology, Age Factors, Gastroenterology, 3. Good health, Oncology, Original Article, 030211 gastroenterology & hepatology, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, legislation, Faecal microbiota transplantation, Donor Selection, Specimen Handling, Contraindications, Procedure, Immunocompromised Host, 03 medical and health sciences, Internal medicine, Humans, business.industry, Clostridioides difficile, Contraindications, Settore MED/09 - MEDICINA INTERNA, Fecal bacteriotherapy, Health Care, Transplantation, 3121 General medicine, internal medicine and other clinical medicine, Clostridium Infections, 616.9-022.363. [udc], Quality Assurance, business, Clostridioides, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BACKGROUND: Fecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of feces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council.OBJECTIVE: Several European and international consensus statements concerning fecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document.METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about fecal microbiota transplantation.RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening.CONCLUSION: The implementation of fecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor feces preparations for patients.

Published
2020

46. Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

Author

Bally, Isabelle, Dalonneau, Fabien, Chouquet, Anne, Gröbner, Rebekka, Amberger, Albert, Kapferer-Seebacher, Ines, Stoiber, Heribert, Zschocke, Johannes, Thielens, Nicole, Rossi, Véronique, Gaboriaud, Christine, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Division of Human Genetics, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Department for Operative and Restorative Dentistry, ISBG (Mass spectrometry, Seq3A), ANR-16-CE91-0004,C1rsinEDS,Implications fonctionnelles des altérations des protéases C1r et C1s identifiées chez des patients atteints du syndrome Ehlers-Danlos de type parodontal.(2016), ANR-16-CE11-0019,C1qEffero,C1q et efferocytose: des mécanismes moléculaires et cellulaires à la tolérance au soi ou l'autoimmunité(2016), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Innsbruck Medical University [Austria] (IMU)

Subjects
HMGB1, lcsh:Immunologic diseases. Allergy, Protein Folding, Complement C1s, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Complement C1r, Immunology, Mutation, Missense, periodontal, C1s protease, HEK293 Cells, Amino Acid Substitution, Immunology and Allergy, Humans, Ehlers-Danlos Syndrome, Ehlers-Danlos, lcsh:RC581-607, Periodontal Diseases, complement system, Original Research
Abstract

Ehlers-Danlos syndromes (EDS) are clinically and genetically heterogeneous disorders characterized by soft connective tissue alteration like joint hypermobility and skin hyper-extensibility. We previously identified heterozygous missense mutations in the C1R and C1S genes, coding for the complement C1 proteases, in patients affected by periodontal EDS, a specific EDS subtype hallmarked by early severe periodontitis leading to premature loss of teeth and connective tissue alterations. Up to now, there is no clear molecular link relating the nominal role of the C1r and C1s proteases, which is to activate the classical complement pathway, to these heterogeneous symptoms of periodontal EDS syndrome. We aim therefore to elucidate the functional effect of these mutations, at the molecular and enzymatic levels. To explore the molecular consequences, a set of cell transfection experiments, recombinant protein purification, mass spectroscopy and N-terminal analyses have been performed. Focusing on the results obtained on two different C1S variants, namely p.Val316del and p.Cys294Arg, we show that HEK293-F cells stably transfected with the corresponding C1s variant plasmids, unexpectedly, do not secrete the full-length mutated C1s, but only a truncated Fg40 fragment of 40 kDa, produced at very low levels. Detailed analyses of the Fg40 fragments purified for the two C1s variants show that they are identical, which was also unexpected. This suggests that local misfolding of the CCP1 module containing the patient mutation exposes a novel cleavage site, between Lys353 and Cys354, which is not normally accessible. The mutation-induced Fg40 fragment contains the intact C-terminal serine protease domain but not the N-terminal domain mediating C1s interaction with the other C1 subunits, C1r, and C1q. Thus, Fg40 enzymatic activity escapes the normal physiological control of C1s activity within C1, potentially providing a loss-of-control. Comparative enzymatic analyses show that Fg40 retains the native esterolytic activity of C1s, as well as its cleavage efficiency toward the ancillary alarmin HMGB1 substrate, for example, whereas the nominal complement C4 activation cleavage is impaired. These new results open the way to further molecular explorations possibly involving subsidiary C1s targets.

Published
2019

47. SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects

Author

Dubail, Johanne, Huber, Céline, Chantepie, Sandrine, Sonntag, Stephan, Tüysüz, Beyhan, Mihci, Ercan, Gordon, Christopher T., Steichen-Gersdorf, Elisabeth, Amiel, Jeanne, Nur, Banu, Stolte-Dijkstra, Irene, van Eerde, Albertien M., van Gassen, Koen L., Breugem, Corstiaan C., Stegmann, Alexander, Lekszas, Caroline, Maroofian, Reza, Karimiani, Ehsan Ghayoor, Bruneel, Arnaud, Seta, Nathalie, Munnich, Arnold, Papy-Garcia, Dulce, De La Dure-Molla, Muriel, Cormier-Daire, Valérie, ARD - Amsterdam Reproduction and Development, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), PolyGene AG [Rümlang, Switzerland], Department of Pediatric Genetics [Istanbul, Turkey] (Cerrahpasa Medicine School), Istanbul University, Paediatric Genetic Department [Antalya, Turkey], Akdeniz University, Innsbruck Medical University [Austria] (IMU), University Medical Center Groningen [Groningen] (UMCG), University Medical Center [Utrecht], Division of Paediatric Plastic Surgery [Utrecht, The Netherlands], Wilhelmina Children´s Hopsital [Utrecht, The Netherlands], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Radboud University Medical Center [Nijmegen], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Next Generation Genetic Clinic [Mashhad, Iran], Razavi Cancer Research Center [Mashhad, Iran] (Razavi Hospital), Imam Reza International University [Mashhad, Iran], CIC Hôpital Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), This work was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 602300 (SYBIL) and the Fondation pour la Recherche Médicale (FRM) funding (DEQ20120323703)., European Project: 602300,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,SYBIL(2013), Gestionnaire, Hal Sorbonne Université, Systems biology for the functional validation of genetic determinants of skeletal diseases - SYBIL - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602300 - VALID, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Julius-Maximilians-Universität Würzburg (JMU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Wilhelmina Children’s Hospital, and École Pratique des Hautes Études (EPHE)

Subjects
Electrophoresis, Chemistry(all), Amelogenesis Imperfecta, DISORDERS, PROTEINS, Science, GROWTH-PLATE, [SDV]Life Sciences [q-bio], Organic Anion Transporters, Sodium-Dependent, HEPARAN-SULFATE PROTEOGLYCANS, PHENOTYPES, Physics and Astronomy(all), Osteochondrodysplasias, Article, CALCIUM, Mice, Chlorocebus aethiops, Animals, Humans, Exome, Child, lcsh:Science, Glycoproteins, GLYCOSAMINOGLYCANS, Mice, Knockout, Bone Diseases, Developmental, Symporters, Biochemistry, Genetics and Molecular Biology(all), Body Weight, CHONDROITIN, Infant, GENE, [SDV] Life Sciences [q-bio], Disease Models, Animal, HEK293 Cells, Child, Preschool, COS Cells, Mutation, lcsh:Q, REGULATOR
Abstract

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7−/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7−/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development., The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

Published
2018

48. C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome

Author

Gröbner, Rebekka, Kapferer-Seebacher, Ines, Amberger, Albert, Redolfi, Rita, Dalonneau, Fabien, Björck, Erik, Milnes, Di, Bally, Isabelle, Rossi, Véronique, Thielens, Nicole, Stoiber, Heribert, Gaboriaud, Christine, Zschocke, Johannes, Division of Human Genetics, Innsbruck Medical University [Austria] (IMU), Department for Operative and Restorative Dentistry, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Genetic Health Queensland, ISBG (SPR, Seq3A), ANR-16-CE91-0004,C1rsinEDS,Implications fonctionnelles des altérations des protéases C1r et C1s identifiées chez des patients atteints du syndrome Ehlers-Danlos de type parodontal.(2016), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Immunology, Immunology and Allergy, C1r/s, Ehlers-Danlos syndrome, periodontitis, complement system, ComputingMilieux_MISCELLANEOUS, Original Research, connective tissue
Abstract

Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.

Published
2019

49. GBA variants in REM sleep behavior disorder: a multicenter study

Author

Jennifer A. Ruskey, Friederike Sixel-Döring, David Kemlink, Michela Figorilli, Giuseppe Plazzi, Gian Luigi Gigli, Christelle Charley Monaca, Alberto J. Espay, Michele T.M. Hu, Monica Puligheddu, Bradley F. Boeve, Abril Beatriz, Lynne Krohn, Wolfgang H. Oertel, Yves Dauvilliers, Elena Antelmi, Marco Toffoli, Ziv Gan-Or, Uladzislau Rudakou, Mariarosaria Valente, Anna Heidbreder, Valérie Cochen De Cock, Etienne Leveille, Mineke Viaene, Ronald B. Postuma, Jean-François Gagnon, Jacques Montplaisir, Ambra Stefani, Claudia Trenkwalder, Birgit Högl, Guy A. Rouleau, Farnaz Asayesh, Luigi Ferini-Strambi, Karel Sonka, Isabelle Arnulf, Brit Mollenhauer, Alex Desautels, Femke Dijkstra, Krohn, L., Ruskey, J. A., Rudakou, U., Leveille, E., Asayesh, F., M. T. M., Hu, Arnulf, I., Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Boeve, B. F., Espay, A. J., De Cock, V. C., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Desautels, A., Montplaisir, J. Y., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., McGill University = Université McGill [Montréal, Canada], McGill University Health Center [Montreal] (MUHC), Institut Interdisciplinaire d'Innovation Technologique [Sherbrooke] (3IT), Université de Sherbrooke (UdeS), Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), University of Bologna/Università di Bologna, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Mayo Clinic [Rochester], University of Cincinnati (UC), Euromov (EuroMov), Université de Montpellier (UM), University Medical Center Göttingen (UMG), Philipps Universität Marburg = Philipps University of Marburg, Charles University [Prague] (CU), First Faculty of Medicine Charles University [Prague], University of Cagliari, Università degli Studi di Udine - University of Udine [Italie], University of Alberta, Université de Montréal (UdeM), Hôpital du Sacré-Coeur de Montréal, National Institutes of Health [Bethesda] (NIH), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Retiveau, Nolwenn

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], REM Sleep Behavior Disorder, MESH: Glucosylceramidase, Gastroenterology, MESH: Neurodegenerative Diseases, Behavior disorder, 0302 clinical medicine, MESH: Genetic Variation, Age of Onset, MESH: Aged, Sanger sequencing, 0303 health sciences, MESH: Middle Aged, Genetic analysis, MESH: Genetic Predisposition to Disease, Neurodegenerative Diseases, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Disease Progression, symbols, Glucosylceramidase, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GBA, Female, medicine.medical_specialty, MESH: Age of Onset, REM sleep behavior disorder, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Dementia with Lewy Bodies, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, Parkinson’s disease, Genetic Variation, Odds ratio, medicine.disease, MESH: Male, Confidence interval, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, Multicenter study, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectiveTo study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates.ResultsGBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87–3.22, p=1×10−10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90–7.14, p=3.5×10−5, while for severe variant carriers it was 17.55, 95% CI=2.11–145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

Published
2019
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50. Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity

Author

James M. Billingsley, Erica H. Parrish, Frank Kirchhoff, Thalia Garcia-Tellez, Nicolas Huot, Guido Silvestri, Ulrike Sauermann, Berit Neumann, Christina M. Stürzel, Gerald H. Learn, Steven E. Bosinger, Christiane Stahl-Hennig, Daniel Sauter, Beatrice H. Hahn, Dietmar Fuchs, Clement W. Gnanadurai, Michaela Müller-Trutwin, Simone Joas, Dominik Hotter, Edina Lump, Cristian Apetrei, Nicholas F. Parrish, Kerstin Mätz Rensing, Universität Ulm - Ulm University [Ulm, Allemagne], University of Pennsylvania, German Primate Centre, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Emory University [Atlanta, GA], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by NIH grants to B.H.H. (R37 AI50529, R01 AI 120810, R01 AI 114266), G.S. (R37 AI66998), and YYY (R01 AI 120860), and the BEAT-HIV Delaney Consortium (UM1 AI 126620), DFG CRC 1279 and SPP 1923, an Advanced ERC investigator grant to F.K., and a grant from Sidaction to M.M.-T. N.H. was supported by VRI (Créteil, France) and T.G.-T. by the Pasteur-Paris University PhD program. We thank the IDMIT center for access to the stellar Imaging platform and acknowledge the Imagopole France–BioImaging infrastructure, supported by the French ANR (10-INSB-04-01, Investments for the Future), for advice and access to the CV1000 system. S.J. and E.L. were part of IGradU Ulm and S.J. was supported by the DFG RTG CEMMA., We thank K. Regensburger, M. Mayer, R. Linsenmeyer, S. Engelhart, D. Krnavek, S. Heine, and J. Hampe for technical assistance, S. Sopper, K. Töpfer, and T. Schultheiss for support with flow cytometry and Nirav Patel and Greg Tharp of the Yerkes NHP Genomics Core for microarray analysis., University of Pennsylvania [Philadelphia], Innsbruck Medical University [Austria] (IMU), HIV, Inflammation et persistance, Institut Pasteur [Paris], and Vaccine Research Institute (VRI)

Subjects
0301 basic medicine, MESH: Signal Transduction, MESH: Human Immunodeficiency Virus Proteins, MESH: CD3 Complex, CD3 Complex, Transcription, Genetic, animal diseases, viruses, Human Immunodeficiency Virus Proteins, Wirtsspezifität, General Physics and Astronomy, MESH: NF-kappa B, MESH: Amino Acid Sequence, Simian, MESH: Virulence, Lymphocyte Activation, Virus Replication, MESH: Bone Marrow Stromal Antigen 2, MESH: HIV-1, DDC 570 / Life sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chlorocebus aethiops, MESH: nef Gene Products, Human Immunodeficiency Virus, Viral Regulatory and Accessory Proteins, MESH: Animals, lcsh:Science, Lentiviren, Immunodeficiency, Multidisciplinary, Retrovirus, biology, Virulence, [SDV.BA]Life Sciences [q-bio]/Animal biology, Bone Marrow Stromal Antigen 2, NF-kappa B, virus diseases, Chronic inflammation, Viral Load, MESH: Gene Expression Regulation, 3. Good health, medicine.anatomical_structure, Host specificity, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Simian Immunodeficiency Virus, MESH: Viral Load, MESH: Lentiviruses, Primate, MESH: Viral Regulatory and Accessory Proteins, Signal Transduction, HIV infections, MESH: Host Specificity, T cell, Science, MESH: Simian Immunodeficiency Virus, MESH: Sequence Alignment, Viremia, General Biochemistry, Genetics and Molecular Biology, Virus, Article, 03 medical and health sciences, ddc:570, medicine, Animals, Humans, Amino Acid Sequence, nef Gene Products, Human Immunodeficiency Virus, ddc:610, MESH: Lymphocyte Activation, Species specificity, Lentiviruses, Primate, Pathogenicity, MESH: Humans, MESH: Transcription, Genetic, MESH: Virus Replication, General Chemistry, biology.organism_classification, medicine.disease, Virology, MESH: Cercopithecus aethiops, 030104 developmental biology, Viral replication, Gene Expression Regulation, Tetherin, HIV-1, lcsh:Q, Sequence Alignment, MESH: Female, DDC 610 / Medicine & health, Viral pathogenesis
Abstract

HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses., In contrast to HIV, simian immunodeficiency viruses (SIV) do not cause disease in their hosts, and the reasons for this are unclear. Here, Joas et al. incorporate two putative HIV virulence factors into SIV and study effects in infected monkeys, suggesting that species-specific host factors are responsible for HIV pathogenesis.

Published
2018

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