Descriptor: "MESH: Female" - Searchworks@Jio Institute Digital Library Search Results

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9,352 results on '"MESH: Female"'

1. mScarlet3

Author: Theodorus W. J. Gadella, Laura van Weeren, Jente Stouthamer, Mark A. Hink, Anouk H. G. Wolters, Ben N. G. Giepmans, Sylvain Aumonier, Jérôme Dupuy, Antoine Royant, Center for Liver, Digestive and Metabolic Diseases (CLDM), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Swammerdam Institute for Life Sciences, Biomedical Sciences of Cells & Systems, University of Groningen [Groningen], 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), and European Synchrotron Radiation Facility (ESRF)
Subjects: MESH: Humans, MESH: Middle Aged, MESH: Fluorescence Resonance Energy Transfer, [SDV]Life Sciences [q-bio], Cell Biology, Biochemistry, MESH: Male, MESH: Trichophytin, MESH: T-Lymphocytes, MESH: HeLa Cells, MESH: Luminescent Proteins, MESH: Female, Molecular Biology, Biotechnology
Abstract: We report the evolution of mScarlet3, a cysteine-free monomeric red fluorescent protein with fast and complete maturation, as well as record brightness, quantum yield (75%) and fluorescence lifetime (4.0 ns). The mScarlet3 crystal structure reveals a barrel rigidified at one of its heads by a large hydrophobic patch of internal residues. mScarlet3 behaves well as a fusion tag, displays no apparent cytotoxicity and it surpasses existing red fluorescent proteins as a Förster resonance energy transfer acceptor and as a reporter in transient expression systems.
Published: 2023

2. Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference

Author: Gavoille, Antoine, Rollot, Fabien, Casey, Romain, Debouverie, Marc, Le Page, Emmanuelle, Ciron, Jonathan, de Seze, Jerome, Ruet, Aurélie, Maillart, Elisabeth, Labauge, Pierre, Zephir, Helene, Papeix, Caroline, Defer, Gilles, Lebrun-Frenay, Christine, Moreau, Thibault, Laplaud, David Axel, Berger, Eric, Stankoff, Bruno, Clavelou, Pierre, Thouvenot, Eric, Heinzlef, Olivier, Pelletier, Jean, Al Khedr, Abdullatif, Casez, Olivier, Bourre, Bertrand, Cabre, Philippe, Wahab, Abir, Magy, Laurent, Camdessanche, Jean-Philippe, Maurousset, Aude, Moulin, Solène, Ben, Nasr Haifa, Boulos, Dalia Dimitri, Hankiewicz, Karolina, Neau, Jean-Philippe, Pottier, Corinne, Nifle, Chantal, Rabilloud, Muriel, Subtil, Fabien, Vukusic, Sandra, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), 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), 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), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), CHU Saint-Antoine [AP-HP], Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHI Poissy-Saint-Germain, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: MESH: Humans, MESH: Multiple Sclerosis, Relapsing-Remitting, MESH: Probability, All CBMRT/Null Hypothesis, MESH: Multiple Sclerosis, MESH: Disabled Persons, MESH: Recurrence, Multiple sclerosis, MESH: Pregnancy, Cohort studies, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), MESH: Female, MESH: Cohort Studies, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: Background and ObjectivesThe question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery).MethodsWe conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18–45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up).ResultsWe included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [−0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93–1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate.DiscussionUsing a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.
Published: 2022

3. Health-related quality of life analysis in ovarian cancer clinical trials involving PARP inhibitors: a critical methodological perspective

Author: Frédéric, Fiteni, Julien, Peron, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), and Université de Lyon
Subjects: Ovarian Neoplasms, MESH: Humans, MESH: Adenosine Diphosphate, Ribose, Health-related quality of life, Public Health, Environmental and Occupational Health, MESH: Quality of Life, Poly(ADP-ribose) Polymerase Inhibitors, Adenosine Diphosphate, MESH: Poly(ADP-ribose) Polymerase Inhibitors, MESH: Ribose, MESH: Ovarian Neoplasms, PARP inhibitor, Ovarian cancer, Statistical analysis, Quality of Life, Humans, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female
Abstract: International audience; The poly (ADP-ribose) polymerase inhibitors (PARPi) have yielded significant clinical benefits as maintenance therapy in women with newly diagnosed and relapsed platinum-sensitive advanced ovarian cancer. These drugs were approved based on progression-free survival, the primary endpoint of their respective pivotal trials. Health-related quality of life (HRQoL) and/or patient-reported outcomes were included in these trials as a secondary exploratory endpoint. Nevertheless, many weaknesses in the analysis of HRQoL across these trials can be noticed. Heterogeneity and suboptimal HRQoL analysis in oncology trials contribute to misconceptions about this endpoint among oncologists and prevent quality of life as being an endpoint used for approvals. In this article, we discuss these HRQoL results from a methodological perspective and propose some solutions for improvement that could be used by regulatory and academic institutions running ovarian cancers trials. Notably, we suggest to measure and analyze HRQoL data after disease progression, to focus dedicated papers on the statistical analyses of HRQoL recommended by the SISAQOL consortium (linear mixed model for repeated measures and time-to-event approaches) and to communicate on available guidelines to ensure compliance with best international practices regarding the measurement and analysis of HRQoL.
Published: 2022

4. Anaphylaxis in Brazil between 2011 and 2019

Author: Luciana Kase Tanno, Nicolas Molinari, Isabella Annesi‐Maesano, Pascal Demoly, Ana Luiza Bierrenbach, Hospital Sírio-Libanês [São Paulo, Brazil], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Médecine de précision par intégration de données et inférence causale (PREMEDICAL), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sanas Epidemiology and Research, and Salvy-Córdoba, Nathalie
Subjects: Adult, Epinephrine, Adrenaline/epinephrine auto-injector, Epidemiology, International classification of diseases, Prevention, Immunology, Insect Bites and Stings, MESH: Adult, Anaphylaxis / epidemiology, Anaphylaxis / etiology, Brazil / epidemiology, Child, Preschool Epinephrine, Classification, Management, Hospitalization, Treatment, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Child, Preschool, MESH: Female, Humans, Insect Bites and Stings / complications, Immunology and Allergy, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Anaphylaxis, Brazil, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract: International audience; Background: there is a lack of population-based studies of anaphylaxis from low-and middle-income countries. This hampers public health planning and investments and may influence availability of adrenaline auto-injectors.Objective: we conducted the first national population-based study of anaphylaxis hospitalization in Brazil.Methods: descriptive study using routinely reported data to the Brazilian Hospital Information System for the years 2011-2019. Information available is coded based on the International Classification of Diseases (ICD)-10 and covers main cause of hospitalization (primary cause) and any conditions contributing to it (secondary cause).Results: over 9 years, we identified 5716 admissions due to anaphylaxis for all causes. The average hospitalization rate related to anaphylaxis was 0.71/100,000 population per year, with a 2.4% (95% CI 1.9%, 2.9%) increase per annum over the study period. Admissions were more frequent among females (52.8%), except for cases due to insect sting. Most admissions occurred in adulthood, from 30 to 59 years (36.3%) but 13.8% in preschool children (0-4 years). There were more young children admitted for food-related anaphylaxis, and more adults admitted for drug/iatrogenic-related anaphylaxis. There were 334 cases (5.8% of admissions) of fatal anaphylaxis over the study period, with increased case fatality rate over time.Conclusions and clinical relevance: this is the first study of anaphylaxis hospital admissions using nation-wide data from a low- or middle-income country. Hospital admissions and fatalities from anaphylaxis in Brazil appear to be increasing.
Published: 2022

5. Spontaneously occurring tumors in different wild-derived strains of hydra

Author: Boutry, Justine, Buysse, Marie, Tissot, Sophie, Cazevielle, Chantal, Hamede, Rodrigo, Dujon, Antoine, Ujvari, Beata, Giraudeau, Mathieu, Klimovich, Alexander, Thomas, Frédéric, Tökölyi, Jácint, Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Deakin University [Waurn Ponds], LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Christian-Albrechts University of Kiel, University of Debrecen Egyetem [Debrecen], The Project is funded by Agence Nationale de la Recherche, Grant no. ANR-18-CE35-0009, Centre National de la Recherche Scientifique, International Associ-ated Laboratory Grant, Magyar Tudományos Akadémia, Grant no. Lendület LP2021/12, and ANR-18-CE35-0009,TRANSCAN,ECOLOGIE ET EVOLUTION DES CANCERS TRANSMISSIBLES(2018)
Subjects: [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, MESH: Humans, MESH: Chlamydiales, Multidisciplinary, MESH: Hydra, MESH: Fresh Water, MESH: Animals, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Female, MESH: Male
Abstract: Hydras are freshwater cnidarians widely used as a biological model to study different questions such as senescence or phenotypic plasticity but also tumoral development. The spontaneous tumors found in these organisms have been so far described in two female lab strains domesticated years ago (Hydra oligactis and Pelmatohydra robusta) and the extent to which these tumors can be representative of tumors within the diversity of wild hydras is completely unknown. In this study, we examined individuals isolated from recently sampled wild strains of different sex and geographical origin, which have developed outgrowths looking like tumors. These tumefactions have common features with the tumors previously described in lab strains: are composed of an accumulation of abnormal cells, resulting in a similar enlargement of the tissue layers. However, we also found diversity within these new types of tumors. Indeed, not only females, but also males seem prone to form these tumors. Finally, the microbiota associated to these tumors is different from the one involved in the previous lineages exhibiting tumors. We found that tumorous individuals hosted yet undescribed Chlamydiales vacuoles. This study brings new insights into the understanding of tumor susceptibility and diversity in brown hydras from different origins.
Published: 2023

6. Liver transplantation for autoimmune hepatitis: Pre‐transplant does not predict the early post‐transplant outcome

Author: Yasmina Chouik, Claire Francoz, Eleonora De Martin, Olivier Guillaud, Armand Abergel, Mario Altieri, Louise Barbier, Camille Besch, Olivier Chazouillères, Filomena Conti, Christophe Corpechot, Sébastien Dharancy, François Durand, Christophe Duvoux, Jean Gugenheim, Jean Hardwigsen, Marie‐Noëlle Hilleret, Pauline Houssel‐Debry, Nassim Kamar, Anne Minello, Martine Neau‐Cransac, Georges‐Philippe Pageaux, Sylvie Radenne, Olivier Roux, Faouzi Saliba, Didier Samuel, Claire Vanlemmens, Marie‐Lorraine Woehl‐Jaegle, Vincent Leroy, Jean‐Charles Duclos‐Vallée, Jérôme Dumortier, Hospices Civils de Lyon (HCL), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Edouard Herriot [CHU - HCL], Clinique de la Sauvegarde [Lyon], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), and Fondation Léon Bouchut
Subjects: early infection, MESH: Liver Transplantation, immunosuppression, MESH: Humans, Hepatology, MESH: Hepatitis, Autoimmune, fulminant hepatitis, MESH: Adult, MESH: Retrospective Studies, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, survival, sepsis, MESH: Massive Hepatic Necrosis, MESH: Female, MESH: Sepsis
Abstract: Background and aims: Autoimmune hepatitis (AIH) is a rare indication (
Published: 2023

7. Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial

Author: Labro, Guylaine, Tubach, Florence, Belin, Lisa, Dubost, Jean-Louis, Osman, David, Muller, Grégoire, Quenot, Jean-Pierre, da Silva, Daniel, Zarka, Jonathan, Turpin, Matthieu, Mayaux, Julien, Lamer, Christian, Doyen, Denis, Chevrel, Guillaume, Plantefeve, Gaétan, Demeret, Sophie, Piton, Gaël, Manzon, Cyril, Ochin, Evelina, Gaillard, Raphael, Dautzenberg, Bertrand, Baldacini, Mathieu, Lebbah, Said, Miyara, Makoto, Pineton de Chambrun, Marc, Amoura, Zahir, Combes, Alain, Palmyre, Jessica, Gimeno, Linda, Kone, Assitan, Vialette, Cedric, Slimi, Ouramdane, Chommeloux, Juliette, Lefevre, Lucie, Schmidt, Matthieu, Hekimian, Guillaume, Luyt, Charles-Edouard, Stiel, Laure, Dureau, Anne-Florence, Khaldoun, Kuteifan, Eid, Hanna, Baldacini, Matthieu, Zyberfajn, Cecile, Manson, Julien, Charrier, Nathanael, Balabanian, Angelique, Contou, Damien, Pajot, Olivier, Fraisse, Megan, Desaint, Paul, Sarfati, Florence, Fartoukh, Muriel, Voirot, Guillaume, Elabbabi, Alexandre, Djibre, Michel, Desnos, Cyrielle, Garcon, Pierre, van Vong, Ly, Issad, Andrea, Pillot, Bertrand, Reither, Delphine, Rouge, Patrick, Foliot, Pascale, Bendjamar, Lynda, Pointurier, Valentin, Winiszewski, Hadrien, Capellier, Gilles, Navellou, Jean-Christophe, Tapponnier, Romain, Panicucci, Emilie, Morand, Lucas, Dellamonica, Jean, Saccheri, Clement, Weiss, Nicolas, Marois, Clemence, Le Guennec, Loic, Rohaut, Benjamin, Ensenat, Luis, Billiou, Cecilia, Aroca, Maria, Baron, Marie, Demoule, Alexandre, Beurton, Alexandra, Bureau, Come, Decavele, Maxens, Dres, Martin, Bayle, Frederique, Le, Quoc Viet, Liron, Lionel, Putegnat, Jean-Baptiste, Salord, Francois, Andreu, Pascal, Slimani, Hakim, Roudeau, Baptiste, Labruyere, Marie, Jacquier, Marine, Anguel, Nadia, Ayed, Soufia, Durand, Edgard, Guerin, Laurent, Lai, Christopher, Aboab, Jerome, Alviset, Sophie, Laine, Laurent, Azzi, Mathilde, Issoufaly, Tazime, Tric, Laurent, Knani, Lyes, Boumezrag, Chahrazad Bey, Viault, Nicolas, Barbier, Francois, Boulain, Thierry, Kamel, Toufik, Nay, Mai-Anh, Tollec, Sophie, Nguyen, an Hung, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), 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 Département de santé publique [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 Hospitalier René Dubos - 6, avenue de l’Ile de France 95303 CERGY-PONTOISE, Service de Pneumologie et Réanimation Respiratoire [AP-HP Hôpital Bicêtre] (DHU TORINO), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Centre de Référence de l'Hypertension Pulmonaire Sévère, Centre Hospitalier Régional d'Orléans (CHRO), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), réanimation et soins continus [CH Saint-Denis], Centre Hospitalier de Saint-Denis [Ile-de-France], Grand Hôpital de l'Est Francilien (GHEF), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Médico-Universitaire APPROCHES, Sorbonne Université (SU), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut Mutualiste de Montsouris (IMM), Hôpital l'Archet, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Sud Francilien, Centre Hospitalier Victor Dupouy, REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aigüE [CHU Pitié-Salpêtrière] (GRC RESPIRE), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Réanimation, Médipole Lyon Villeurbanne. Service de réanimation. 158 rue Léon Blum. 69100 VILLEURBANNE, France, Service de médecine intensive-réanimation Hôpital Simone Veil, Eaubonne, France, GHU Paris Psychiatrie et Neurosciences, Université Paris Cité (UPCité), Service de Pneumologie - R3S [CHU Pitié-Salpêtrière] (SPMIR-R3S), Institut Arthur Vernes, Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], 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), Service de Réanimation Médicale [CHU Pitié-Salpétrière], and TUBACH, Florence
Subjects: Adult, Male, Nicotine, [SDV]Life Sciences [q-bio], Acute respiratory failure, Critical Care and Intensive Care Medicine, MESH: Nicotine, Nicotinic receptor, Double-Blind Method, MESH: COVID-19, Humans, MESH: SARS-CoV-2, MESH: Double-Blind Method, MESH: Respiration, Artificial, MESH: Treatment Outcome, MESH: Humans, SARS-CoV-2, COVID-19, MESH: Adult, Respiration, Artificial, Ventilation, MESH: Male, [SDV] Life Sciences [q-bio], Intensive Care Units, Treatment Outcome, Artificial, MESH: Intensive Care Units, Female, Randomized trial, MESH: Female
Abstract: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia.In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score ( or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28.Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups.In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.
Published: 2022

8. Breast reconstruction and quality of life five years after cancer diagnosis: VICAN French National cohort

Author: Memoli Victoria, Bannier Marie, Rey Dominique, Alleaume Caroline, Ben Diane Marc-Karim, Mancini Julien, Lauzier Sophie, Bouhnik Anne-Déborah, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santé publique France, Ile de France, Paris, France (SpF-Ile de France), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Laval [Québec] (ULaval), and Centre de recherche Université Laval Robert Giffard (CRULRG)
Subjects: MESH: Aged, Cancer Research, MESH: Humans, MESH: Mastectomy, [SDV]Life Sciences [q-bio], Mammaplasty, MESH: Quality of Life, Breast Neoplasms, MESH: Cancer Survivors, Breast cancer, Cancer Survivors, Oncology, Psychosocial outcomes, Quality of Life, MESH: Mammaplasty, Humans, Breast reconstruction, Female, MESH: Female, MESH: Breast Neoplasms, Mastectomy, Aged
Abstract: International audience; Purpose: Women with breast cancer (BC) who have a mastectomy may subsequently undergo breast reconstruction (BR). This study aimed to identify (1) factors associated with having BR, (2) factors associated with immediate BR (IBR) and delayed BR (DBR), and (3) associations between no BR, IBR and DBR and physical and mental quality of life (QoL) 5 years after diagnosis.Methods: Analyses were based on data from the national French cancer cohort VICAN, which followed a representative sample of cancer survivors, including BC survivors, for 5 years after diagnosis. BR and BR type (IBR/DBR) were identified using medico-administrative databases. The SF12 scale was used to measure mental and physical QoL. Multivariate logistic regressions were used to identify factors associated with BR, and linear models to evaluate associations between BR and BR type with QoL.Results: Of the 1192 BC survivors in VICAN, 32.6% (n = 388) had a mastectomy. Among them, 60.1% (n = 233) had BR. Of these, 38.6% (n = 90) and 61.4% (n = 143) had IBR and DBR, respectively. Compared with women who had BR, women who did not were more likely to be older and to have a lower level of health literacy. Compared with women who did not have BR, those with IBR had better mental QoL, while those who had either IBR or DBR had better physical QoL.Conclusion: Older women and those with inadequate health literacy were less likely to have BR. This may reflect women's preferences, inequalities in care options offered after a mastectomy, and socioeconomic barriers to accessing BR. These issues need further exploration. Furthermore, BR was associated with a better long-term physical QoL. IBR was associated with better mental QoL and should be promoted when possible.
Published: 2022

9. A network analysis of rest-activity rhythms in young people with emerging bipolar disorders

Author: Jan, Scott, Bruno, Etain, Ashlee, Grierson, Sharon, Naismith, Elizabeth, Scott, Ian, Hickie, Newcastle University [Newcastle], The University of Sydney, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Vincent's Hospital, Sydney, and Etain, Bruno
Subjects: Male, Sleep Wake Disorders, Bipolar Disorder, Youth, MESH: Actigraphy, Adolescent, MESH: Sleep, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Bipolar Disorder, Bipolar disorders, Humans, MESH: Circadian Rhythm, Aged, MESH: Adolescent, MESH: Aged, MESH: Humans, Circadian, Actigraphy, MESH: Sleep Wake Disorders, MESH: Male, Circadian Rhythm, Psychiatry and Mental health, Clinical Psychology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Biomarkers, Female, Network analysis, Sleep, MESH: Female, Biomarkers
Abstract: International audience; Aims: Actigraphy studies of individuals with bipolar disorders (BD) suggest that illness progression may be associated with a range of progressive disruptions in 24-hour rest-activity rhythms (RAR). However, those longitudinal studies were undertaken in older adults with extended histories or illness and treatment rather than young people with emerging BD. To our knowledge, this is the first study to use network modelling to examine the statistical associations between clinical phenotypes of BD and different subsets of RAR markers.Methods: This study of adolescents and young adults (mean age 22 years; 69% female) uses network modelling to examine which self-rated or actigraphic markers of RAR are more strongly associated with full threshold BD (referred to as Stage 2; N = 15) compared with BD-at risk syndromes (subthreshold presentations referred to as Stage 1; N = 25).Results: Network analysis demonstrated that some RAR are associated with both stage of BD and a family history of BD (such as longer sleep duration and higher levels of daytime impairment). Markers of circadian rhythmicity indicated that regulation of this system is weaker in Stage 2 compared with Stage 1 of BD.Limitations: The small subgroup samples may have undermined the ability to detect some associations between phenotypes and RAR.Conclusions: Network modelling may offer a useful strategy for visualizing and analysing patterns of association between RAR and clinical phenotypes defined by stage of illness, familial loading or symptom profile. This could prove useful in understanding the underlying pathophysiology of sleep-wake cycle and circadian rhythm disturbances in BD.
Published: 2022

10. Genomics of Clear-cell Renal Cell Carcinoma: A Systematic Review and Meta-analysis

Author: Thi Oanh Bui, Van Tu Dao, Van Tai Nguyen, Jean-Paul Feugeas, Frédéric Pamoukdjian, Guilhem Bousquet, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Nord, and leboeuf, Christophe
Subjects: MESH: Humans, MESH: Genomics, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Genomics, MESH: Carcinoma, Renal Cell, Metastases, Renal cell carcinoma, MESH: Male, MESH: Prognosis, Primary tumor, [SDV.CAN] Life Sciences [q-bio]/Cancer, Mutation, MESH: DNA Copy Number Variations, MESH: Kidney Neoplasms, MESH: Female
Abstract: International audience; Context: Although antiangiogenic treatments and immunotherapies have significantly improved the prognosis of metastatic renal cell carcinoma (RCC), many patients will develop resistance, leading to treatment failure. Genetic tumor heterogeneity is a major cause of this resistance.Objective: To perform a meta-analysis of genomic data for clear-cell RCC obtained from primary tumors and metastases to assess the prevalence of gene mutations and copy number alterations (CNAs).Evidence acquisition: Articles were selected from Medline and Embase libraries using the search algorithm ("Kidney Neoplasms"[Mesh] OR "Renal Cell Carcinoma") AND ("Genomics"[Mesh] OR "Mutation") from January 1999 to February 2021. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Ninety-three publications were selected for inclusion in this meta-analysis.Evidence synthesis: Our meta-analysis included a total 14 696 patients, 14 299 primary tumor samples, and 969 metastatic samples. We evaluated the overall and subgroup prevalence of gene mutations and CNAs, including comparisons between primary tumors and metastases. In particular, for metastases we observed that the mutation prevalence was significantly more marked for ten genes compared to primary tumors, with no or little heterogeneity across studies. The VHL mutation prevalence increased significantly from 64% in primary tumors to 75% in metastases (p < 0.001). There was a significant increase in CNA prevalence from primary tumors to metastases for chromosomes 1p36.11, 9p21.3, and 18 in terms of losses, and for chromosomes 1q21.3, 7q36.3, 8q, and 20q11.21 in terms of gains. CDKN2A, also called p16 and involved in cell-cycle progression, is located at the 9p21.3 locus and was lost in 76% of metastatic samples. ASXL1, located on 20p11.21 and amplified in 50% of metastatic RCCs compared to 21% of primary tumors (p < 0.001), is closely linked to BAP1 function.Conclusions: Our results underline the added value of preferential biopsies on RCC metastases to fully explore the biology of metastatic disease for therapeutic purposes.Patient summary: We reviewed the literature on genetic mutations in primary tumors and metastatic lesions in kidney cancer. Our pooled results for all the relevant studies show a higher level of mutations in metastases than in primary tumors. This highlights the importance of taking biopsies of metastases to analyze genetic mutations and potentially guide selection of the most suitable treatment strategy.
Published: 2022

11. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish

Author: Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, Marion Delous, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Genève = University of Geneva (UNIGE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Morvan [Brest], CH Morlaix, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Louis Mourier - AP-HP [Colombes], Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hôpital Robert Debré, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by CNRS, Inserm, Université de Montpellier, Université Paris 7 and Université Lyon 1 through recurrent funding, the Fondation Maladies Rares ('Small Animal Models and Rare Diseases' program, no. 20161207), the Agence Nationale de la Recherche (no. ANR-18CE12-0007-01), and the Fondation pour la recherche sur le Cerveau « Espoir en tête » (confocal microscope). E.B. was supported by an European Molecular Biology Organization long-term fellowship (ALTF-284-2019) and the Novartis Foundation for medical-biological Research (18B112)., and ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018)
Subjects: minor introns, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, MESH: Humans, MESH: Mutation, MESH: Fetal Growth Retardation, MESH: RNA, Small Nuclear, U4atac, splicing, genetic disease, MESH: Ciliopathies, MESH: Animals, MESH: Zebrafish, MESH: Female, MESH: Spliceosomes, primary cilium
Abstract: In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.
Published: 2023

12. A Homozygous Missense Variant in Hedgehog Acyltransferase (HHAT) Gene Associated with 46,XY Gonadal Dysgenesis

Author: Inas, Mazen, Alaa, Kamel, Kenneth, McElreavey, Anu, Bashamboo, Aya, Elaidy, Mohamed S, Abdel-Hamid, National Research Centre - NRC (EGYPT), Génétique du Développement humain - Human developmental genetics, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Exome sequencing, MESH: Mutation, Missense, MESH: Humans, MESH: Mutation, [SDV]Life Sciences [q-bio], XY DSD, Missense variant, MESH: Hedgehog Proteins, MESH: Gonadal Dysgenesis, 46,XY, MESH: Acyltransferases, MESH: Phenotype, Hedgehog acyltransferase, MESH: Female, Egyptian patient, MESH: Homozygote
Abstract: International audience; Introduction: Disorders of gonadal development represent a clinically and genetically heterogeneous group of DSD, and the etiology in many cases remains unknown, indicating that our knowledge of factors controlling sex determination is still limited. Methods: We describe a 46,XY DSD patient from Egypt. The patient was reared as female, born to consanguineous parents, and was referred to us at the age of 5 years because of ambiguous genitalia. On examination, the girl was microcephalic (head circumference –3 SD), but her height and weight were normal for her age and sex. Results: Exome sequencing identified a homozygous variant in the hedgehog acyltransferase (HHAT) gene, which encodes an enzyme that is required for multimerization and signaling potency of the hedgehog secreted proteins. The variant is a novel homozygous missense change c.1329C>A (p.N443K), located within transmembrane domain 9, which segregated with the phenotype in the family. Discussion/Conclusion: Our results expand the phenotypic spectrum associated with HHAT variants to include 46,XY gonadal dysgenesis and reinforce the role of exome sequencing in unraveling new genes that play a pivotal role in sexual development.
Published: 2023

13. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Author: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Meagan E. Cochran, Tanner F. Coleman, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C.E. Hurst, Pascal Joset, Melissa A. Kelly, Stanislav Kmoch, Benjamin R. Leadem, Michael J. Lyons, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J.L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine B. Nowak, Amanda G. Noyes, Matthew Osmond, Eloise J. Prijoles, Jada Pugh, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela E. Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Elliot Stolerman, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Camerun Washington, Lance H. Rodan, Richard M. Myers, Gregory M. Cooper, Human Genetics, Amsterdam Cardiovascular Sciences, Human genetics, CCA - Cancer biology and immunology, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], and Clinical Genetics
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, ZMYM3, transcriptional coregulators, MESH: Phenotype, MESH: Gene Expression Regulation, MESH: Nervous System Malformations, neurodevelopmental disorder, MESH: Male, MESH: Intellectual Disability, X-linked intellectual disability, chromatin modifiers, MESH: Histone Demethylases, Genetics, MESH: Female, MESH: Face, MESH: Nuclear Proteins, Genetics (clinical), MESH: Neurodevelopmental Disorders
Abstract: Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
Published: 2023

14. Pan-Genomic Regulation of Gene Expression in Normal and Pathological Human Placentas

Author: Clara Apicella, Camino S. M. Ruano, Basky Thilaganathan, Asma Khalil, Veronica Giorgione, Géraldine Gascoin, Louis Marcellin, Cassandra Gaspar, Sébastien Jacques, Colin E. Murdoch, Francisco Miralles, Céline Méhats, Daniel Vaiman, Des gamètes à la naissance : génomique, épigénétique et physiopathologie de la reproduction | From Gametes To Birth (FGTB), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and European Project: 765274,H2020-MSCA-ITN-2017,iPLACENTA(2018)
Subjects: preeclampsia, MESH: Humans, MESH: Pregnancy, placenta, expression Quantitative Trait Loci, MESH: Trophoblasts, MESH: Transcriptome, MESH: Genomics, [SDV]Life Sciences [q-bio], General Medicine, MESH: Placenta, MESH: Female, MESH: Gene Expression Regulation
Abstract: International audience; In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology.
Published: 2023

15. Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study

Author: Elom K. Aglago, Amanda J. Cross, Elio Riboli, Veronika Fedirko, David J. Hughes, Agnes Fournier, Paula Jakszyn, Heinz Freisling, Marc J. Gunter, Christina C. Dahm, Kim Overvad, Anne Tjønneland, Cecilie Kyrø, Marie-Christine Boutron-Ruault, Joseph A. Rothwell, Gianluca Severi, Verena Katzke, Bernard Srour, Matthias B. Schulze, Clemens Wittenbecher, Domenico Palli, Sabina Sieri, Fabrizio Pasanisi, Rosario Tumino, Fulvio Ricceri, Bas Bueno-de-Mesquita, Jeroen W. G. Derksen, Guri Skeie, Torill Enget Jensen, Marko Lukic, Maria-Jose Sánchez, Pilar Amiano, Sandra Colorado-Yohar, Aurelio Barricarte, Ulrika Ericson, Bethany van Guelpen, Keren Papier, Anika Knuppel, Corinne Casagrande, Inge Huybrechts, Alicia K. Heath, Konstantinos K. Tsilidis, Mazda Jenab, 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), Imperial College London, The University of Texas M.D. Anderson Cancer Center [Houston], University College Dublin [Dublin] (UCD), 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), Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, L´Hospitallet de Llobregat, La Salle [Ramon Llull University], Centre international de Recherche sur le Cancer (CIRC), Aarhus University [Aarhus], Institute of Cancer Epidemiology, Danish Cancer Society, Danish Cancer Society Research Center, Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Università degli Studi di Firenze = University of Florence (UniFI), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Potsdam = Universität Potsdam, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), and IRCCS Istituto Nazionale dei Tumori [Milano]
Subjects: MESH: Iron, Cancer Research, MESH: Humans, [SDV]Life Sciences [q-bio], MESH: Eating, MESH: Male, MESH: Prospective Studies, MESH: Diet, Oncology, MESH: Risk Factors, MESH: Heme, MESH: Female, MESH: Cohort Studies, MESH: Colorectal Neoplasms
Abstract: BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive.METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method.RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HR Q5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HR Q5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HR Q5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HR Q5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HR Q5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HR Q5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). CONCLUSIONS: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.
Published: 2023

16. Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development

Author: Rjiba, Khouloud, Mougou-Zerelli, Soumaya, Hamida, Imen Hadj, Saad, Ghada, Khadija, Bochra, Jelloul, Afef, Slimani, Wafa, Hasni, Yosra, Dimassi, Sarra, Khelifa, Hela Ben, Sallem, Amira, Kammoun, Molka, Abdallah, Hamza Hadj, Gribaa, Moez, Bignon-Topalovic, Joelle, Chelly, Sami, Khairi, Hédi, Bibi, Mohamed, Kacem, Maha, Saad, Ali, Bashamboo, Anu, Mcelreavey, Kenneth, Centre Hospitalo-Universitaire Farhat Hached, Université de Monastir - University of Monastir (UM), Université de Sousse, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), CHU Fattouma Bourguiba [Monastir] (HFB), This work is funded in part by a research grant from the European Society of Pediatric Endocrinology, a scholarship from the Tunisian government, and by the Agence Nationale de la Recherche (ANR), ANR-10-LABX-73 REVIVE, ANR-17-CE14-0038–01, ANR-19-CE14-0022, ANR-20-CE14-0007 and ANR-19-CE14-0012., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017), ANR-19-CE14-0022,SexDiff,Régulation de la détermination du sexe et de la différenciation ovarienne : implications dans les troubles du développement sexuel(2019), ANR-20-CE14-0007,Goldilocks,Analyse intégrée du rôle du facteur de transcription SF-1 / NR5A1 et de ses gènes cibles dépendants du dosage dans la fonction gonadique et les troubles du développement sexuel (DSD)(2020), and ANR-19-CE14-0012,RNA-SEX,Fonction de l'ARN hélicase dans la détermination du sexe chez les vertébrés et les troubles du développement du sexe chez l'homme (DSD)(2019)
Subjects: Cytogenetic abnormalities, MESH: Humans, MESH: Mutation, MESH: Sexual Development, MESH: Testis, [SDV]Life Sciences [q-bio], MESH: Sex Differentiation, XY DSD, Obstetrics and Gynecology, MESH: Gonadal Dysgenesis, 46,XY, MESH: Acyltransferases, MESH: Phenotype, MESH: SOXE Transcription Factors, MESH: Ubiquitin-Protein Ligases, MESH: Male, MESH: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Endocrinology, Reproductive Medicine, Disorders of sex development (DSD), MESH: Membrane Proteins, Whole exome sequencing(WES), MESH: Female, Developmental Biology
Abstract: Abstract Background Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic. Methods To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed. Results Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients. Conclusion Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.
Published: 2023

17. In vitro cellular reprogramming to model gonad development and its disorders

Author: Gonen, Nitzan, Eozenou, Caroline, Mitter, Richard, Elzaiat, Maëva, Stévant, Isabelle, Aviram, Rona, Bernardo, Andreia Sofia, Chervova, Almira, Wankanit, Somboon, Frachon, Emmanuel, Commere, Pierre-Henri, Brailly-Tabard, Sylvie, Valon, Léo, Barrio Cano, Laura, Levayer, Romain, Mazen, Inas, Gobaa, Samy, Smith, James C., McElreavey, Kenneth, Lovell-Badge, Robin, Bashamboo, Anu, Bar-Ilan University [Israël], The Francis Crick Institute [London], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imperial College London, Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris] (IP), Biomatériaux et Microfluidiques (plateforme) - Biomaterials and Microfluidics (platform), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Mort cellulaire et homéostasie des épithéliums / Cell death and epithelial homeostasis, National Research Center [Caire, Egypte], This work is funded in part by a research grant (40000767) from the European Society of Pediatric Endocrinology (to A.B.) and by the Agence Nationale de la Recherche (ANR, ANR-10-LABX-73 REVIVE, ANR-17-CE14-0038-01, and ANR 20CE14 0007 to K.M., and ANR-19-CE14-0022 and ANR-19-CE14-0012 to A.B.). N.G., A.S.B., R.M., J.C.S., and R.L.-B. were funded by the Francis Crick Institute. The Francis Crick Institute receives its core funding from Cancer Research UK (CC2116), the UK Medical Research Council (CC2116), and the Wellcome Trust (CC2116). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. . N.G., I.S., and R.A. are funded by the ERC Starting Grant EnhanceSex (101039928). A.S.B. was also funded by the British Heart Foundation (BHF-FS/12/37/29516) and the Wellcome Trust (210987/Z/18/Z)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017), ANR-20-CE14-0007,Goldilocks,Analyse intégrée du rôle du facteur de transcription SF-1 / NR5A1 et de ses gènes cibles dépendants du dosage dans la fonction gonadique et les troubles du développement sexuel (DSD)(2020), ANR-19-CE14-0022,SexDiff,Régulation de la détermination du sexe et de la différenciation ovarienne : implications dans les troubles du développement sexuel(2019), and ANR-19-CE14-0012,RNA-SEX,Fonction de l'ARN hélicase dans la détermination du sexe chez les vertébrés et les troubles du développement du sexe chez l'homme (DSD)(2019)
Subjects: Model organisms, Chemical Biology & High Throughput, Multidisciplinary, MESH: Humans, FOS: Clinical medicine, Stem Cells, [SDV]Life Sciences [q-bio], Genome Integrity & Repair, Neurosciences, Gene Expression, MESH: Gonadal Dysgenesis, 46,XY, Tumour Biology, MESH: Induced Pluripotent Stem Cells, MESH: Cellular Reprogramming, MESH: Male, Signalling & Oncogenes, MESH: Gonads, MESH: Animals, Genetics & Genomics, MESH: Mice, MESH: Female, Developmental Biology, Computational & Systems Biology
Abstract: During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro–derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9–mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.
Published: 2023

18. Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor

Author: Ahmad Joshkon, Alexandrine Foucault-Bertaud, Wael Traboulsi, Christophe Demattei, Françoise Dignat-George, Nadia Alfaidy, Richard Bachelier, Odile Paulmyer-Lacroix, Jean-Christophe Gris, Aurélie S. Leroyer, Marcel Blot-Chabaud, Sylvie Bouvier Pharm, V. Letouzey, Nathalie Bardin, Mathieu Fortier, Sandra M. Blois, Marie Nollet, Eve Mousty, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes] (BESPIM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Grenoble Alpes (UGA), Sechenov First Moscow State Medical University, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Institut de Recherches en Technologies et Sciences pour le Vivant (IRTSV), and GRIS, Jean-Christophe
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Galectin 1, MESH: Pre-Eclampsia, MESH: Trophoblasts, CD146 Antigen, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Preeclampsia, Andrology, MESH: Pregnancy, Pre-Eclampsia, Trophoblast migration, Pregnancy, Galectin-1, Blocking antibody, Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target, medicine, Humans, Prospective Studies, Receptor, reproductive and urinary physiology, MESH: Galectin 1, MESH: Humans, Eclampsia, business.industry, Trophoblast, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Trophoblasts, MESH: Prospective Stufies, carbohydrates (lipids), [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.anatomical_structure, CD146/sCD146, Female, Signal transduction, MESH: CD146 Antigen, business, MESH: Female
Abstract: International audience; Objective: To explore the regulatory role of soluble CD146 (sCD146) and its interaction with galectin-1 (Gal1) in placenta-mediated complications of pregnancy.Design: Prospective pilot and experimental studies.Setting: University-affiliated hospital and academic research laboratory.Patient(s): One hundred fifteen women divided into three groups: 30 healthy, nonpregnant women, 50 women with normal pregnancies, and 35 with placenta-mediated pregnancy complications.Intervention(s): Wound-healing experiments were conducted to study trophoblast migration.Main outcome measure(s): Quantification of sCD146 and Gal1 by enzyme-linked immunosorbent assay. Analysis of trophoblast migration by wound closure.Result(s): Concomitant detection of sCD146 and Gal1 showed lower sCD146 and higher Gal1 concentrations in women with normal pregnancies compared with nonpregnant women. In addition, follow-up of these women revealed a decrease in sCD146 associated with an increase in Gal1 throughout pregnancy. In contrast, in women with preeclampsia, we found significantly higher sCD146 concentrations compared with women with normal pregnancies and no modification of Gal1. We emphasize the opposing effects of sCD146 and Gal, since, unlike Gal1, sCD146 inhibits trophoblast migration. Moreover, the migratory effect of Gal1 was abrogated with the use of an anti-CD146 blocking antibody or the use of small interfering RNA to silence VEGFR2 expression. This suggests that trophoblast migration is mediated though the interaction of Gal1 with CD146, further activating the VEGFR2 signaling pathway. Significantly, sCD146 blocked the migratory effects of Gal1 on trophoblasts and inhibited its secretion, suggesting that sCD146 acts as a ligand trap.Conclusion(s): Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target. Clinical trial registration number: NCT 01736826.Trial registration: ClinicalTrials.gov NCT01736826.
Published: 2022

19. Tonate Virus and Fetal Abnormalities, French Guiana, 2019

Author: Veronique Lambert, Antoine Enfissi, Mathilde Lefebvre, Leo Pomar, Sobhi Kedous, Fabien Guimiot, Gabriel Carles, Anne Lavergne, Dominique Rousset, Najeh Hcini, Centre Hospitalier de l'Ouest Guyanais Franck Joly [Saint-Laurent-du-Maroni, Guyane Française], Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Guyane (UG), Laboratoire des Interactions Virus-Hôtes [Cayenne, Guyane Française], and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: fetal abnormalities, Microbiology (medical), brain diseases, Epidemiology, Alphavirus, Infectious and parasitic diseases, RC109-216, MESH: Brain, MESH: Pregnancy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: French Guiana, Humans, viruses, reproductive and urinary physiology, vertical disease transmission, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, prenatal diagnosis, MESH: Humans, MESH: Alphavirus, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], tonate virus, Dispatch, Brain, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Infectious Disease Transmission, Vertical, French Guiana, MESH: Infectious Disease Transmission, Vertical, Venezuelan equine encephalitis, Infectious Diseases, arboviruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Tonate Virus and Fetal Abnormalities, French Guiana, 2019, meningitis/encephalitis, pregnancy, MESH: Female
Abstract: International audience; V enezuelan equine encephalomyelitis (VEE) complex viruses consist of antigenically related arboviruses widely distributed throughout the Americas (1). Only subtype I varieties AB and C cause severe equine epizootics and human outbreaks marked by the occurrence of encephalitis and fetal damage (2). The other subtypes are endemic in small areas of South America (3). In 1973, subtype III-B, the Tonate virus (TONV), was isolated in birds from French Guiana (4). It has since been found in neighboring countries and in South Dakota and Colorado in the United States (5,6). The wild cycle of TONV is still poorly understood. Transmission by Culicidae insects has been observed during the rainy season (4). Birds and bats are the only identifi ed vertebrate hosts (7). In humans in French Guiana, TONV seroprevalence suggests endemic transmission, particularly along the coast of the Bas Maroni region (8). However, clinical descriptions remain scarce, and no adverse pregnancy outcomes or vertical transmission have been reported (9,10). We report a case of vertical transmission of TONV from a pregnant woman to her fetus and describe ultrasonographic and fetopathological fi ndings. The Study During the 2019 rainy season, a 33-year-old woman living in the Bas Maroni region of French Guiana was referred to the prenatal diagnosis unit at West French Guiana Hospital Center (Saint-Laurent-du-Maroni, French Guiana) for fetal anomalies. This healthy G8P7 woman had no history of genetic disorders or birth defects from previous pregnancies. She was asymptomatic during the fi rst trimester of pregnancy and tested negative for syphilis, toxoplasmosis, rubella, cytomegalovirus, chikungunya, and Zika. An ultrasound screening performed at 20 weeks of gestation showed a hydropic fetus with microcephaly. The atrophic cerebral mantle exhibited calcifi cations and moderate ventriculomegaly. The corpus callosum, the cerebellum, and the brain stem were dysplastic. The fetus manifested limb malformations and an absence of swallowing at the time of the serially performed sonograms (Appendix Figure, https:// wwwnc.cdc.gov/EID/article/28/2/21-0884-App1. pdf). Therefore, we performed amniocentesis for etiological investigation. Because of the poor prognosis, the mother elected to terminate the pregnancy. After approval by the multidisciplinary center for prenatal diagnosis, the pregnancy was terminated without complication. The patient gave written informed consent for the publication of her case. Karyotype and array comparative genomic hybridization were normal. Results of screening for metabolic diseases were negative. All PCR and reverse transcription PCR (RT-PCR) for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, and common arboviruses from the Amazon were negative. However, we reproducibly detected the presence of a VEE complex virus in the amniotic fl uid with a real-time RT-PCR test yielding cycle threshold values of 30. Furthermore, although maternal serum samples collected 2 months before pregnancy were negative for TONV IgM, the test was positive at the time of pregnancy termination.
Published: 2022

20. Transcranial direct current stimulation (tDCS) reduces motivation to drink ethanol and reacquisition of ethanol self-administration in female mice

Author: Pedron, Solene, Dumontoy, Stephanie, Gonzalez-Marin, Maria Del Carmen, Coune, Fabien, Van Schuerbeek, Andries, Haffen, Emmanuel, Naassïla, Mickaël, Van Waes, Vincent, Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoires de neurosciences intégratives et cliniques (EA 481), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vrije Universiteit Brussel (VUB), Fondation FondaMental [Créteil], haffen, emmanuel, and Laboratoire de recherches Intégratives en Neurosciences et Psychologie Cognitive (LINC)
Subjects: MESH: Ethanol, Alcohol Drinking, [SDV]Life Sciences [q-bio], Science, MESH: Motivation, Drug-Seeking Behavior, MESH: Conditioning, Operant, Self Administration, Transcranial Direct Current Stimulation, Article, Extinction, Psychological, Mice, Reward, MESH: Behavior, Animal, Animals, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, MESH: Drug-Seeking Behavior, Motivation, Behavior, Animal, Ethanol, MESH: Transcranial Direct Current Stimulation, MESH: Extinction, Psychological, MESH: Models, Animal, Preclinical research, Models, Animal, Conditioning, Operant, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Female, MESH: Alcohol Drinking, MESH: Self Administration, Neuroscience
Abstract: International audience; Abstract Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.
Published: 2022

21. Histone variant H2A.Z regulates zygotic genome activation

Author: Alejandro Gomez-Auli, Nicola Iovino, Michael Rauer, Dafne Ibarra-Morales, Mariana Schulte-Sasse, Francesco Cardamone, Leily Rabbani, Piergiuseppe Quarato, Fides Zenk, Germano Cecere, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, Mécanismes de l'Hérédité épigénétique / Mechanisms of epigenetic inheritance, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Open Access funding enabled and organized by Projekt DEAL, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Epigenomics, Male, Zygote, MESH: Drosophila, [SDV]Life Sciences [q-bio], MESH: Epigenomics, General Physics and Astronomy, RNA polymerase II, Genome, MESH: Down-Regulation, Histones, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, MESH: Embryonic Development, MESH: Animals, Histone variants, Adenosine Triphosphatases, MESH: Histones, 0303 health sciences, Genes, Essential, Multidisciplinary, biology, MESH: Histone Chaperones, Gene Expression Regulation, Developmental, Chromatin, Cell biology, Housekeeping gene, Histone, Gene Knockdown Techniques, Chromatin Immunoprecipitation Sequencing, MESH: Cell Division, Drosophila, Female, RNA Polymerase II, MESH: Transcription Initiation Site, Transcription Initiation Site, MESH: Chromatin Immunoprecipitation Sequencing, Cell Division, Transcriptional Activation, Epigenetic memory, animal structures, Science, Down-Regulation, Embryonic Development, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Chromatin, 03 medical and health sciences, MESH: Adenosine Triphosphatases, Animals, Histone Chaperones, MESH: Genome, Gene, MESH: Genes, Essential, 030304 developmental biology, Pioneer factor, General Chemistry, MESH: Gene Knockdown Techniques, MESH: Male, MESH: RNA Polymerase II, biology.protein, MESH: Transcriptional Activation, Maternal to zygotic transition, MESH: Zygote, MESH: Female, 030217 neurology & neurosurgery
Abstract: During embryogenesis, the genome shifts from transcriptionally quiescent to extensively active in a process known as Zygotic Genome Activation (ZGA). In Drosophila, the pioneer factor Zelda is known to be essential for the progression of development; still, it regulates the activation of only a small subset of genes at ZGA. However, thousands of genes do not require Zelda, suggesting that other mechanisms exist. By conducting GRO-seq, HiC and ChIP-seq in Drosophila embryos, we demonstrate that up to 65% of zygotically activated genes are enriched for the histone variant H2A.Z. H2A.Z enrichment precedes ZGA and RNA Polymerase II loading onto chromatin. In vivo knockdown of maternally contributed Domino, a histone chaperone and ATPase, reduces H2A.Z deposition at transcription start sites, causes global downregulation of housekeeping genes at ZGA, and compromises the establishment of the 3D chromatin structure. We infer that H2A.Z is essential for the de novo establishment of transcriptional programs during ZGA via chromatin reorganization., Nature Communications, 12 (1), ISSN:2041-1723
Published: 2021

22. Timing of Kidney Clamping and Deceased Donor Kidney Transplant Outcomes

Author: Simon, Ville, Marine, Lorent, Clarisse, Kerleau, Anders, Asberg, Christophe, Legendre, Emmanuel, Morelon, Fanny, Buron, Valérie, Garrigue, Moglie, Le Quintrec, Sophie, Girerd, Marc, Ladrière, Laetitia, Albano, Antoine, Sicard, Denis, Glotz, Carmen, Lefaucheur, Julien, Branchereau, David, Jacobi, Magali, Giral, Etienne, Sicard, Institut de Transplantation et de Recherche en Transplantation [CHU Nantes] (ITERT), Centre hospitalier universitaire de Nantes (CHU Nantes), European cohort for Kidney Transplantation Epidemiology (EKiTE), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Oslo University Hospital [Oslo], Réseau CENTAURE, Service Néphrologie et transplantation rénale Adultes [CHU Necker], 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 Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Lapeyronie [Montpellier] (CHU), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de Néphrologie - Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Service d'Urologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), and Salvy-Córdoba, Nathalie
Subjects: Graft Rejection, Male, Time Factors, Databases, Factual, Epidemiology, Kidney, Critical Care and Intensive Care Medicine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Organ transplantation, MESH: Kidney Transplantation, MESH: Delayed Graft Function, Kidney transplantation / nephrology, MESH: Incidence, Prospective Studies, Kidney transplantation, MESH: Aged, MESH: Middle Aged, Norway, Ischemia-reperfusion, Incidence, Graft Survival, Hazard ratio, Middle Aged, Constriction, medicine.anatomical_structure, Nephrology, Cardiology, Female, France, Adult, medicine.medical_specialty, MESH: Circadian Clocks, MESH: Graft Survival, Delayed Graft Function, MESH: Graft Rejection, Cadaver organ transplantation, MESH: Norway, Circadian Clocks, Internal medicine, medicine, Humans, Circadian rhythm, Aged, Transplantation, MESH: Humans, business.industry, MESH: Time Factors, MESH: Adult, Original Articles, Odds ratio, medicine.disease, Organ transplant, MESH: Databases, Factual, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Kidney Transplantation, MESH: Male, MESH: Prospective Studies, Confidence interval, MESH: France, business, MESH: Female
Abstract: International audience; Background and objectives The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. Design, setting, participants, & measurements We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon ( ante meridiem [ am ] clamping group; 65%) or clamped between noon and midnight ( post meridiem [ pm ] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). Results Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P =0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P =0.37). No significant association of declamping time with delayed graft function or graft survival was observed. Conclusions Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.
Published: 2021

23. Multi-omic approach identifies a transcriptional network coupling innate immune response to proliferation in the blood of COVID-19 cancer patients

Author: Salvatore Sciacchitano, Arianna Di Napoli, Benjamin Terrier, Carlo Capalbo, Frauke Goeman, Francesca De Nicola, Michela D'Ascanio, Alberto Ricci, Christian Napoli, Simona di Martino, Giulia Piaggio, Agostino Tafuri, Andrea Sacconi, Maurizio Fanciulli, Luisa de Latouliere, Darragh Duffy, Luciano De Biase, Andrea Negro, Valentina Salvati, Claudia De Vitis, Carla Mottini, Rita Mancini, Francesca Paolini, Giovanni Blandino, Paolo Anibaldi, Paolo Marchetti, Gennaro Ciliberto, IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Azienda Ospedaliera Sant'Andrea [Roma], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Université de Paris (UP), University Niccolò Cusano (UNICUSANO), This work was supported in part by funds Ricerca Corrente from the Ministry of Health, Italy, and by Grant COMETA To GC and RM from Istituto Buddista Italiano Soka Gakkai., We would like to thank the medical directorates of the participating hospitals who made this work possible. We thank the patients who have donated their blood for this study., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), and University Niccolò Cusano = Università Niccoló Cusano (UNICUSANO)
Subjects: Male, Cancer Research, medicine.medical_treatment, Antibodies, Viral, 0302 clinical medicine, Neoplasms, MESH: COVID-19, MESH: Neoplasms, Cancer, 0303 health sciences, education.field_of_study, MESH: Cytokines, MESH: Case-Control Studies, 3. Good health, MESH: Leukocytes, Mononuclear, Cytokine, 030220 oncology & carcinogenesis, Cytokines, Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Immunology, Population, Inflammation, Peripheral blood mononuclear cell, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Immune system, medicine, Humans, education, 030304 developmental biology, Innate immune system, MESH: Humans, QH573-671, business.industry, COVID-19, Cell Biology, medicine.disease, MESH: Male, Case-Control Studies, Leukocytes, Mononuclear, business, Cytology, MESH: Female, CD8, MESH: Antibodies, Viral, covid-19 and h-ras and ras
Abstract: Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer leading to elevated mortality rates. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes have so far been poorly investigated. We conducted a multi-omic analysis of immunological parameters in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with and without cancer. Healthy donors and SARS-CoV-2-negative cancer patients were also included as controls. At the infection peak, cytokine multiplex analysis of blood samples, cytometry by time of flight (CyTOF) cell population analyses, and Nanostring gene expression using Pancancer array on PBMCs were performed. We found that eight pro-inflammatory factors (IL-6, IL-8, IL-13, IL-1ra, MIP-1a, IP-10) out of 27 analyzed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8+T, CD4+T central memory, Mucosal-associated invariant T (MAIT), natural killer (NK), and γδ T cells were reduced, while B plasmablasts were expanded in COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients. A 19-gene expression signature of PBMCs is able to discriminate COVID-19 patients with and without solid cancers. Gene set enrichment analysis highlights an increased gene expression linked to Interferon α, γ, α/β response and signaling which paired with aberrant cell cycle regulation in cancer patients. Ten out of the 19 genes, validated in a real-world consecutive cohort, were specific of COVID-19 cancer patients independently from different cancer types and stages of the diseases, and useful to stratify patients in a COVID-19 disease severity-manner. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients.
Published: 2021

24. Female sex workers and police violence during the Covid-19 health crisis in 2020–2021: results from the EPIC multi-country community-based research program in Argentina

Author: Aristegui, I., Castro Avila, J., Villes, V., Delabre, R, Orellano, G., Aguilera, M., Romero, M., Riegel, L., Kretzer, L., Cardozo, N., Radusky, P, Rojas Castro, D., Fundación Huésped [Buenos Aires], Università degli studi di Palermo - University of Palermo, Coalition PLUS [Pantin, France] (Community Research Laboratory Pantin), Asociación de Mujeres Meretrices de Argentina [Buenos Aires, Argentina] (AMMAR), Asociación de Travestis Transexuales y Transgénero de Argentina [Buenos Aires, Argentina] (ATTTA), Universidad de Buenos Aires [Buenos Aires] (UBA), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), and EPIC Study Group.
Subjects: Adult, MESH: Pandemics, MESH: Humans, Sex Workers, MESH: Sex Workers, [SDV]Life Sciences [q-bio], Argentina, Public Health, Environmental and Occupational Health, Female sex worker, COVID-19, Medicine (miscellaneous), MESH: Adult, HIV Infections, Community-based organizations, MESH: HIV Infections, Psychiatry and Mental health, MESH: Cross-Sectional Studies, Cross-Sectional Studies, Police violence, MESH: COVID-19, Humans, Female, MESH: Female, Pandemics
Abstract: Background Female sex workers (FSW) have been disproportionately impacted by the Covid-19 crisis. Data show increases of police violence toward key populations (KP), likely a consequence of their role in enforcing health government measures. This study aimed to identify factors associated with police violence experienced by FSW during the Covid-19 crisis in Argentina. Methods EPIC is a multi-country, cross-sectional, community-based research program evaluating the impact of Covid-19 among KP. In Argentina, the study was conducted in collaboration with FSW community-based organizations (CBO). Participants completed an online survey (October 2020–April 2021). Police violence was measured as having experienced episodes of violence (physical, verbal, psychological or sexual) by security forces since the start of the health crisis. Factors associated with police violence were assessed in logistic regression models. Results Among 173 respondents, median age was 34 [IQR 27–42], 39.3% were transgender women (TW), 78.1% declared sex work as their only income and 71.7% mentioned their financial situation has deteriorated with the health crisis. Nearly half of FSW (44.5%) reported experiencing police violence within the first year of the Covid-19 pandemic, and among them, 76.6% declared more frequent violence episodes since the beginning of the health crisis. After adjustment for age, being a TW (aOR [95% CI] = 2.71 [1.21;6.05]), reporting non-injection drug use (2.92 [1.02;8.36]), having a considerably deteriorated financial situation (3.67 [1.47;9.21]), having had a consultation with a CBO worker for medical care/treatments (5.56 [2.15;14.37]) and declaring fear or experiences of discrimination by physicians/other health workers (2.97 [1.21;7.29]), since the beginning of the Covid-19 health crisis, were independently associated with police violence. Conclusions FSW in Argentina have experienced an increase in police violence since the beginning of the health crisis. Belonging to multiple KP (FSW, TW, people who use drugs) increases the likelihood of experiencing police violence, highlighting the need of an intersectional approach to develop interventions to reduce stigma and violence against FSW. CBOs have provided essential support and services during the crisis to FSWs, and other KPs, who may have avoided traditional healthcare structures due to fear or experiences of discrimination.
Published: 2022

25. Role of non-invasive methods in detecting liver impairment in familial Mediterranean fever adult patients with persistent hepatic cytolysis

Author: Samuel Deshayes, Thibault Fraisse, Soraya Fellahi, Olivier Steichen, Léa Savey, Bruno Turlin, Mona Munteanu, Achille Aouba, Rim Bourguiba, Véronique Hentgen, Jean-Manuel Faintuch, Irina Giurgea, Gilles Grateau, Jean-Philippe Bastard, Sophie Georgin-Lavialle, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CHU Tenon] (CeréMAIA), CHU Tenon [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 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), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie et Stratégies d'Imagerie du Remodelage cardiovasculaire (PSIR), 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), 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 Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor, Service d'anatomopathologie [Rennes], Hôpital Pontchaillou, Centre Hospitalier de Versailles André Mignot (CHV), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Service d'Imageries Radiologiques et Interventionnelles [CHU Tenon] (IRIS), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Couvet, Sandrine, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Groupe de recherche clinique Amylose AA Sorbonne Université (GRC 28 - GRAASU), Sorbonne Université (SU), CHU Henri Mondor [Créteil], and Maladies génétiques d'expression pédiatrique (U933)
Subjects: Adult, MESH: Mutation, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], MESH: Pyrin, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Humans, Multidisciplinary, MESH: Humans, MESH: Middle Aged, MESH: Familial Mediterranean Fever, MESH: Adult, Middle Aged, Pyrin, Fibrosis, Familial Mediterranean Fever, [SDV] Life Sciences [q-bio], MESH: Colchicine, Liver, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, MESH: Fibrosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Colchicine, MESH: Female, MESH: Liver
Abstract: Familial Mediterranean fever (FMF) patients may have hepatic cytolysis, although its origin is not formally elucidated. We aimed to evaluate liver involvement in familial Mediterranean fever (FMF) using non-invasive methods. All adult FMF patients harboring two non-ambiguous mutations of the MEFV gene with hepatic cytolysis were identified in a French tertiary adult center for FMF. Liver impairment was explored with FibroMax (a non-invasive method to estimate hepatic steatosis, necrosis, inflammation and fibrosis) and liver ultrasound. Among 520 FMF adult patients, 43 had persistent hepatic cytolysis and 20 patients were included (11 women, median age at inclusion: 49.5 years). According to the FibroMax results, patients were classified as having steatosis, fibrosis, and possible or definite nonalcoholic steato-hepatitis in 10 (50%), 9 (45%) and 7 (35%) of cases, respectively. The score of steatosis did not seem associated with the usual metabolic risk factors. No significant association was found between the cumulated dose of colchicine and any of the scores included in FibroMax. In adult FMF patients with persistent hepatic cytolysis, steatosis is the first cause to consider even in the absence of usual metabolic risk factors, suggesting other mechanisms. Colchicine did not seem to be involved in this toxicity.
Published: 2022

26. TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks

Author: Alexandre Nore, Ariadna B. Juarez-Martinez, Julie Clément, Christine Brun, Boubou Diagouraga, Hamida Laroussi, Corinne Grey, Henri Marc Bourbon, Jan Kadlec, Thomas Robert, Bernard de Massy, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), 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), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Clement, Julie, Thomas, Frank, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université Grenoble Alpes (UGA)
Subjects: Male, Spo11, Catalytic complex, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], Mutant, MESH: DNA Breaks, Double-Stranded, General Physics and Astronomy, MESH: Spermatocytes, General Biochemistry, Genetics and Molecular Biology, Chromosomes, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, chemistry.chemical_compound, Mice, Meiosis, Spermatocytes, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, DNA Breaks, Double-Stranded, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Double strand, [SDV.BDD.GAM] Life Sciences [q-bio]/Development Biology/Gametogenesis, Autosome, Multidisciplinary, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Point mutation, fungi, MESH: DNA, General Chemistry, DNA, MESH: Meiosis / genetics, MESH: Male, Cell biology, MESH: Meiosis, biology.protein, Female, MESH: Chromosomes, MESH: Female
Abstract: Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. In male and female meiotic cells, DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, but only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity by integrating specific chromosomal features.
Published: 2022

27. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Primary Breast Cancer

Author: Thomas Bachelot, Paul Cottu, Sylvie Chabaud, Florence Dalenc, Djelila Allouache, Suzette Delaloge, Jean-Philippe Jacquin, Julien Grenier, Laurence Venat Bouvet, Apurna Jegannathen, Mario Campone, Francesco Del Piano, Marc Debled, Anne-Claire Hardy-Bessard, Sylvie Giacchetti, Marie-Ange Mouret-Reynier, Philippe Barthelemy, Laure Kaluzinski, Audrey Mailliez, Eric Legouffe, Matthew Sephton, Judith Bliss, Jean-Luc Canon, Frederique Penault-Llorca, Jerome Lemonnier, David Cameron, Fabrice Andre, Rhodia Opérations, RHODIA, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Léon Bérard [Lyon], Department of Medical Oncology, Institut Curie, Paris 75248, France, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service Oncologie Médicale [Saint Priest en Jarez], Institut de Cancérologie Lucien Neuwirth [Saint Priest en Jarez], Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Institut Bergonié [Bordeaux], Centre Armoricain de Radiothérapie, d'Imagerie médicale et d'Oncologie [Plérin, Saint-Brieuc] (CARIO), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), ChemBioPharm, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Qingdao Agricultural University Qingdao, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), CRLCC Paul Papin, Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), École des Hautes Études en Santé Publique [EHESP] (EHESP), Laboratoire d'Ergonomie et d'Épidémiologie en Santé au Travail (LEEST), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Institut de Veille Sanitaire (INVS)
Subjects: Cancer Research, MESH: Xenograft Model Antitumor Assays, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], H3K27me3, JMJD3, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Everolimus, Disease-Free Survival, AR status, GSK-J4, Double-Blind Method, Antineoplastic Combined Chemotherapy Protocols, Humans, asymptomatic, MESH: Double-Blind Method, Everolimus, epidrugs, COVID, Prostate cancer, MESH: Humans, epigenetics, Cancer patients, MESH: Receptor, ErbB-2, MESH: Antineoplastic Combined Chemotherapy Protocols, xenografts, Oncology, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, MESH: Pyrimidines, MESH: Disease-Free Survival, Female, MESH: Female, MESH: Breast Neoplasms
Abstract: PURPOSE Everolimus, an oral inhibitor of the mammalian target of rapamycin, improves progression-free survival in combination with endocrine therapy (ET) in postmenopausal women with aromatase inhibitor–resistant metastatic breast cancer. However, the benefit of adding everolimus to ET in the adjuvant setting in early breast cancer is unknown. PATIENTS AND METHODS In this randomized double-blind phase III study, women with high-risk, hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer were randomly assigned to everolimus or placebo for 2 years combined with standard ET. Stratification factors included ET agent, receipt of neoadjuvant versus adjuvant chemotherapy, progesterone receptor status, duration of ET before random assignment, and lymph node involvement. The primary end point was disease-free survival (DFS). The trial is registered with ClinicalTrials.gov (identifier: NCT01805271 ). RESULTS Between June 2013 and March 2020, 1,278 patients were randomly allocated to receive everolimus or placebo. At the first interim analysis, the trial was stopped for futility and a full analysis undertaken once data snapshot complete. One hundred forty-seven patients have had a DFS event reported and at 3 years, DFS did not differ between patients who received ET plus everolimus (88% [95% CI, 85 to 91]) or ET plus placebo (89% [95% CI, 86 to 91; hazard ratio, 0.95; 95% CI, 0.69 to 1.32; P = .77]). Grade ≥ 3 adverse events were reported in 22.9% of patients (29.9% with everolimus v 15.9% with placebo, P < .001). 53.4% everolimus-treated patients permanently discontinued experimental treatment early compared with placebo-treated 22.3%. CONCLUSION Among high-risk patients, everolimus added to adjuvant ET did not improve DFS. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting.
Published: 2022

28. Adherence to opioid agonist therapy predicts uptake of direct-acting antivirals in people who use drugs: results from the French national healthcare database (the ANRS FANTASIO study)

Author: Benjamin Rolland, Caroline Lions, Vincent Di Beo, Patrizia Carrieri, Nicolas Authier, Tangui Barré, Jessica Delorme, Philippe Mathurin, François Bailly, Camelia Protopopescu, Fabienne Marcellin, Service Universitaire d’Addictologie de Lyon [CH Le Vinatier, Bron] (Pôle MOPHA - SUAL), Centre Hospitalier le Vinatier [Bron], Psychiatric Disorders, Neuroscience Research and Clinical Research (PSYR2), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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)-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), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), 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), Service d'hépatologie et d’addictologie [GH Nord, Lyon], HCL Groupement Hospitalier Nord [Lyon], Hôpital de la Croix-Rousse [CHU - HCL], and Hospices Civils de Lyon (HCL)
Subjects: Male, MESH: Antiviral Agents, [SDV]Life Sciences [q-bio], MESH: Delivery of Health Care, Medicine (miscellaneous), Hepacivirus, MESH: Analgesics, Opioid, Antiviral Agents, Humans, MESH: Hepacivirus, Drug use, DAA, MESH: Hepatitis C, MESH: Humans, Public Health, Environmental and Occupational Health, Hepatitis C, Chronic, Hepatitis C, MESH: Male, Buprenorphine, MESH: Hepatitis C, Chronic, Analgesics, Opioid, Psychiatry and Mental health, Female, Delivery of Health Care, MESH: Female, Methadone
Abstract: Background Opioid agonist therapy (OAT) is associated with reduced injection, reduced HCV transmission, and more opportunities to initiate hepatitis C virus (HCV) treatment in people who use drugs (PWUD). We aimed to study the extent to which adherence to OAT was predictive of increased uptake of direct-acting antivirals (DAA) in PWUD with chronic HCV infection. Methods Using the French national healthcare system database, we targeted PWUD (i.e. with a history of OAT) who had chronic HCV infection and were eligible for DAA during 2014–2016. Adherence to OAT was computed as a time-varying variable expressing the proportion of days covered by OAT receipt, over any six-month interval before DAA receipt. We used a Cox proportional hazards model to estimate the association between adherence to OAT and the rate of DAA uptake after adjustment for age, sex, alcohol use disorder, socioeconomic status, and liver disease severity. Results Among the 22,615 persons included in the ANRS FANTASIO study, 3438 (15.2%) initiated DAA during the study period. After multivariable adjustment, adherence to OAT was associated with a higher rate of DAA initiation. However, this association was not linear, and only individuals on OAT for 20% or more of the time in the previous six-month period had a higher rate of DAA initiation (adjusted hazard ratio [95% confidence interval]: 1.28 [1.18–1.38]). Other variables associated with DAA initiation were male sex, older age, cirrhosis or liver cancer, and higher socioeconomic status. Conclusions Adherence to OAT is a major predictor of DAA initiation in PWUD living with chronic HCV infection in France. Our results also suggest that even moderate adherence to OAT can facilitate DAA uptake. Adequate HCV training for OAT prescribers together with interventions to ensure adherence to OAT will help improve DAA initiation rates and reach HCV elimination goals.
Published: 2022

29. The Role of Regulator Catabolite Control Protein A (CcpA) in Streptococcus agalactiae Physiology and Stress Response

Author: Roux, Anne-Emmanuelle, Robert, Sylvie, Bastat, Mathilde, Rosinski-Chupin, Isabelle, Rong, Vanessa, Holbert, Sébastien, Mereghetti, Laurent, Camiade, Emilie, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de bactériologie et d'hygiène hospitalière [Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: group B Streptococcus, MESH: Gene Expression Regulation, Bacterial, MESH: Humans, MESH: Infant, Newborn, Usp proteins, adaptation, stress response, CcpA, MESH: Streptococcus agalactiae, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Streptococcus agalactiae, stress adaptation, stress, oxidative stress, MESH: Staphylococcal Protein A, acid resistance, carbon catabolite repression (CCR), MESH: Bacterial Proteins, MESH: Female, catabolite repression
Abstract: International audience; Abstract : Streptococcus agalactiae is a leading cause of infections in neonates. This opportunistic pathogen colonizes the vagina, where it has to cope with acidic pH and hydrogen peroxide produced by lactobacilli. Thus, in the host, this bacterium possesses numerous adaptation mechanisms in which the pleiotropic regulators play a major role. The transcriptional regulator CcpA (catabolite control protein A) has previously been shown to be the major regulator involved in carbon catabolite repression in Gram-positive bacteria but is also involved in other functions. By transcriptomic analysis, we characterized the CcpA-dependent gene regulation in S. agalactiae. Approximately 13.5% of the genome of S. agalactiae depends on CcpA for regulation and comprises genes involved in sugar uptake and fermentation, confirming the role of CcpA in carbon metabolism. We confirmed by electrophoretic mobility shift assays (EMSAs) that the DNA binding site called cis-acting catabolite responsive element (cre) determined for other streptococci was effective in S. agalactiae. We also showed that CcpA is of capital importance for survival under acidic and oxidative stresses and is implicated in macrophage survival by regulating several genes putatively or already described as involved in stress response. Among them, we focused our study on SAK_1689, which codes a putative UspA protein. We demonstrated that SAK_1689, highly downregulated by CcpA, is overexpressed under oxidative stress conditions, this overexpression being harmful for the bacterium in a ΔccpA mutant.Importance : Streptococcus agalactiae is a major cause of disease burden leading to morbidity and mortality in neonates worldwide. Deciphering its adaptation mechanisms is essential to understand how this bacterium manages to colonize its host. Here, we determined the regulon of the pleiotropic regulator CcpA in S. agalactiae . Our findings reveal that CcpA is not only involved in carbon catabolite repression, but is also important for acidic and oxidative stress resistance and survival in macrophages.
Published: 2022

30. Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study

Author: Helena Huerga, Mathieu Bastard, Alex Vicent Lubega, Milcah Akinyi, Natalia Tamayo Antabak, Liesbet Ohler, Winnie Muyindike, Ivan Mugisha Taremwa, Rosanna Stewart, Claire Bossard, Nothando Nkosi, Zibusiso Ndlovu, Catherine Hewison, Turyahabwe Stavia, Gordon Okomo, Jeremiah Okari Ogoro, Jacqueline Ngozo, Mduduzi Mbatha, Couto Aleny, Stephen Wanjala, Mohammed Musoke, Daniel Atwine, Alexandra Ascorra, Elisa Ardizzoni, Martina Casenghi, Gabriella Ferlazzo, Lydia Nakiyingi, Ankur Gupta-Wright, Maryline Bonnet, Epicentre [Paris] [Médecins Sans Frontières], Epicentre Ouganda [Mbarara] [Médecins Sans Frontières], Médecins sans Frontières [Nairobi, Kenya], Médecins Sans Frontières [Cape Town, South Africa], Médecins Sans Frontières [Paris] (MSF), Uganda Ministry of Health, Ministry of Health [Nairobi, Kenya], Ministry of Health [Mozambique], Institute of Tropical Medicine [Antwerp] (ITM), Elizabeth Glaser Pediatric AIDS Foundation, Makerere University College of Health Sciences, University College of London [London] (UCL), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and This study was funded by the ANRS (grant number 20314) and Médecins Sans Frontières. FujiLAM tests were donated by the Foundation for Innovative Diagnostics.
Subjects: MESH: Humans, MESH: Mycobacterium tuberculosis, MESH: African People, MESH: South Africa, MESH: CD4 Lymphocyte Count, MESH: Tuberculosis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: HIV Infections, General Medicine, MESH: Lipopolysaccharides, MESH: Female, MESH: Male, MESH: Sensitivity and Specificity
Abstract: International audience; Background: Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients.Methods: We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count
Published: 2022

31. Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial

Author: Julien Guiraud, Giovanni Addolorato, Mariangela Antonelli, Henri-Jean Aubin, Andrea de Bejczy, Amine Benyamina, Roberto Cacciaglia, Fabio Caputo, Maurice Dematteis, Anna Ferrulli, Anna E Goudriaan, Antoni Gual, Otto-Michael Lesch, Icro Maremmani, Antonio Mirijello, David J Nutt, François Paille, Pascal Perney, Roch Poulnais, Quentin Raffaillac, Jürgen Rehm, Benjamin Rolland, Claudia Rotondo, Bruno Scherrer, Nicolas Simon, Katrin Skala, Bo Söderpalm, Lorenzo Somaini, Wolfgang H Sommer, Rainer Spanagel, Gabriele A Vassallo, Henriette Walter, Wim van den Brink, Amsterdam UMC - Amsterdam University Medical Center, University of Amsterdam [Amsterdam] (UvA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 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, Hôpital Paul Brousse, University of Gothenburg (GU), Laboratorio Farmaceutico CT [San Remo, Italy] (LFCT), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université Grenoble Alpes (UGA), IRCCS Ospedale San Raffaele [Milan, Italy], Università degli Studi di Milano = University of Milan (UNIMI), Amsterdam School of Public Health [the Netherlands], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Vienna [Vienna], University of Pisa - Università di Pisa, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Imperial College London, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), D&A Pharma Paris - Laboratoires pharmaceutiques (DAPP), Centre for Addiction and Mental Health [Toronto] (CAMH), University of Toronto, Technische Universität Dresden = Dresden University of Technology (TU Dresden), I.M. Sechenov First Moscow State Medical University [Moscow, Russia] (MSMU), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), Centro di Riferimento Alcologico della Regione Lazio [Roma, Italy] (CRARL), Bruno Scherrer Conseil [Saint Arnoult en Yvelines] (BSC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie Clinique [AP-HM Hôpital Ste Marguerite], Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Medizinische Universität Wien = Medical University of Vienna, Addiction Treatment Center [ASL Biella, Italy] (ATC - Local Health Unit), Universität Heidelberg [Heidelberg] = Heidelberg University, Barone Lombardo Hospital [Canicattì, Italy] (BLH), Amsterdam University Medical Centers (Amsterdam UMC), Adult Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and APH - Digital Health
Subjects: Adult, Male, MESH: Ethanol, Alcohol Drinking, Alcohol use disorders, Double-Blind Method, MESH: Alcoholism, Humans, Maintenance of abstinence, Pharmacology (medical), MESH: Double-Blind Method, MESH: Treatment Outcome, Pharmacology, MESH: Humans, Ethanol, Sodium oxybate, Alcohol dependence, MESH: Adult, MESH: Male, Psychiatry and Mental health, Alcoholism, Treatment Outcome, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Sodium Oxybate, GHB, MESH: Female, RCT, MESH: Alcohol Drinking
Abstract: Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423
Published: 2022

32. Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study

Author: Balazs Acs, Samuel C.Y. Leung, Kelley M. Kidwell, Indu Arun, Renaldas Augulis, Sunil S. Badve, Yalai Bai, Anita L. Bane, John M.S. Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C. Chang, Robin L. Dietz, Andrew Dodson, Susan Fineberg, Cornelia M. Focke, Dongxia Gao, Allen M. Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M. Levenson, Rustin Mahboubi-Ardakani, Mauro G. Mastropasqua, Sharon Nofech-Mozes, C. Kent Osborne, Frédérique M. Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T. Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert van der Vegt, Giuseppe Viale, Lila A. Zabaglo, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen, David L. Rimm, Lisa M. McShane, Torsten Nielsen, Samuel Leung, Signe Borgquist, Angela Chan, Carsten Denkert, Anna Ehinger, Matthew Ellis, Margaret Flowers, Chad Galderisi, Abhi Gholap, Douglas J. Hartman, Judith C. Hugh, Anagha Jadhav, Elizabeth N. Kornaga, Hans Kreipe, Richard Levenson, Mauro Mastropasqua, Takuya Moriya, Hongchao Pan, Liron Pantanowitz, Ernesta Paola Neri, Mei-Yin Polley, Jason Ruan, Takashi Sakatani, Lois Shepherd, Ian Smith, Joseph Sparano, Melanie Spears, Malini Srinivasan, Jane Starczynski, Austin Todd, Shakeel Virk, Yihong Wang, Hua Yang, Zhiwei Zhang, Inti Zlobec, Rigshospitalet [Copenhagen], Copenhagen University Hospital, CHUV, Lausanne (Departement d'Oncologie), St Jude Children's Research Hospital, Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Memorial Sloan Kettering Cancer Center (MSKCC), Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)
Subjects: [SDV]Life Sciences [q-bio], Biopsy, Image Processing, DIGITAL-IMAGE-ANALYSIS, MULTICENTER, Medical and Health Sciences, MESH: Biopsy, Computer-Assisted, REPRODUCIBILITY, NEEDLE BIOPSIES, Receptors, Image Processing, Computer-Assisted, Pathology, MESH: Protein Kinase Inhibitors, 610 Medicine & health, Cancer, Tumor, PROLIFERATION, MESH: Receptor, trkA, KI-67 LABELING INDEX, MESH: Image Processing, Computer-Assisted, Immunohistochemistry, INTERNATIONAL KI67, Receptors, Estrogen, TRK fusion, RELIABILITY, MESH: Receptors, Estrogen, Female, MESH: Biomarkers, Tumor, NTRK gene fusions, MESH: Ki-67 Antigen, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Settore MED/08 - Anatomia Patologica, Non-interventional study, Pathology and Forensic Medicine, Clinical Research, Biomarkers, Tumor, Humans, Ki-67 Antigen, Breast Cancer, BIOMARKER ASSESSMENT, Larotrectinib, MESH: Humans, MESH: Immunohistochemistry, Estrogen, MESH: Pyrimidines, 570 Life sciences, biology, MESH: Female, MESH: Pyrazoles, MESH: Breast Neoplasms, Biomarkers
Abstract: International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.
Published: 2022

33. [Contraception after bariatric surgery: Importance of a specific gynecologic course]

Author: A. Fèvre, Eric Bertin, Isabelle Gaubil-Kaladjian, B. Delemer, C. Têtu, M. Barrois, Coralie Barbe, A. Diaz Cives, Université de Reims Champagne-Ardenne (URCA), and Centre Hospitalier Universitaire de Reims (CHU Reims)
Subjects: Bariatric surgery, MESH: Contraception, Gynecology, medicine.medical_specialty, MESH: Humans, business.industry, Obstetrics and Gynecology, 030209 endocrinology & metabolism, Chirurgie bariatrique, 3. Good health, 03 medical and health sciences, Contraception, 0302 clinical medicine, Reproductive Medicine, Medicine, Obesity, Obésité, MESH: Bariatric Surgery, 030212 general & internal medicine, business, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

34. The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: Lakeman, Inge M. M., Van Den Broek, Alexandra J., Vos, Juliën A. M., Barnes, Daniel R., Adlard, Julian, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Balmaña, Judith, Barrowdale, Daniel, Giraud, Sophie, Golmard, Lisa, Hake, Christopher R., Houdayer, Claude, Risch, Harvey A., Lasset, Christine, Laurent, Maïté, Spurdle, Amanda B., Hooning, Maartje J., Hopper, John L., Kets, Carolien M., Leroux, Dominique, Longy, Michel, Mari, Véronique, Mazoyer, Sylvie, Mebirouk, Noura, Mortemousque, Isabelle, Blok, Marinus J., Prieur, Fabienne, Hamann, Ute, Pujol, Pascal, Konstantopoulou, Irene, Heemskerk Gerritsen, Bernadette A. M., Isaacs, Claudine, Saule, Claire, Piedmonte, Marion, Schuster, Helene, Sevenet, Nicolas, Sobol, Hagay, Sokolowska, Johanna, Gómez Garcia, Encarna B., Venat Bouvet, Laurence, Claes, Kathleen B. M., Ahmed, Munaza, Teixeira, Manuel R., Barwell, Julian, Brady, Angela, Izatt, Louise, Hogervorst, Frans B. L., Brennan, Paul, Harrington, Patricia A., Henderson, Alex, Hodgson, Shirley, Kwong, Ava, Borg, Ake, Kennedy, M. John, Porteous, Mary E., Rogers, Mark T., Side, Lucy E., Snape, Katie, Walker, Lisa, Collée, J. Margriet, Jakubowska, Anna, Couch, Fergus J., Hahnen, Eric, Daly, Mary B., Dennis, Joe, Teo, Soo Hwang, Jensen, Uffe Birk, Rantala, Johanna, Dhawan, Mallika, Benitez, Javier, Domchek, Susan M., Eeles, Ros, Engel, Christoph, Legrand, Clémentine, Evans, D. Gareth, James, Paul A., Feliubadaló i Elorza, Maria Lídia, Teulé-Vega, Àlex, Foretova, Lenka, Castera, Laurent, Friedman, Eitan, Frost, Debra, Rennert, Gad, Ganz, Patricia A., Leslie, Goska, Garber, Judy, Hulick, Peter J., Imyanitov, Evgeny N., Glendon, Gord, Thomassen, Mads, Janavicius, Ramunas, Mulligan, Anna Marie, Hollestelle, Antoinette, Jager, Agnes, Koppert, Linetta B., Cook, Jackie, Koudijs, Marco, Kriege, Mieke, Meijers Heijboer, Hanne E. J., Schmutzler, Rita K., Mensenkamp, Arjen R., Dunning, Alison M., Mooij, Thea M., Oosterwijk, Jan C., Caux Moncoutier, Virginie, Singer, Christian F., Berthet, Pascaline, Caldés, Trinidad, Van den Ouweland, Ans M. W., Van der Baan, Frederieke H., Van der Hout, Annemieke H., Van der Kolk, Lizet E., Van der Luijt, Rob B., Thull, Darcy L., Van Deurzen, Carolien H. M., Sharma, Priyanka, Van Doorn, Helena C., Bignon, Yves Jean, Colas, Chrystelle, Van Engelen, Klaartje, Brewer, Carole, Van Hest, Liselotte P., Van Os, Theo A. M., Caligo, Maria A., Verhoef, Senno, Tischkowitz, Marc, Vogel, Maartje J., Wijnen, Juul T., Lalloo, Fiona, Beesley, Jonathan, Fox, Stephen, Collonge Rame, Marie Agnès, Simard, Jacques, Holland, Helene, Jiao, Yue, John, Esther M., Joseph, Vijai, Gerdes, Anne Marie, Karlan, Beth Y., Lesueur, Fabienne, Loud, Jennifer T., Lubiński, Jan, Manoukian, Siranoush, Mcguffog, Lesley, Miller, Austin, Coupier, Isabelle, Gomes, Denise Molina, Barouk Simonet, Emmanuelle, Montagna, Marco, Miller, Clare, Elan, Camille, Davidson, Rosemarie, Mouret Fourme, Emmanuelle, Gayther, Simon A., Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Pauw, Antoine de, Olah, Edith, Morrison, Patrick J., Olopade, Olufunmilayo I., Van Asperen, Christi J., Park, Sue K., Parsons, Michael T., Donaldson, Alan, Belotti, Muriel, Peterlongo, Paolo, Stadler, Zsofia, Stoppa Lyonnet, Dominique, Sutter, Christian, Ong, Kai Ren, Delnatte, Capucine, Tan, Yen Yen, Toland, Amanda E., Tung, Nadine, Van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Devilee, Peter, Eason, Jacqueline, Chung, Wendy K., Bernstein, Jonine L., Offit, Kenneth, Aalfs, Cora M., Hanson, Helen, Godwin, Andrew K., Easton, Douglas F., Bonadona, Valérie, Rookus, Matti A., Chenevix-Trench, Georgia, Antoniou, Antonis C., O’shaughnessy Kirwan, Aoife, Robson, Mark, Eccles, Diana M., Schmidt, Marjanka K., Adank, Muriel A., Gemo Study Collaborators, Phillips, Kelly Anne, Embrace Collaborators, Ocgn Investigators, Goldgar, David E., Hebon Investigators, Perkins, Jo, Kconfab Investigators, Bressac de Paillerets, Brigitte, Buecher, Bruno, Caputo, Sandrine, Ausems, Margreet G. E. M., Gregory, Helen, Caron, Olivier, Faivre, Laurence, Fert Ferrer, Sandra, Gauthier Villars, Marion, Radice, Paolo, Gesta, Paul, Clinical Genetics, Medical Oncology, Surgery, Pathology, Gynecological Oncology, Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Schmidt, Marjanka K [0000-0002-2228-429X], HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Lakeman IMM] Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. [van den Broek AJ, Vos JAM] Division of Molecular Pathology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. [Barnes DR] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Adlard J] Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK. [Andrulis IL] Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Pediatric surgery, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Epidemiology and Data Science, Human Genetics, ARD - Amsterdam Reproduction and Development, APH - Personalized Medicine, APH - Quality of Care, Chapel Allerton Hospital, University of Leeds, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Reykjavík University, Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig–Holstein, The University of Texas M.D. Anderson Cancer Center [Houston], Unitat d'Alt Risc i Prevenció del Càncer, Vall d'Hebron University Hospital [Barcelona], University of Cambridge [UK] (CAM), Group of Human Genetics, Human Cancer Genetics Programme, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Section of Genetic Oncology, University of Pisa - Università di Pisa, Columbia University [New York], Ghent University Hospital, Department of Clinical Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Laboratory Medicine and Pathology, Mayo Clinic, Division of Population Science, Fox Chase Cancer Center, Institut Curie [Paris], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), CHU Grenoble, CHI Poissy-Saint-Germain, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: 0301 basic medicine, Percentile, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [DISEASES], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], SUSCEPTIBILITY ALLELES, Diàtesi, FAMILIES, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], MESH: BRCA2 Protein, Breast cancer, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Other subheadings::/diagnosis [Other subheadings], Medicine and Health Sciences, Medicine, Mama - Càncer - Diagnòstic, Family history, skin and connective tissue diseases, Genetics (clinical), MESH: Heterozygote, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Factors de risc en les malalties, BRCA1 Protein, Hazard ratio, MESH: Genetic Predisposition to Disease, 1184 Genetics, developmental biology, physiology, article, OVARIAN, BRCA2 Protein/genetics, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, 030220 oncology & carcinogenesis, Female, Malalties congènites, Adult, Heterozygote, medicine.medical_specialty, MESH: Mutation, Risk factors in diseases, Otros calificadores::/diagnóstico [Otros calificadores], Breast Neoplasms, Context (language use), MUTATION CARRIERS, Càncer de mama, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::susceptibilidad a enfermedades::predisposición genética a la enfermedad [ENFERMEDADES], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Humans, Genetic Predisposition to Disease, MESH: BRCA1 Protein, Retrospective Studies, BRCA2 Protein, MESH: Humans, business.industry, Proportional hazards model, CONSORTIUM, Breast Neoplasms/diagnosis, MESH: Adult, MESH: Retrospective Studies, Retrospective cohort study, medicine.disease, Confidence interval, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, business, MESH: Female, MESH: Breast Neoplasms
Abstract: Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC
Published: 2021

35. Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia

Author: Christelle Le Dantec, Cristina Adela Iuga, Ioana-Ecaterina Pralea, Melanie Cornen, Wesley H. Brooks, Jacques-Olivier Pers, Hussam Saad, Tiffany Bergot, Adrian Tempescul, Anne Bordron, Delphine G. Bernard, Jean-Christophe Ianotto, Cristina Bagacean, Mihnea Zdrenghea, Christian Berthou, Yves Renaudineau, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Technical University of Cluj-Napoca, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), University of South Florida [Tampa] (USF), Iuliu Hatieganu University of Medicine & Pharmacy, The authors express thanks to the 'Ligue contre le cancer,' 'Region Bretagne,' sections 29/35/49 for partially funding this study, and Touzanné, Gisèle
Subjects: Male, MESH: Leukemia, Lymphocytic, Chronic, B-Cell / genetics, Proteome, [SDV]Life Sciences [q-bio], Chronic lymphocytic leukemia, Disease, Stable Disease, hemic and lymphatic diseases, Immunology and Allergy, Longitudinal Studies, RNA-Seq, liquid chromatography-tandem mass spectrometry, MESH: Leukemia, Lymphocytic, Chronic, B-Cell / pathology, MESH: Longitudinal Studies, Wnt Signaling Pathway, B-Lymphocytes, MESH: Middle Aged, Wnt signaling pathway, MESH: Follow-Up Studies, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, Cell cycle, Prognosis, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], MESH: B-Lymphocytes / metabolism, RNA splicing, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, cell cycle, [SDV.IMM] Life Sciences [q-bio]/Immunology, RNA Splicing, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, splicing, Biology, MESH: Prognosis, MESH: Leukemia, Lymphocytic, Chronic, B-Cell / metabolism, MESH: Biomarkers, Tumor / genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, Aged, Retrospective Studies, Proteomic Profile, Proteomic Profiling, Cell Biology, MESH: B-Lymphocytes / pathology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, MESH: Male, Cancer research, chronic lymphocytic leukemia, MESH: Female, Follow-Up Studies
Abstract: Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells’ proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography–tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.
Published: 2021

36. Serum glial fibrillary acidic protein is a predictor of brain metastases in patients with metastatic breast cancer

Author: Caroline Mollevi, Nelly Ginestet, Amélie Darlix, William Jacot, Christophe Hirtz, Laurent Tiers, Sylvain Lehmann, Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: MESH: Combined Modality Therapy, Cancer Research, glial fibrillary astrocytic protein, Gastroenterology, brain metastases, MESH: Glial Fibrillary Acidic Protein, Univariate analysis, MESH: Middle Aged, Glial fibrillary acidic protein, biology, Brain Neoplasms, Area under the curve, UCHL1 protein, MESH: Follow-Up Studies, Middle Aged, Prognosis, Combined Modality Therapy, Metastatic breast cancer, Survival Rate, neurofilament light chain, Oncology, MESH: Brain Neoplasms, Biomarker (medicine), Female, MESH: Biomarkers, Tumor, Adult, medicine.medical_specialty, MESH: Survival Rate, Tau protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, tau protein, MESH: Prognosis, breast cancer, Breast cancer, Internal medicine, Glial Fibrillary Acidic Protein, Biomarkers, Tumor, medicine, Humans, Retrospective Studies, MESH: Humans, Receiver operating characteristic, business.industry, MESH: Adult, MESH: Retrospective Studies, MESH: ROC Curve, medicine.disease, ROC Curve, biology.protein, business, MESH: Female, MESH: Breast Neoplasms, Follow-Up Studies
Abstract: International audience; In patients with metastatic breast cancer (MBC), brain metastases (BM) are associated with high morbidity and mortality. However, there is no validated serum biomarker that accurately predicts BM occurrence in these patients, and the role of serum biomarkers for prognosis remains unclear. Here, we evaluated the association of neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP) and tau serum levels with BM presence and prognosis in patients with MBC. In serum samples from patients with MBC with (n = 100) and without BM (n = 47), we measured the biomarker serum levels using single molecule array (Simoa) technology (Neurology-4-Plex assay). To evaluate their accuracy to identify patients with BM, we determined the receiver operating characteristic curve and the area under the curve (AUC) for each biomarker and calculated their sensitivity and specificity. The median serum levels of NfL, UCHL1, tau and GFAP were significantly higher in patients with BM. The AUC for GFAP (0.82, 95% confidence interval [CI] 0.75-0.88) was significantly higher than those of the other biomarkers considered independently. Using the medians as cutoff values, elevated serum levels of NfL, UCHL1, tau and GFAP were associated with BM in univariate analysis, but only high GFAP levels in multivariate analysis (odd ratio 23.4, 95% CI 6.8-80.5, P
Published: 2021

37. Factors associated with remission at 5-year follow-up in recent-onset axial spondyloarthritis: results from the DESIR cohort

Author: Philippe Le Corvoisier, Salah Ferkal, Daniel Wendling, Philippe Goupille, Bijan Ghaleh, Emilie Sbidian, Laura Pina Vegas, Pascal Claudepierre, Alain Luciani, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de rhumatologie [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, EPI-PHARE (EPI-PHARE), Caisse nationale d'assurance maladie des travailleurs salariés [CNAMTS]-Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Epigénétique des infections virales et des maladies inflammatoires (UR 4266) (EPILAB), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Plateforme de Ressources Biologiques [Henri Mondor AP-HP, Créteil] (PRB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), CHI Créteil, IMRB - PROTECT/'Pharmacologie et Technologies pour les Maladies Cardiovasculaires' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and VO, alexandra
Subjects: Male, medicine.medical_specialty, MESH: Spondylarthritis, Logistic regression, Severity of Illness Index, remission, Rheumatology, MESH: Severity of Illness Index, Internal medicine, Spondylarthritis, medicine, Humans, Spondylitis, Ankylosing, Pharmacology (medical), Mass index, prognostic factor, Recent onset, BASDAI, MESH: Treatment Outcome, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Ankylosing spondylitis, MESH: Humans, business.industry, cohort, MESH: Axial Spondyloarthritis, MESH: Follow-Up Studies, Odds ratio, spondyloarthritis, MESH: Spondylitis, Ankylosing, medicine.disease, MESH: Male, Confidence interval, Treatment Outcome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cohort, MESH: Tumor Necrosis Factor Inhibitors, Female, Tumor Necrosis Factor Inhibitors, business, MESH: Female, Axial Spondyloarthritis, Follow-Up Studies
Abstract: Objective The factors contributing to long-term remission in axial SpA (axSpA) are unclear. We aimed to characterize individuals with axSpA at the 5-year follow-up to identify baseline factors associated with remission. Methods We included all patients from the DESIR cohort (with recent-onset axSpA) with an available Ankylosing Spondylitis Disease Activity Score–CRP (ASDAS-CRP) at 5-year follow-up. Patients in remission (ASDAS-CRP Results Overall, 111/449 patients (25%) were in remission after 5 years. Among those never exposed to TNFi, 31% (77/247) were in remission compared with 17% (34/202) of those exposed to TNFi. Patients in remission after 5 years were more likely to be male, HLA-B27+, have a lower BMI, and a higher education level. Baseline factors associated with 5-year remission in patients never exposed to TNFi included lower BASDAI [adjusted odds ratio (ORa) 0.9, 95% CI: 0.8, 0.9) and history of peripheral arthritis (ORa 2.1, 95% CI: 1.2, 5.3). In those exposed to TNFi, remission was associated with higher education level (ORa 2.9, 95% CI: 1.6, 5.1), lower enthesitis index (ORa 0.8, 95% CI: 0.7, 0.9), lower BASDAI (ORa 0.9, 95% CI: 0.9, 0.9) and lower BMI (ORa 0.8, 95% CI: 0.7, 0.9). Conclusion This study highlights the difficulty in achieving 5-year remission in those with recent-onset axSpA, especially for the more active cases, despite the use of TNFi. Socio-economic factors and BMI are implicated in the outcome at 5 years.
Published: 2021

38. Evolution of the prevalence of obesity in the adult population in France, 2013–2016: the Constances study

Author: Sébastien, Czernichow, Adeline, Renuy, Claire, Rives-Lange, Claire, Carette, Guillaume, Airagnes, Emmanuel, Wiernik, Anna, Ozguler, Sofiane, Kab, Marcel, Goldberg, Marie, Zins, Joane, Matta, Demarquay, Sandrine, 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), Université Paris Cité (UPCité), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and the Constances cohort is supported by the National Health Insurance Fund ('Caisse nationale d'assurance maladie des travailleurs salariés', CNAMTS), the ministry of health, the ministry of research and the Nationale Institute for Health and Medical research. The Constances Cohort benefits from a grant from ANR (ANR-11-INBS-0002). Constances is also partly funded by MSD, AstraZeneca, Lundbeck and l'Oréal handled by INSERM.
Subjects: Adult, Male, MESH: Smoking, Adolescent, [SDV]Life Sciences [q-bio], Science, MESH: Logistic Models, Article, MESH: Multivariate Analysis, Body Mass Index, MESH: Body Mass Index, Young Adult, MESH: Health Surveys, Odds Ratio, Prevalence, Humans, MESH: Obesity, Nutrition disorders, Obesity, Exercise, MESH: Prevalence, Aged, MESH: Adolescent, MESH: Aged, MESH: Humans, MESH: Middle Aged, Smoking, MESH: Adult, Middle Aged, MESH: Income, Health Surveys, MESH: Male, MESH: Odds Ratio, [SDV] Life Sciences [q-bio], MESH: France, Logistic Models, MESH: Young Adult, MESH: Exercise, Multivariate Analysis, Income, Educational Status, Medicine, Female, France, MESH: Educational Status, MESH: Female
Abstract: International audience; Abstract This study provides trends in obesity prevalence in adults from 2013 to 2016 in France. 63,582 men and women from independent samples upon inclusion from the Constances cohort were included. Anthropometrics were measured at Health Screening Centers and obesity defined as a Body mass index (BMI) ≥ 30 kg/m 2 ; obesity classes according to BMI are as follows: class 1 [30–34.9]; class 2 [35–39.9]; class 3 [≥ 40 kg/m 2 ]. Linear trends across obesity classes by sex and age groups were examined in regression models and percentage point change from 2013 to 2016 for each age category calculated. All analyses accounted for sample weights for non-response, age and sex-calibrated to the French population. Prevalence of obesity ranged from 14.2 to 15.2% and from 14 to 15.3% in women and men respectively from 2013 to 2016. Class 1 obesity category prevalence was the only one to increase significantly across survey years in both men and women ( p for linear trend = 0.04 and 0.01 in women and men respectively). The only significant increase for obesity was observed in the age group 18–29 y in both women and men (+ 2.71% and + 3.26% point increase respectively, equivalent to an approximate rise of 50% in women and 93% in men, p = 0.03 and 0.02 respectively). After adjustment for survey non-response and for age and sex distribution, the results show that class 1 obesity prevalence has significantly increased in both women and men from 2013 to 2016, and only in young adults in a representative sample of the French population aged 18–69 years old.
Published: 2021

39. Security and reliability of CUSTOMBONE cranioplasties: A prospective multicentric study

Author: Amelot, A., Nataloni, A., François, P., Cook, A.-R., Lejeune, J.-P., Baroncini, M., Hénaux, P.-L., Toussaint, P., Peltier, J., Buffenoir, K., Hamel, O., Hieu, P Dam, Chibbaro, S., Kehrli, P., Lahlou, M.A., Menei, P., Lonjon, M., Mottolese, C., Peruzzi, P., Mahla, K., Scarvada, D., Le Guerinel, C, Caillaud, P., Nuti, C., Pommier, B., Faillot, T., Iakovlev, G., Goutagny, Stéphane, Lonjon, N., Cornu, P., Bousquet, P., Sabatier, P., Debono, B., Lescure, J.-P., Vicaut, E., Froelich, S., Hieu, P. Dam, Le Guerinel, C., Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Jean Le Rond d'Alembert (DALEMBERT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Agroscope, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Neurochirurgie [Hôpital Pasteur de Nice], Hôpital Pasteur [Nice] (CHU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de neurochirurgie [CHU Clichy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)
Subjects: Male, medicine.medical_treatment, MESH: Autografts, MESH: Plastic Surgery Procedures, Prosthesis, 0302 clinical medicine, Prospective Studies, CUSTOMBONE, Stage (cooking), Autografts, Explantation, MESH: Middle Aged, MESH: Follow-Up Studies, Prostheses and Implants, Middle Aged, Cranioplasty, MESH: Reproducibility of Results, 030220 oncology & carcinogenesis, Bone consolidation, MESH: Skull, Female, Infection, Craniotomy, Adult, medicine.medical_specialty, MESH: Prostheses and Implants, MESH: Craniotomy, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, MESH: Prosthesis Implantation, Prosthesis Implantation, 03 medical and health sciences, medicine, Humans, MESH: Humans, business.industry, Skull, Reproducibility of Results, MESH: Adult, Mean age, Plastic Surgery Procedures, Surgical procedures, Bone defect, MESH: Male, MESH: Prospective Studies, Surgery, Durapatite, Multicenter study, Neurology (clinical), Reconstruction, MESH: Durapatite, business, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis.To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years.Mean age of patients included in the study was 42±15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection.Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (1 year). Thus assiduous, regular and long-term surveillances are necessary.
Published: 2021

40. Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy

Author: Devauchelle-Pensec, Valérie, Carvajal-Alegria, Guillermo, Dernis, Emmanuelle, Richez, Christophe, Truchetet, Marie-Elise, Wendling, Daniel, Toussirot, Eric, Perdriger, Aleth, Gottenberg, Jacques-Eric, Felten, Renaud, Fautrel, Bruno Jean, Chiche, Laurent, Hilliquin, Pascal, Le Henaff, Catherine, Dervieux, Benjamin, Direz, Guillaume, Chary-Valckenaere, Isabelle, Cornec, Divi, Guellec, Dewi, Marhadour, Thierry, Nowak, Emmanuel, Saraux, Alain, Inserm UMR 1227 Immunothérapies et Pathologies Lymphocytaires B, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Pontchaillou [Rennes], Université de Rennes (UR), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, and The funders of this study were the French National Program for Clinical Research and the study sponsor (ie, the Brest University Hospital). Roche-Chugai Pharmaceutical provided an unconditional grant for the study and donated the tocilizumab used for the study.
Subjects: MESH: Aged, MESH: Humans, MESH: Administration, Intravenous, [SDV]Life Sciences [q-bio], MESH: Giant Cell Arteritis, MESH: Interleukin-6, MESH: Male, MESH: Drug Tapering, MESH: Polymyalgia Rheumatica, MESH: Antibodies, Monoclonal, Humanized, MESH: Anti-Inflammatory Agents, MESH: Administration, Oral, MESH: C-Reactive Protein, MESH: Double-Blind Method, MESH: Glucocorticoids, MESH: Prednisone, MESH: Female
Abstract: International audience; Importance: Few treatments are available for patients with glucocorticoid-dependent polymyalgia rheumatica. IL-6 antagonists may reduce disease activity in patients with active glucocorticoid-dependent polymyalgia rheumatica.Objective: To compare the efficacy of tocilizumab vs placebo in patients with glucocorticoid-dependent polymyalgia rheumatica.Design, setting, and participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial enrolled 101 patients with polymyalgia rheumatica at 17 hospitals in France from February 2017 to October 2019. Final follow-up occurred in November 2020. Inclusion criteria were persistent disease activity (polymyalgia rheumatica activity score computed using the C-reactive protein level [CRP PMR-AS] >10) and prednisone dose greater than or equal to 10 mg per day.Interventions: Patients were randomly assigned to receive intravenous tocilizumab (8 mg/kg; n = 51) or placebo (n = 50) every 4 weeks for 24 weeks, combined with predefined standardized tapering of oral prednisone.Main outcomes and measures: The primary efficacy end point was CRP PMR-AS less than 10 (range, 0-100; higher values indicate greater activity; no minimal clinically important difference defined) combined with either prednisone dose less than or equal to 5 mg per day or a decrease in prednisone dose greater than or equal to 10 mg from baseline at week 24. There were 11 secondary outcomes assessed at week 24 included in this report, including disease activity (measured by CRP PMR-AS) and the proportion of patients no longer taking prednisone.Results: Of the 101 randomized patients (mean age, 67.2 years; 68 [67.3%] women), 100 (99%) received at least 1 infusion and 100 completed the trial. The primary end point was achieved in 67.3% of patients in the tocilizumab group and 31.4% of patients in the placebo group (adjusted difference, 36.0% [95% CI, 19.4%-52.6%]; adjusted relative risk, 2.3 [95% CI, 1.5-3.6]; P < .001). Of 11 reported secondary end points at 24 weeks, 7 showed significant differences favoring tocilizumab, including mean CRP PMR-AS score (7.5 [95% CI, 5.4-9.6] vs 14.9 [95% CI, 11.4-18.4]; adjusted difference, -7.5 [95% CI, -11.2 to -3.8]; P < .001) and the percentage of patients no longer receiving prednisone (49.0% vs 19.6%; adjusted difference, 29.3% [95% CI, 18.9%-39.7%]; adjusted relative risk, 2.5 [95% CI, 1.8-3.5]; P < .001). The most frequent adverse events were infections, experienced by 23 patients (46.9%) in the tocilizumab group and 20 (39.2%) in the placebo group.Conclusions and relevance: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms.
Published: 2022

41. Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

Author: Nicolas Penel, Sylvie Bonvalot, André-Michel Bimbai, Alexandra Meurgey, François Le Loarer, Sébastien Salas, Sophie Piperno-Neumann, Christine Chevreau, Pascaline Boudou-Rouquette, Pascale Dubray-Longeras, Jean-Emmanuel Kurtz, Cécile Guillemet, Emmanuelle Bompas, Antoine Italiano, Axel Le Cesne, Daniel Orbach, Julien Thery, Marie-Cécile Le Deley, Jean-Yves Blay, Olivier Mir, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut Curie [Paris], Université de Bordeaux (UB), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Claudius Regaud, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Laboratory of Solid Tumors Genetics, Nice University Hospital, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 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 Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre d'Etudes Médiévales de Montpellier (CEMM), Université Paul-Valéry - Montpellier 3 (UPVM), Centre de recherche en épidémiologie et santé des populations (CESP), 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), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: Cancer Research, MESH: Humans, Oncology, MESH: beta Catenin, MESH: Fibromatosis, Aggressive, MESH: Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Female, MESH: Cohort Studies, MESH: Neoplasm Recurrence, Local, MESH: Male, MESH: Prognosis, MESH: Prospective Studies
Abstract: Purpose: This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations. Experimental Design: ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy. Results: Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71). Conclusions: We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS. See related commentary by Greene and Van Tine, p. 3911
Published: 2022

42. Fear of stigma from health professionals and family/neighbours and healthcare avoidance among PLHIV in Morocco: results from the Stigma Index survey Morocco

Author: Rosemary M, Delabre, Amal Ben, Moussa, Virginie, Villes, Mohammed, Elkhammas, Lahoucine, Ouarsas, Daniela, Castro Rojas Castro, Mehdi, Karkouri, Coalition PLUS [Pantin, France] (Community Research Laboratory Pantin), Association de Lutte Contre le SIDA [Marrakech, Morocco], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut des sciences de la santé publique [Marseille] (ISSPAM)
Subjects: Male, Health Personnel, [SDV]Life Sciences [q-bio], Social Stigma, MESH: Delivery of Health Care, MESH: Fear, HIV Infections, Surveys and Questionnaires, Humans, MESH: Surveys and Questionnaires, Key Populations, MESH: Humans, Public Health, Environmental and Occupational Health, HIV, Fear, Healthcare access, MESH: HIV Infections, MESH: Male, Morocco, Stigma, MESH: Morocco, MESH: Health Personnel, Female, MESH: Social Stigma, Delivery of Health Care, MESH: Female
Abstract: Background Enacted or anticipated stigma among people living with HIV (PLHIV) can negatively impact healthcare engagement. We identified factors associated with having avoided HIV health services for fear of stigma among PLHIV in Morocco. Methods The Stigma Index survey was conducted in Morocco in March-June 2016. Factors associated with avoiding HIV testing and treatment services for fear of stigma by (A) health personnel or family/neighbours and (B) health personnel and family/neighbours compared to people who did not avoid health services for fear of stigma from either of the two sources were assessed using multinomial logistic regression models. Results Among 583 respondents, 280 (48.0%) were women and median number of years living with HIV was 5[IQR:2–7]. Half of the respondents reported avoiding health services for fear of stigma by health personnel and/or family/neighbours: (A) n = 228, 39.1% and (B) n = 68, 11.7%. After adjustment on perceived health status, not having had easy access to antiretroviral treatment ((A) aRR [95% CI] = 1.76[1.16; 2.68]; (B) 2.18[1.11; 4.27]), discrimination by PLHIV ((A) 1.87[1.12; 3.13]; (B) 3.35[1.63; 6.88]) and exclusion from social activities ((A) 1.70[1.10; 2.61]; (B) 2.63[1.39; 5.00]) were associated with having avoided health services for fear of stigma by health personnel or/and family/neighbours. Being female (2.85[1.48; 5.47]), not having been referred for an HIV test for suspected symptoms 3.47[1.67; 7.22], having discussed sexual/reproductive health with a health professional (4.56[2.38; 8.71]), and not having the feeling to influence decisions on local projects for PLHIV (3.47[1.37; 7.83], were associated with having avoided health services for fear of stigma by both sources. Conclusion Results suggest a cumulative effect of fear of stigma and discrimination among PLHIV in Morocco. PLHIV who have experienced discrimination may seek to avoid similar situations at the expense of their health. These results should inform multi-level interventions and broader advocacy efforts to reduce stigma and discrimination.
Published: 2022

43. Trends in the relation between hyperglycemia correction and active Charcot neuroarthropathy: results from the EPICHAR study

Author: Dured Dardari, Sophie Schuldiner, Carole-Anne Julien, Georges Ha Van, Jocelyne M’Bemba, Muriel Bourgeon, Ariane Sultan, Marc Lepeut, Sylvie Grandperret-Vauthier, Florence Baudoux, Maud François, Sylvaine Clavel, Jacques Martini, Julien Vouillarmet, Paul Michon, Myriam Moret, Arnaud Monnier, Vaneva Chingan-Martino, Vincent Rigalleau, Isabelle Dumont, Laurence Kessler, Ionela Stifii, Benjamin Bouillet, Pierre Bonnin, Amal Lemoine, Enrique Da Costa Correia, Marie Martine Bonello Faraill, Marie Muller, Marie Cazaubiel, Mohammed Zakarya Zemmache, Agnes Hartemann, Laboratoire de Biologie de l'Exercice pour la Performance et la Santé (LBEPS), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre Hospitalier Sud Francilien, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Roubaix, Service de Génétique Biologique, Histologie Biologie du Développement et de la reproduction, Centre Hospitalier Régional universitaire Jean Minjoz (Service de Génétique Biologique, Histologie Biologie du Développement et de la reproduction, Centre Hospitalier Régional universitaire Jean Minjoz), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Hôtel-Dieu [Paris], Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Louis Pradel [CHU - HCL], CHU Pointe-à-Pitre/Abymes [Guadeloupe], 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Hôpital Lucien Hussel Vienne [Vienne, France] (HLHV), Centre Hospitalier de Vichy (CH Vichy), Hôpital Archet 2 [Nice] (CHU), Hôpital Michallon, Centre Hospitalier de Tourcoing, and BESPIM
Subjects: Male, HbA1c, MESH: Glycated Hemoglobin, Endocrinology, Diabetes and Metabolism, MESH: Diabetic Neuropathies / epidemiology, Cohort Studies, Diabetic Neuropathies, Diabetes complications, Diagnosis, MESH: Diabetes Mellitus, Type 2 / complications, Humans, Aged, MESH: Hyperglycemia / complications, Glycated Hemoglobin, MESH: Aged, MESH: Humans, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Male, MESH: Middle aged, Diabetes Mellitus, Type 2, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Hyperglycemia, MESH: Cohort studies, Neuroarthropathy, Female, MESH: Female, MESH: Diabetic Neuropathies / etiology
Abstract: IntroductionThe pathophysiology of Charcot neuroarthropathy (CN) remains unclear. There are a number of hypotheses but these are not exclusive. In its clinical presentation, this complication intersects with the semiology of diabetic-induced neuropathy, such as peripheral hypervascularization and the appearance of arteriovenous shunt. The EPICHAR study is as yet an unpublished cohort of people living with diabetes complicated by CN (in active or chronic phase). Based on the findings of the EPICHAR study, this study aimed to investigate whether a reduction in the rate of hyperglycemia accompanies the onset of an active phase of CN.Research design and methodsHemoglobin A1c (HbA1c) levels were assessed 3 months (M3) and 6 months (M6) before the diagnosis of active CN (M0).Results103 patients living with diabetes and presenting active CN were included between January and December 2019 from the 31 centers participating in this study (30 in France and 1 in Belgium). The mean age of the participants was 60.2±12.2 years; the vast majority were men (71.8%) living with type 2 diabetes (75.5%). Mean HbA1c levels significantly declined between M6 (median 7.70; Q1, Q3: 7.00, 8.55) and M3 (median 7.65; Q1, Q3: 6.90, 8.50) (p=0.012), as well as between M6 and M0 (median 7.40; Q1, Q3: 6.50, 8.50) (p=0.014). No significant difference was found between M3 and M0 (p=0.072).ConclusionsA significant reduction in HbA1c levels seems to accompany the onset of the active phase of CN.Trial registration numberNCM03744039.
Published: 2022

44. What can lead to late diagnosis of HIV in an illegal gold mining environment? A qualitative study at the French Guiana’s border with Brazil

Author: Floersheim, Charlotte, Musso, Sandrine, Eubanks, August, Douine, Maylis, Spire, Bruno, Sagaon-Teyssier, Luis, Parriault, Marie, Girard, Gabriel, Mosnier, Emilie, Département des Centres Délocalisés de Prévention et de Soins [Cayenne, Guyane Française], Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre population et développement (CEPED - UMR_D 196), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre Norbert Elias (CNELIAS), École des hautes études en sciences sociales (EHESS)-Avignon Université (AU)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], and Service des maladies infectieuses et tropicales [Cayenne, Guyane Française]
Subjects: MESH: Aged, Public health, MESH: Humans, MESH: Middle Aged, Epidemiology, [SDV]Life Sciences [q-bio], HIV & AIDS, MESH: Adult, MESH: HIV Infections, MESH: Mining, MESH: Male, MESH: Delayed Diagnosis, MESH: French Guiana, MESH: Gold, MESH: Brazil, MESH: Female
Abstract: International audience; Objective The present study aimed to understand what factors can lead to late HIV diagnosis of illegal gold miners at French Guiana's border with Brazil. Design An exploratory qualitative study with in-depth interviews and observations was conducted between November 2019 and February 2020. Setting The study was conducted in the main medical healthcare service and two non-governmental organisation premises in the Oyapock border region, which is a supply area for illegal gold mining sites. Participants Fifteen people living with HIV diagnosed with CD4 count
Published: 2022

45. Long-Term Functional Outcomes of an Anorectal Malformation French National Cohort

Author: Françoise Schmitt, Aurélien Scalabre, Pierre Yves Mure, Claude Borrione, Jean Louis Lemelle, Dyuti Sharma, Stéphan De Napoli, Sabine Irtan, Guillaume Levard, François Becmeur, Philippe Buisson, Laurent Fourcade, Alexis Arnaud, Philine De Vries, Sophie Branchereau, Cynthia Garignon, Frédérique Sauvat, Nicolas Kalfa, Hubert Lardy, Sandy Jochault-Ritz, Emmanuel Sapin, Hélène Coridon, Marc Margaryan, Myriam Pouzac, Luana Carfagna, Marie Laurence Polimerol, François Varlet, Sabine Sarnacki, Célia Cretolle, Guillaume Podevin, Groupe d'Electromagnétisme Appliqué (GEA), Université Paris Nanterre (UPN), ISA NMR Methods for Metabolism - Methodes RMN en métabolomique (2014-2018), Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de chirurgie pédiatrique [CHU Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Amiens-Picardie, Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Service de chirurgie pédiatrique [Rennes] = Paediatric / Pediatric surgery [Rennes], CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département de chirurgie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre Hospitalier de St Brieuc, Partenaires INRAE, CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), National Reference Network DSD DevGen, Département Chirurgie Pédiatrique [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de recherche Nutrition et Sécurité Alimentaire (LNSA), and Institut National de la Recherche Agronomique (INRA)
Subjects: Adult, Male, Adolescent, Anal Canal, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Young Adult, MESH: Cross-Sectional Studies, MESH: Rectum, MESH: Defecation, MESH: Child, Humans, MESH: Anorectal Malformations, Child, Defecation, Retrospective Studies, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, MESH: Anal Canal, Gastroenterology, Rectum, MESH: Adult, MESH: Retrospective Studies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Male, Anorectal Malformations, Cross-Sectional Studies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, [SHS.ENVIR]Humanities and Social Sciences/Environmental studies, Pediatrics, Perinatology and Child Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, MESH: Constipation, MESH: Female, Constipation
Abstract: The present study aimed to assess long-term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France.Retrospective cross-sectional study of patients ages 6-30 years that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups.Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR] = 1.84 [1.31-2.57], P 0.001), or soiling (OR = 1.72 [1.31-2.25], P 0.001), which was also associated with the inability to discriminate between stool and gas (OR = 2.45 [1.28-4.67], P = 0.007) and the presence of constipation (OR = 2.97 [1.74-5.08], P 0.001). Risk factors for constipation were sacral abnormalities [OR = 2.26 [1.23-4.25], P = 0.01) and surgical procedures without an abdominal approach (OR = 2.98 [1.29-6.87], P = 0.01). Only the holding of voluntary bowel movements and soiling rates improved with age.This cross-sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long-term follow-up of all patients to help them with supportive care.
Published: 2022

46. A long noncoding RNA influences the choice of the X chromosome to be inactivated

Author: Andreas Hierholzer, Corinne Chureau, Alessandra Liverziani, Nerea Blanes Ruiz, Bruce M. Cattanach, Alexander N. Young, Manish Kumar, Andrea Cerase, Phil Avner, European Molecular Biology Laboratory [Rome] (EMBL), Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrates Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Queen Mary University of London (QMUL), and MRC Harwell Institute [UK]
Subjects: X Chromosome, [SDV]Life Sciences [q-bio], female mouse embryo, noncoding RNA, MESH: Mammals, Mice, pluripotency factors, Genetic, X Chromosome Inactivation, Dosage Compensation, Genetic, Animals, MESH: Animals, MESH: Mice, Alleles, Mammals, MESH: X Chromosome Inactivation, Multidisciplinary, MESH: Alleles, MESH: Dosage Compensation, Genetic, MESH: RNA, Long Noncoding, X chromosome inactivation, X-controlling element, Female, RNA, Long Noncoding, Dosage Compensation, RNA, Long Noncoding, MESH: Female
Abstract: X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element ( Xce ). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA , one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist . This effect is counteracted by enhanced binding of Rex1 in DxPas34 , another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34 , and that Lppnx represents a decisive factor in explaining the action of the Xce .
Published: 2022

47. Acceptance, efficacy, and safety of COVID-19 vaccination in older patients with cancer

Author: Anne-Laure Couderc, Laetitia Ninove, Emilie Nouguerède, Dominique Rey, Marina Rebroin, Aurélie Daumas, Pascale Tomasini, Laurent Greillier, Sebastien Salas, Florence Duffaud, Laetitia Dahan, Muriel Duluc, Marie-Eve Garcia, Johan Pluvy, Solène Chaléat, Laure Farnault, Geoffroy Venton, Toscane Fourié, Elif Nurtop, Xavier de Lamballerie, Patrick Villani, Remi Charrel, Florian Correard, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), 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), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité de coordination en oncogériatrie (UCOG Paca ouest), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Marseille, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Male, COVID-19 Vaccines, Medical oncology, Second-line, Drug-related side effects and adverse reactions, MESH: Aged, 80 and over, Neoplasms, Humans, Lenvatinib, MESH: COVID-19, Thymic epithelial tumors, MESH: Neoplasms, MESH: BNT162 Vaccine, BNT162 Vaccine, Aged, Aged, 80 and over, MESH: Aged, Vaccines, MESH: Humans, Vaccination, COVID-19, MESH: Vaccination, Geriatric assessment, MESH: Male, MESH: Vaccines, Oncology, MESH: COVID-19 Vaccines, Female, Immunotherapy, Geriatrics and Gerontology, Pembrolizumab, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer.From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose.Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose.Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients.This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).
Published: 2022

48. Determining the Set of Items to Include in Breast Operative Reports, Using Clustering Algorithms on Retrospective Data Extracted from Clinical DataWarehouse

Author: Adrien Boukobza, Maxime Wack, Antoine Neuraz, Daniela Geromin, Cécile Badoual, Anne-Sophie Bats, Anita Burgun, Meriem Koual, Rosy Tsopra, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), 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), TSOPRA, Rosy, École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: MESH: Data Warehousing, MESH: Humans, [SDV]Life Sciences [q-bio], MESH: Algorithms, MESH: Retrospective Studies, Breast Neoplasms, [INFO] Computer Science [cs], NLP, MESH: Cluster Analysis, Clustering, [SDV] Life Sciences [q-bio], Breast cancer, Data Warehousing, Machine learning, Cluster Analysis, Humans, [INFO]Computer Science [cs], Female, MESH: Female, MESH: Breast Neoplasms, Algorithms, Retrospective Studies
Abstract: International audience; Medical reports are key elements to guarantee the quality, and continuity of care but their quality remains an issue. Standardization and structuration of reports can increase their quality, but are usually based on expert opinions. Here, we hypothesize that a structured model of medical reports could be learnt using machine learning on retrospective medical reports extracted from clinical data warehouses (CDW). To investigate our hypothesis, we extracted breast cancer operative reports from our CDW. Each document was preprocessed and split into sentences. Clustering was performed using TFIDF, Paraphrase or Universal Sentence Encoder along with K-Means, DBSCAN, or Hierarchical clustering. The best couple was TFIDF/K-Means, providing a sentence coverage of 89 % on our dataset; and allowing to identify 7 main categories of items to include in breast cancer operative reports. These results are encouraging for a document preset creation task and should then be validated and implemented in real life.
Published: 2022

49. Recurrence of an early postzygotic rescue of an inherited unbalanced translocation resulting in mosaic segmental uniparental isodisomy of chromosome 11q in siblings

Author: Alice Goldenberg, Gaël Nicolas, Maud Blanluet, Sandra Chantot-Bastaraud, Gabriella Vera, Boris Keren, Géraldine Joly-Helas, Thierry Frebourg, Didier Hannequin, Jean-Pierre Siffroi, Kévin Cassinari, Nathalie Le Meur, Bertrand Mace, Pascal Chambon, Couvet, Sandrine, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Service de Génétique médicale [CHU Pitié-Salpêtrière], and CHU Pitié-Salpêtrière [AP-HP]
Subjects: MESH: Abnormalities, Multiple, MESH: Chromosome Deletion, [SDV]Life Sciences [q-bio], MESH: Chromosomes, Human, Pair 2, Chromosomal translocation, Chromosomal rearrangement, postzygotic, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Cervical Vertebrae, Germline, MESH: Intellectual Disability, MESH: Uniparental Disomy, Gene duplication, Genetics, medicine, MESH: In Situ Hybridization, Fluorescence, Genetics (clinical), MESH: Humans, medicine.diagnostic_test, MESH: Genetic Predisposition to Disease, MESH: Scoliosis, Chromosome, Karyotype, MESH: Male, MESH: Translocation, Genetic, MESH: Siblings, [SDV] Life Sciences [q-bio], MESH: Karyotyping, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Uniparental Isodisomy, rescue, unbalanced translocation, MESH: Chromosome Banding, MESH: Chromosomes, mosaic, MESH: Mosaicism, MESH: Kyphosis, MESH: Chromosomes, Human, Pair 11, MESH: Female, Fluorescence in situ hybridization
Abstract: Balanced translocations are associated with a risk of transmission of unbalanced chromosomal rearrangements in the offspring. Such inherited chromosomal abnormalities are typically non-mosaic as they are present in the germline. We report the recurrence in two siblings of a mosaicism for a chromosomal rearrangement inherited from their asymptomatic father who carried a balanced t(2;11)(q35;q25) translocation. Both siblings exhibited a similar phenotype including intellectual disability, dysmorphic features, kyphoscoliosis, and cervical spinal stenosis. Karyotyping, fluorescence in situ hybridization and SNP array analysis of blood lymphocytes of both siblings identified two cell lines: one carrying a 2q35q37.3 duplication and a 11q25qter deletion (~90% cells), and one carrying an 11q uniparental isodisomy of maternal origin (~10% cells). We hypothesize that these mosaics were related to a postzygotic rescue mechanism which unexpectedly recurred in both siblings.
Published: 2021

50. Most randomized controlled trials for psoriasis used placebo comparators despite the availability of effective treatments

Author: Nadia Oubaya, Laurence Le Cleach, Emilie Sbidian, Theodoros Evrenoglou, Sivem Afach, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French Cochrane Centre, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and CCSD, Accord Elsevier
Subjects: medicine.medical_specialty, Epidemiology, education, MESH: Placebos, Placebo, Placebo group, law.invention, 03 medical and health sciences, MESH: Aged, 80 and over, 0302 clinical medicine, Randomized controlled trial, law, Psoriasis, Internal medicine, medicine, Clinical Trials, 030212 general & internal medicine, Ethics, MESH: Aged, MESH: Psoriasis, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Biomedical Research, MESH: Research Design, MESH: Guidelines as Topic, Linear Regression, MESH: Adult, medicine.disease, Therapeutic trial, MESH: Male, Clinical trial, Meta-analysis, MESH: Randomized Controlled Trials as Topic, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Anti-Inflammatory Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Background: The availability of effective treatments for psoriasis raises ethical questions about the use of a placebo group in therapeutic trials. We evaluated the use of the placebo over time in such trials.Methods: From trials in a living Cochrane review and network meta-analysis for psoriasis, we included trials comparing a biologic to a placebo or other systemic treatment. First, we tested the changes in placebo rate from 2001 to 2019 by linear regression, then constructed networks for 2004-2019 and evaluated the contribution of the placebo to the network meta-analysis estimates per trial and per comparison.Results: We included 81 trials (36,774 patients). The placebo rate did not decrease significantly over time. The proportion contribution of trials with a placebo decreased from 100% in 2004 to 86% in 2008 and 75% in 2019. However, the proportion contribution of trials without a placebo remained low (from 0% in 2004 to 25% in 2019).Conclusion: The design of future psoriasis trials should be reviewed to improve the number of patients to be included in a placebo group.
Published: 2021

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