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1. Risk of symptomatic venous thromboembolism in mild and moderate COVID-19: A comparison of two prospective European cohorts

Author: Jérémie Riou, Rafael Mahieu, Dominique Savary, Pierre-Marie Roy, Caroline Soulie, Delphine Douillet, Francois Morin, A Penaloza, Thomas Moumneh, UCL - SSS/IREC/EPID - Pôle d'épidémiologie et biostatistique, UCL - (SLuc) Service des urgences, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), F-CRIN, Innovative clinical research network in vaccinology (I-REIVAC), Université d'Angers (UA), Université Catholique de Louvain = Catholic University of Louvain (UCL), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Plate-forme de Recherche en Imagerie et Spectroscopie Multi-modales [SFR ICAT - UA] (PRISM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), French Clinical Research Infrastructure Network on Venous Thromboembolism (FCRIN INNOVTE), Chard-Hutchinson, Xavier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), Plate-forme de Recherche en Imagerie et Spectroscopie Multi-modales (PRISM [SFR ICAT - UA]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: medicine.medical_specialty, Deep vein, [SDV]Life Sciences [q-bio], VTE risk, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Full Length Article, medicine, Humans, Prospective Studies, cardiovascular diseases, Prospective cohort study, 030304 developmental biology, Aged, Retrospective Studies, 0303 health sciences, business.industry, SARS-CoV-2, Incidence (epidemiology), SARS-CoV-2 infection, COVID-19, Hematology, Emergency department, Venous Thromboembolism, medicine.disease, Thrombosis, 3. Good health, Pulmonary embolism, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cohort, Propensity score matching, business, Venous thromboembolism
Abstract: International audience; Background: Severely ill patients with SARS-CoV-2 have an increased risk of venous thromboembolism (VTE) i.e., deep vein thrombosis and pulmonary embolism. However, the VTE risk in patients with mild and moderate COVID-19, hospitalized or managed at home, remain uncertain. The aims of this study were to assess the rate and the risk factors symptomatic VTE, in patients with mild and moderate COVID-19 and to compare them to a cohort of similar patients without COVID-19. Methods: Patients presenting to the emergency department (ED) of participating centers for confirmed or probable mild or moderate COVID-19 and not having acute VTE were included. This COVID-19 cohort was retrospectively compared to a prospective cohort of similar ED patients using propensity score matching. The main outcome was the rate of symptomatic VTE within the 28 days after ED presentation. Results: A total of 2292 patients were included in the COVID-19 cohort. The 28-day incidence of symptomatic VTE was 1.3% (n = 29/2292, 95%CI: 0.9 to 1.8), 2.3% (n = 20/866, 95%CI: 1.5 to 3.5) in moderate COVID-19 patients and 0.6% (n = 9/1426; 95%CI: 0.3 to 1.2) in mild COVID-19 patients managed as outpatients. An age over 65 years and hospitalization were independent risk factors of VTE. After adjustment, patients in the COVID19 cohort had an absolute increase in over symptomatic VTE risk of +1.69% (95%CI, 0.88 to 2.51) versus patients in the comparison cohort (n = 1539). Conclusions: Patients with moderate COVID-19 presenting to the ED had a high risk of subsequent VTE. Trial registration: Ethics committee of the CHU of Angers (N degrees 2020/87).
Published: 2021
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2. Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility

Author: Mariam Rusidzé, Mélanie C. Faure, Pierre Sicard, Isabelle Raymond-Letron, Frank Giton, Emilie Vessieres, Vincent Prevot, Daniel Henrion, Jean-François Arnal, Charlotte A. Cornil, Françoise Lenfant, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), GIGA [Université Liège], Université de Liège, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), STROMALab, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, MORNET, Dominique, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), CHU Toulouse [Toulouse], and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Trophoblast cells, Estradiol, Placenta, [SDV]Life Sciences [q-bio], Estrogen Receptor alpha, Parturition, Trophoblasts, Oestrogen receptor ERα (ESR1), [SDV] Life Sciences [q-bio], Mice, Fertility, Membrane signalling, Receptors, Estrogen, Pregnancy, Spiral arterial remodelling, Animals, Humans, Female, Molecular Biology, Progesterone, Developmental Biology
Abstract: The binding of 17β-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.
Published: 2022
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3. Use of troponin assay after electrical injuries: a 15-year multicentre retrospective cohort in emergency departments

Author: Yara Amro, Quentin Le Bastard, Benjamin Gicquel, Idriss Arnaudet, Dominique Savary, Delphine Douillet, François Javaudin, Stéphanie Kalwant, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), 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 ), Microbiotes, Hôtes, Antibiotiques et Résistances bactériennes (MiHAR) (MiHAR), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes (UN), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), and Chard-Hutchinson, Xavier
Subjects: Adult, Cardiac arrhythmias, Chest Pain, medicine.medical_specialty, [SDV]Life Sciences [q-bio], MACE, 030204 cardiovascular system & hematology, Electric injuries, Critical Care and Intensive Care Medicine, Likelihood ratios in diagnostic testing, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, ST segment, Prospective Studies, 030212 general & internal medicine, Child, Retrospective Studies, Original Research, Predictive marker, biology, business.industry, RC86-88.9, Correction, Retrospective cohort study, Medical emergencies. Critical care. Intensive care. First aid, Emergency department, Emergency Department, Troponin, 3. Good health, [SDV] Life Sciences [q-bio], Emergency Medicine, biology.protein, Emergency Service, Hospital, business, Biomarkers, Mace
Abstract: Background Patients with electrical injury are considered to be at risk of cardiac arrhythmia. Assessing the risk of developing a major adverse cardiac event (MACE) is the cornerstone of patient management. The aim of this study was to assess the performance of initial troponin and troponin rise to predict Major Adverse Cardiac Events (MACEs) in all patients with electrical injuries admitted to the Emergency Department. Methods This is a multicentre retrospective study in which consecutive patients with electrical injuries admitted to the Emergency Departments (ED) (adult and paediatric) of five French Hospitals were included between 2005 and 2019. The threshold for troponin elevation is based on the European Society of Cardiology guidelines for patients presenting without persistent ST segment elevation. The primary endpoint was the rate of MACE. Results A total of 785 included patients were admitted to ED with a first diagnosis of electrical injury during the study period. Troponin assays were performed in 533 patients (67.9%), including 465 of 663 adults (70.1%) and 68 of 122 children (55.7%) and 17/533 (3.2%) of patients had an initial elevated troponin. If none of the clinical criteria for MACE were present (i.e., previous known heart disease, exposure to a high voltage of ≥ 1000 Volts, initial loss of consciousness, or an abnormal initial ECG), this defined a low-risk subgroup (n = 573, 76.0%) that could be safely discharged. The initial positive troponin assay had a sensitivity of 83.3 (95% CI 35.9–99.6%), a specificity of 97.7 (95% CI 96.1–98.8%), a positive likelihood ratio 36.6 (95% CI 18.8–71.1%) and a negative predictive value of 99.9 (95% CI 99.2–99.9%) in predicting a MACE. Conclusions Troponin assay appears to be a predictive marker of MACE risk and should be considered in high-risk patients.
Published: 2021
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4. Longitudinal changes in compliance, oxygenation and ventilatory ratio in COVID-19 versus non-COVID-19 pulmonary acute respiratory distress syndrome

Author: Ferhat Meziani, Julien Demiselle, Nicolas Fage, Antoine Studer, Sibylle Cunat, Jean-Christophe Richard, Alain Mercat, François Beloncle, Satar Mortaza, Hamid Merdji, Laurent Brochard, Bertrand Pavlovsky, Christophe Desprez, Julie Helms, Valérie Seegers, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Université de Strasbourg (UNISTRA), Integrated Center for Oncology [Angers] (ICO), 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), LUNAM Université [Nantes Angers Le Mans], Regenerative NanoMedicine [Strasbourg] (RNM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), St. Michael's Hospital, University of Toronto, RICHARD, Jean-Christophe, and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Male, ARDS, Letter, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], medicine.medical_treatment, Respiratory mechanics, Respiratory failure, Critical Care and Intensive Care Medicine, Severity of Illness Index, Body Mass Index, Positive-Pressure Respiration, 03 medical and health sciences, Dead space, 0302 clinical medicine, Mechanical ventilation, Medicine, Humans, 030212 general & internal medicine, Respiratory system, Propensity Score, Acute Respiratory Distress Syndrome, Aged, Respiratory Distress Syndrome, Pulmonary Gas Exchange, business.industry, SARS-CoV-2, RC86-88.9, Research, Medical emergencies. Critical care. Intensive care. First aid, Oxygenation, Middle Aged, medicine.disease, Respiration, Artificial, Respiratory Function Tests, [SDV] Life Sciences [q-bio], Compliance (physiology), Clinical trial, Intensive Care Units, 030228 respiratory system, Anesthesia, Female, Blood Gas Analysis, business, Covid-19, Body mass index
Abstract: Background Differences in physiology of ARDS have been described between COVID-19 and non-COVID-19 patients. This study aimed to compare initial values and longitudinal changes in respiratory system compliance (CRS), oxygenation parameters and ventilatory ratio (VR) in patients with COVID-19 and non-COVID-19 pulmonary ARDS matched on oxygenation. Methods 135 patients with COVID-19 ARDS from two centers were included in a physiological study; 767 non-COVID-19 ARDS from a clinical trial were used for the purpose of at least 1:2 matching. A propensity-matching was based on age, severity score, oxygenation, positive end-expiratory pressure (PEEP) and pulmonary cause of ARDS and allowed to include 112 COVID-19 and 198 non-COVID pulmonary ARDS. Results The two groups were similar on initial oxygenation. COVID-19 patients had a higher body mass index, higher CRS at day 1 (median [IQR], 35 [28–44] vs 32 [26–38] ml cmH2O−1, p = 0.037). At day 1, CRS was correlated with oxygenation only in non-COVID-19 patients; 61.6% and 68.2% of COVID-19 and non-COVID-19 pulmonary ARDS were still ventilated at day 7 (p = 0.241). Oxygenation became lower in COVID-19 than in non-COVID-19 patients at days 3 and 7, while CRS became similar. VR was lower at day 1 in COVID-19 than in non-COVID-19 patients but increased from day 1 to 7 only in COVID-19 patients. VR was higher at days 1, 3 and 7 in the COVID-19 patients ventilated using heat and moisture exchangers compared to heated humidifiers. After adjustment on PaO2/FiO2, PEEP and humidification device, CRS and VR were found not different between COVID-19 and non-COVID-19 patients at day 7. Day-28 mortality did not differ between COVID-19 and non-COVID-19 patients (25.9% and 23.7%, respectively, p = 0.666). Conclusions For a similar initial oxygenation, COVID-19 ARDS initially differs from classical ARDS by a higher CRS, dissociated from oxygenation. CRS become similar for patients remaining on mechanical ventilation during the first week of evolution, but oxygenation becomes lower in COVID-19 patients. Trial registration: clinicaltrials.gov NCT04385004
Published: 2021
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5. In vitro effects of the endocrine disruptor p,p′DDT on human choriogonadotropin/luteinizing hormone receptor signalling

Author: L. Gourdin, Patrice Rodien, Daniel Henrion, Mohammed Akli Ayoub, Mathilde Munier, Valentine Suteau, Eric Reiter, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), United Arab Emirates University (UAEU), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE)
Subjects: 0301 basic medicine, endocrine system, medicine.medical_specialty, Allosteric modulator, Endocrine disrupting chemical, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, 010501 environmental sciences, Toxicology, 01 natural sciences, DDT, 03 medical and health sciences, Internal medicine, parasitic diseases, medicine, Secretion, HCG/LHR signaling, reproductive and urinary physiology, 0105 earth and related environmental sciences, Chemistry, Chinese hamster ovary cell, luteinizing hormone/choriogonadotropin receptor, General Medicine, Progesterone secretion, In vitro, 3. Good health, 030104 developmental biology, Endocrinology, Steroidogenesis, Endocrine disruptor, Luteinizing hormone, hormones, hormone substitutes, and hormone antagonists
Abstract: International audience; Dichlorodiphenyltrichloroethane (p,p ' DDT) is an endocrine-disrupting chemical (EDC). Several studies showed an association between p,p ' DDT exposure and reprotoxic effects. We showed that p,p ' DDT was a positive allosteric modulator of human follitropin receptor (FSHR). In contrast, we demonstrated that p,p ' DDT decreased the cyclic AMP (cAMP) production induced by human choriogonadotropin (hCG). This study evaluated further the effects of p,p ' DDT on Gs-, beta-arrestin 2- and steroidogenesis pathways induced by hCG or luteinizing hormone (LH). We used Chinese hamster ovary cells line stably expressing hCG/LHR. The effects of 10-100 mu M p,p ' DDT on cAMP production and on beta-arrestin 2 recruitment were measured using bioluminescence and time-resolved resonance energy transfer technology. The impact of 100 mu M of p,p ' DDT on steroid secretion was analysed in murine Leydig tumor cell line (mLTC-1). In cAMP assays, 100 mu M p,p ' DDT increased the EC50 by more than 300% and reduced the maximum response of the hCG/LHR to hCG and hLH by 30%. This inhibitory effect was also found in human granulosa cells line and in mLTC-1 cells. Likewise, 100 mu M p,p ' DDT decreased the hCG- and hLH-promoted beta-arrestin 2 recruitment down to 14.2 and 26.6%, respectively. Moreover, 100 mu M p,p ' DDT decreased by 30 and 47% the progesterone secretion induced by hCG or hLH, respectively, without affecting testosterone secretion. This negative effect of p,p'DDT was independent of cytotoxicity. p,p ' DDT acted as a negative allosteric modulator of the hCG/LHR signalling. This emphasizes the importance of analyzing all receptor-downstream pathways to fully understand the deleterious effects of EDC on human health.
Published: 2021
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6. Sinusoidal changes in transcutaneous oxygen pressure, suggesting Cheyne-Stokes respiration, are frequent and of poor prognosis among patients with suspected critical limb ischemia

Author: Jean Picquet, Frédéric Gagnadoux, Wojciech Trzepizur, Jeanne Hersant, Pierre Abraham, Pierre Ramondou, Samir Henni, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Université d'Angers (UA), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, medicine.medical_specialty, Poor prognosis, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Cheyne–Stokes respiration, 03 medical and health sciences, 0302 clinical medicine, Ischemia, Internal medicine, Respiration, Risk of mortality, Humans, Medicine, Mortality, Transcutaneous oxygen pressure, education, Retrospective Studies, Leg, education.field_of_study, integumentary system, business.industry, Hazard ratio, Critical limb ischemia, Prognosis, Lower extremity artery disease, Cheyne-Stokes respiration, 3. Good health, Oxygen, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cardiology, Transcutaneous oxygen, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Blood Gas Monitoring, Transcutaneous
Abstract: International audience; Background and aims: Transcutaneous oxygen pressure (TcpO2) is used in patients with suspected critical limb ischemia (CLI). Sinusoidal changes (SC~) in TcpO2 are found in patients with Cheyne-Stokes respiration (CSR). We aimed to determine the characteristics of TcpO2 changes at rest in patients with suspected CLI, define the objective criteria for SC ~ TcpO2 patterns (SC+), and estimate the prevalence of SC+ in our population and its impact on the outcome.Methods: We retrospectively analyzed 300 chest TcpO2 recordings performed in a 16-month period. We determined the presence/absence of SC ~ TcpO2 by visual analysis. We determined the acceptable error in the regularity of peaks of the cross-correlation with ROC curve analysis, among patients with typical SC ~ TcpO2 and non-sinusoidal patterns. Then, we defined SC + as a minimum of five peaks, a standard deviation of TcpO2 >1.25 mmHg, an error in regularity of peaks of the cross-correlation < 10%, and a cycle length between 30 and 100 s. In patients included until October 2019, we compared the outcome as a function of SC + or SC- with Cox models.Results: Mathematical detection of SC + found that 43 patients (14.3%) fulfilled all four defined criteria at the chest level, but only 23 did so at the limb level. In the follow-up of 207 patients, the presence of Sc ~ TcpO2 at the chest significantly increased the risk of mortality: hazard ratio: 2.69 [95%CI: 1.37-5.30]; p < 0.005.Conclusions: SC ~ TcpO2 is frequent, and is associated with a poor outcome in patients with suspected CLI.
Published: 2021
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7. Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples

Author: Philippe Guardiola, Sarah Ghamrawi, Séverine Férec, Mathilde Hunault-Berger, Simon Souchet, Chadi Abbara, Guillaume Drevin, Marie Briet, Jean-Baptiste Robin, Aline Schmidt, Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Service de Génomique Onco-Hématologique [CHU Angers], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies du sang [CHU Angers], Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Bernardo, Elizabeth
Subjects: Male, 0301 basic medicine, Cancer Research, Time Factors, medicine.medical_treatment, Toxicology, Gastroenterology, 0302 clinical medicine, Drug Stability, AML, Tandem Mass Spectrometry, hemic and lymphatic diseases, Pharmacology (medical), Chromatography, High Pressure Liquid, Randomized Controlled Trials as Topic, Cytarabine, In vitro degradation, Area under the curve, Myeloid leukemia, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Oncology, Deamination, 030220 oncology & carcinogenesis, Female, Multiple linear regression analysis, Stability, Half-Life, medicine.drug, Adult, Antimetabolites, Antineoplastic, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Clinical pharmacokinetic, Specimen Handling, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cytidine Deaminase, Internal medicine, medicine, Humans, Clinical significance, Pharmacology, Chemotherapy, business.industry, 030104 developmental biology, Clinical Trials, Phase III as Topic, Case-Control Studies, business
Abstract: International audience; Purpose: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients.Methods: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach.Results: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship.Conclusion: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.
Published: 2020
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8. Guidelines: Anaesthesia in the context of COVID-19 pandemic

Author: Lionel Velly, Etienne Gayat, Hervé Quintard, Emmanuel Weiss, Audrey De Jong, Philippe Cuvillon, Gérard Audibert, Julien Amour, Marc Beaussier, Matthieu Biais, Sébastien Bloc, Marie Pierre Bonnet, Pierre Bouzat, Gilles Brezac, Claire Dahyot-Fizelier, Souhayl Dahmani, Mathilde de Queiroz, Sophie Di Maria, Claude Ecoffey, Emmanuel Futier, Thomas Geeraerts, Haithem Jaber, Laurent Heyer, Rim Hoteit, Olivier Joannes-Boyau, Delphine Kern, Olivier Langeron, Sigismond Lasocki, Yoan Launey, Frederic le Saché, Anne Claire Lukaszewicz, Axel Maurice-Szamburski, Nicolas Mayeur, Fabrice Michel, Vincent Minville, Sébastien Mirek, Philippe Montravers, Estelle Morau, Laurent Muller, Jane Muret, Karine Nouette-Gaulain, Jean Christophe Orban, Gilles Orliaguet, Pierre François Perrigault, Florence Plantet, Julien Pottecher, Christophe Quesnel, Vanessa Reubrecht, Bertrand Rozec, Benoit Tavernier, Benoit Veber, Francis Veyckmans, Hélène Charbonneau, Isabelle Constant, Denis Frasca, Marc-Olivier Fischer, Catherine Huraux, Alice Blet, Marc Garnier, Assistance Publique - Hôpitaux de Marseille (APHM), 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 de Paris (UP)-Université Sorbonne Paris Nord, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Anesthésie et Réanimation [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mutualiste de Montsouris (IMM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Pharmacologie des anti-infectieux (PHAR), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anesthésie-réanimation, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'anesthésie réanimation chirurgicale [Rennes], Hôpital Pontchaillou-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, CHU Toulouse [Toulouse], Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Physiopathologie et Pharmacologie Clinique de la Douleur, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique Juge - Clinique du sport [Marseille], Pôle d'Anesthésie-Réanimation [CHU Rangueil], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'anesthésie - réanimation chirurgicale [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'Anesthésie Réanimation, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de réanimation médicale [CHU de Carémeau, Nîmes], Institut Curie [Paris], Réanimation Médico-Chirurgicale, Service d'Anesthésie Réanimation, CHU Necker - Enfants Malades [AP-HP], Département d'anesthésie-réanimation[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Mitochondries, stress oxydant et protection musculaire (Strasbourg), Mitochondrie, stress oxydant et protection musculaire (MSP), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de soins intensifs [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Groupe d’Anesthésie-Réanimation Chirurgie cardio-thoracique et vasculaire [Toulouse], Clinique Pasteur [Toulouse], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Département d'anesthésiologie [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), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU), Hôpital Beaujon [AP-HP], 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 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), 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), Université de Rennes (UR)-Hôpital Pontchaillou, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Pôle Anesthésie Réanimation [CHU de Toulouse], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Histoire et Cultures de l'Antiquité et du Moyen Âge (HISCANT-MA), Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Emergency Department, Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin - Bordeaux, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Anaesthesiology, Robert Debré Hospital, Service d'anesthésie réanimation chirurgicale, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), 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), Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Anesthésiologie, Université Pierre et Marie Curie - Paris 6 (UPMC), and Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis - Lariboisière, AP-HP, Paris, France.
Subjects: Infection prevention and control, [SDV]Life Sciences [q-bio], Psychological intervention, Airway management, Context (language use), Critical Care and Intensive Care Medicine, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030202 anesthesiology, Informed consent, Personal protective equipment, Pandemic, Health care, Medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Modalities, SARS-CoV-2, business.industry, COVID-19, 030208 emergency & critical care medicine, General Medicine, Guideline, 3. Good health, Anesthesiology and Pain Medicine, Universal precautions, Anesthesia, Viruses, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Objectives The world is currently facing an unprecedented healthcare crisis caused by the COVID-19 pandemic. The objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the COVID-19 pandemic. Methods The group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas: (1) protection of staff and patients; (2) benefit/risk and patient information; (3) preoperative assessment and decision on intervention; (4) modalities of the preanaesthesia consultation; (5) specificity of anaesthesia and analgesia; (6) dedicated circuits and (7) containment exit type of interventions. Results The SFAR Guideline panel provides 51 statements on anaesthesia management in the context of COVID-19 pandemic. After one round of discussion and various amendments, a strong agreement was reached for 100% of the recommendations and algorithms. Conclusion We present suggestions for how the risk of transmission by and to anaesthetists can be minimised and how personal protective equipment policies relate to COVID-19 pandemic context.
Published: 2020
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9. Extracorporeal Membrane Oxygenation for Respiratory Failure Related to COVID-19: A Nationwide Cohort Study

Author: Nicolas, Nesseler, Guillaume, Fadel, Alexandre, Mansour, Marylou, Para, Pierre-Emmanuel, Falcoz, Nicolas, Mongardon, Alizée, Porto, Astrid, Bertier, Bruno, Levy, Cyril, Cadoz, Pierre-Grégoire, Guinot, Olivier, Fouquet, Jean-Luc, Fellahi, Alexandre, Ouattara, Julien, Guihaire, Vito-Giovanni, Ruggieri, Philippe, Gaudard, François, Labaste, Thomas, Clavier, Kais, Brini, Nicolas, Allou, Corentin, Lacroix, Juliette, Chommeloux, Guillaume, Lebreton, Michael A, Matthay, Sophie, Provenchere, Erwan, Flécher, André, Vincentelli, James T, Ross, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], 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), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Strasbourg, Nouvel Hôpital Civil de Strasbourg, 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, Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Bicêtre, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Marie-Lannelongue, Groupe Hospitalier Paris Saint-Joseph (hpsj), Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), 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 Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Rouen, Normandie Université (NU), Institut Mutualiste de Montsouris (IMM), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of California [San Francisco] (UC San Francisco), University of California (UC), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Lille, ECMOSARS Investigators: Marc Pierrot, Sidney Chocron, Guillaume Flicoteaux, Philippe Mauriat, Hadrien Roze, Olivier Huet, Marc-Olivier Fischer, Claire Alessandri, Raphel Bellaïche, Ophélie Constant, Quentin de Roux, André Ly, Arnaud Meffert, Jean-Claude Merle, Lucile Picard, Elena Skripkina, Thierry Folliguet, Antonio Fiore, Nicolas d'Ostrevy, Marie-Catherine Morgan, Maxime Nguyen, Lucie Gaide-Chevronnay, Nicolas Terzi, Gwenhaël Colin, Olivier Fabre, Arash Astaneh, Justin Issard, Elie Fadel, Dominique Fabre, Antoine Girault, Iolande Ion, Jean Baptiste Menager, Delphine Mitilian, Olaf Mercier, François Stephan, Jacques Thes, Jerôme Jouan, Thibault Duburcq, Valentin Loobuyck, Sabrina Manganiello, Mouhammed Moussa, Agnes Mugnier, Natacha Rousse, Olivier Desebbe, Roland Henaine, Matteo Pozzi, Jean-Christophe Richard, Zakaria Riad, Christophe Guervilly, Sami Hraiech, Laurent Papazian, Matthias Castanier, Charles Chanavaz, Sebastien Gette, Guillaume Louis, Erick Portocarrero, Nicolas Bischoff, Antoine Kimmoun, Mathieu Mattei, Pierre Perez, Alexandre Bourdiol, Yannick Hourmant, Pierre-Joachim Mahé, Bertrand Rozec, Mickaël Vourc'h, Stéphane Aubert, Florian Bazalgette, Claire Roger, Pierre Jaquet, Brice Lortat-Jacob, Pierre Mordant, Patrick Nataf, Juliette Patrier, Morgan Roué, Romain Sonneville, Alexy Tran-Dinh, Paul-Henri Wicky, Charles Al Zreibi, Bernard Cholley, Yannis Guyonvarch, Sophie Hamada, Claudio Barbanti, Anatole Harrois, Jordi Matiello, Thomas Kerforne, Nicolas Brechot, Alain Combes, Jean Michel Constantin, Cosimo D'Alessandro, Pierre Demondion, Alexandre Demoule, Martin Dres, Muriel Fartoukh, Guillaume Hekimian, Charles Juvin, Pascal Leprince, David Levy, Charles Edouard Luyt, Marc Pineton de Chambrun, Matthieu Schmidt, Thibaut Schoell, Pierre Fillâtre, Nicolas Massart, Roxane Nicolas, Maud Jonas, Charles Vidal, Salvatore Muccio, Dario Di Perna, Bruno Mourvillier, Amedeo Anselmi, Karl Bounader, Maxime Esvan, Claire Fougerou-Leurent, Yoann Launey, Thomas Lebouvier, Alessandro Parasido, Florian Reizine, Philippe Seguin, Emmanuel Besnier, Dorothée Carpentier, Anne Olland, Fanny Bounes, Vincent Minville, Antoine Guillon, Yannick Fedun, James T Ross, Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CHU Toulouse [Toulouse], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), University of California [San Francisco] (UCSF), University of California, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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)
Subjects: Cohort Studies, Male, [SDV] Life Sciences [q-bio], Anesthesiology and Pain Medicine, Extracorporeal Membrane Oxygenation, [SDV]Life Sciences [q-bio], COVID-19, Humans, Respiratory Insufficiency, Pandemics, Retrospective Studies
Abstract: Background Despite expanding use, knowledge on extracorporeal membrane oxygenation support during the COVID-19 pandemic remains limited. The objective was to report characteristics, management, and outcomes of patients receiving extracorporeal membrane oxygenation with a diagnosis of COVID-19 in France and to identify pre-extracorporeal membrane oxygenation factors associated with in-hospital mortality. A hypothesis of similar mortality rates and risk factors for COVID-19 and non–COVID-19 patients on venovenous extracorporeal membrane oxygenation was made. Methods The Extracorporeal Membrane Oxygenation for Respiratory Failure and/or Heart failure related to Severe Acute Respiratory Syndrome-Coronavirus 2 (ECMOSARS) registry included COVID-19 patients supported by extracorporeal membrane oxygenation in France. This study analyzed patients included in this registry up to October 25, 2020, and supported by venovenous extracorporeal membrane oxygenation for respiratory failure with a minimum follow-up of 28 days after cannulation. The primary outcome was in-hospital mortality. Risk factors for in-hospital mortality were analyzed. Results Among 494 extracorporeal membrane oxygenation patients included in the registry, 429 were initially supported by venovenous extracorporeal membrane oxygenation and followed for at least 28 days. The median (interquartile range) age was 54 yr (46 to 60 yr), and 338 of 429 (79%) were men. Management before extracorporeal membrane oxygenation cannulation included prone positioning for 411 of 429 (96%), neuromuscular blockage for 419 of 427 (98%), and NO for 161 of 401 (40%). A total of 192 of 429 (45%) patients were cannulated by a mobile extracorporeal membrane oxygenation unit. In-hospital mortality was 219 of 429 (51%), with a median follow-up of 49 days (33 to 70 days). Among pre-extracorporeal membrane oxygenation modifiable exposure variables, neuromuscular blockage use (hazard ratio, 0.286; 95% CI, 0.101 to 0.81) and duration of ventilation (more than 7 days compared to less than 2 days; hazard ratio, 1.74; 95% CI, 1.07 to 2.83) were independently associated with in-hospital mortality. Both age (per 10-yr increase; hazard ratio, 1.27; 95% CI, 1.07 to 1.50) and total bilirubin at cannulation (6.0 mg/dl or more compared to less than 1.2 mg/dl; hazard ratio, 2.65; 95% CI, 1.09 to 6.5) were confounders significantly associated with in-hospital mortality. Conclusions In-hospital mortality was higher than recently reported, but nearly half of the patients survived. A high proportion of patients were cannulated by a mobile extracorporeal membrane oxygenation unit. Several factors associated with mortality were identified. Venovenous extracorporeal membrane oxygenation support should be considered early within the first week of mechanical ventilation initiation. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
Published: 2022
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10. A novel capnogram analysis to guide ventilation during cardiopulmonary resuscitation: clinical and experimental observations

Author: Lesimple, Arnaud, Fritz, Caroline, Hutin, Alice, Charbonney, Emmanuel, Savary, Dominique, Delisle, Stéphane, Ouellet, Paul, Bronchti, Gilles, Lidouren, Fanny, Piraino, Thomas, Beloncle, François, Prouvez, Nathan, Broc, A, Mercat, Alain, Brochard, Laurent, Tissier, Renaud, Richard, Jean-Christophe, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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), SAMU 75 [Paris], 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), Université du Québec à Trois-Rivières (UQTR), École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 ), Université de Montréal (UdeM), St. Michael's Hospital, University of Toronto, French society of intensive care medicine (SRLF), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), and Chard-Hutchinson, Xavier
Subjects: Cardiopulmonary resuscitation, MESH: Out-of-Hospital Cardiac Arrest, MESH: Humans, Swine, MESH: Cardiopulmonary Resuscitation, [SDV]Life Sciences [q-bio], Carbon Dioxide, Critical Care and Intensive Care Medicine, Cardiac arrest, MESH: Carbon Dioxide, [SDV] Life Sciences [q-bio], Intrathoracic airway closure, Cadaver, Animals, Humans, Thoracic distension, MESH: Cadaver, MESH: Lung, CO2 pattern, Lung, MESH: Swine, Out-of-Hospital Cardiac Arrest
Abstract: Background Cardiopulmonary resuscitation (CPR) decreases lung volume below the functional residual capacity and can generate intrathoracic airway closure. Conversely, large insufflations can induce thoracic distension and jeopardize circulation. The capnogram (CO2 signal) obtained during continuous chest compressions can reflect intrathoracic airway closure, and we hypothesized here that it can also indicate thoracic distension. Objectives To test whether a specific capnogram may identify thoracic distension during CPR and to assess the impact of thoracic distension on gas exchange and hemodynamics. Methods (1) In out-of-hospital cardiac arrest patients, we identified on capnograms three patterns: intrathoracic airway closure, thoracic distension or regular pattern. An algorithm was designed to identify them automatically. (2) To link CO2 patterns with ventilation, we conducted three experiments: (i) reproducing the CO2 patterns in human cadavers, (ii) assessing the influence of tidal volume and respiratory mechanics on thoracic distension using a mechanical lung model and (iii) exploring the impact of thoracic distension patterns on different circulation parameters during CPR on a pig model. Measurements and main results (1) Clinical data: 202 capnograms were collected. Intrathoracic airway closure was present in 35%, thoracic distension in 22% and regular pattern in 43%. (2) Experiments: (i) Higher insufflated volumes reproduced thoracic distension CO2 patterns in 5 cadavers. (ii) In the mechanical lung model, thoracic distension patterns were associated with higher volumes and longer time constants. (iii) In six pigs during CPR with various tidal volumes, a CO2 pattern of thoracic distension, but not tidal volume per se, was associated with a significant decrease in blood pressure and cerebral perfusion. Conclusions During CPR, capnograms reflecting intrathoracic airway closure, thoracic distension or regular pattern can be identified. In the animal experiment, a thoracic distension pattern on the capnogram is associated with a negative impact of ventilation on blood pressure and cerebral perfusion during CPR, not predicted by tidal volume per se.
Published: 2022
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11. Deciphering the Role of Klf10 in the Cerebellum

Author: Kammoun, Malek, Nadal-Desbarats, Lydie, Même, Sandra, Lafoux, Aude, Huchet, Corinne, Meyer-Dilhet, Géraldine, Courchet, Julien, Montigny, Frédéric, Szeremeta, Frédéric, Même, William, Veksler, Vladimir, Piquereau, Jérôme, Pouletaut, Philippe, Subramaniam, Malayannan, Hawse, J., Constans, Jean-Marc, Bensamoun, S, Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), UMR 1253 IBrain Imagerie & Cerveau Equipe 3 'Imagerie, Biomarqueurs & Thérapie' (IBT), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nantes Université (Nantes Univ), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 (TARGET), 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), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT), Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Mayo Clinic [Rochester], CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), National Institutes of Health (R01 DE14036), Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA, Pouletaut, Philippe, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-forme Therassay Onco-Hématologie, Capacités [UN Nantes], Université de Nantes (UN), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Scientifique et Technique 'Analyses des Systèmes Biologiques' (PST-ASB), Université Francois Rabelais [Tours], Signalisation et physiopathologie cardiovasculaire (UMRS1180), and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SPI]Engineering Sciences [physics], Mice, Magnetic Resonance Imaging and Spectroscopy, Cerebellum, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Metabolomics, Klf10, ComputingMilieux_MISCELLANEOUS, Mitochondria
Abstract: International audience; Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.
Published: 2022
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12. Do Not Throw Out the Baby With the Bathwater

Author: Thomas Moumneh, Delphine Douillet, Dominique Savary, Pierre-Marie Roy, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP), 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 ), Chard-Hutchinson, Xavier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)
Subjects: [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], 010102 general mathematics, Emergency Medicine, 030212 general & internal medicine, 0101 mathematics, 01 natural sciences, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2022
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13. Impact of COVID-19 pandemic and lockdowns on the consumption of anxiolytics, hypnotics and antidepressants according to age groups: a French nationwide study

Author: M. Levaillant, M. Wathelet, A. Lamer, E. Riquin, B. Gohier, J.-F. Hamel-Broza, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Ressources et de Résilience [Lille] (CN2R), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), 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 ), None, Chard-Hutchinson, Xavier, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Centre National de Ressources et Résilience (CN2R), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)
Subjects: pharmacoepidemiology, [SDV]Life Sciences [q-bio], COVID-19, psychiatry, psychotropic drugs, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Original Article, 030212 general & internal medicine, 030217 neurology & neurosurgery, Applied Psychology, mental health
Abstract: Background Previous studies have shown a negative impact of the COVID-19 pandemic and its associated sanitary measures on mental health, especially among adolescents and young adults. Such a context may raise many concerns about the COVID-19 pandemic long-term psychological effects. An analysis of administrative databases could be an alternative and complementary approach to medical interview-based epidemiological surveys to monitor the mental health of the population. We conducted a nationwide study to describe the consumption of anxiolytics, antidepressants and hypnotics during the first year of the COVID-19 pandemic, compared to the five previous years. Methods A historic cohort study was conducted by extracting and analysing data from the French health insurance database between 1 January 2015 and 28 February 2021. Individuals were classified into five age-based classes. Linear regression models were performed to assess the impact of the COVID-19 pandemic period on the number of drug consumers, in introducing an interaction term between time and COVID-19 period. Results Since March 2020, in all five age groups and all three drug categories studied, the number of patients reimbursed weekly has increased compared to the period from January 2015 to February 2020. The youngest the patients, the more pronounced the magnitude. Conclusions Monitoring the consumption of psychiatric medications could be of great interest as reliable indicators are essential for planning public health strategies. A post-crisis policy including reliable monitoring of mental health must be anticipated.
Published: 2021
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14. Multicentric randomized evaluation of a tricuspid valve percutaneous repair system (clip for the tricuspid valve) in the treatment of severe secondary tricuspid regurgitation Tri.Fr Design paper

Author: Erwan Donal, Guillaume Leurent, Anne Ganivet, Philip Lurz, Augustin Coisne, Pascal De Groote, Stephane Lafitte, Lionel Leroux, Nicole Karam, Loic Biere, Frederic Rouleau, Catherine Sportouch, Julien Dreyfus, Mohammed Nejjari, Jean-Michel Josselin, Amedeo Anselmi, Elena Galli, Emma Bajeux, Patrice Guerin, Jean-François Obadia, Jean-Noel Trochu, Emmanuel Oger, CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Leipzig University, CHU Lille, CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinique du Millénaire - Oc Santé [Montpellier], Oc Santé [Montpellier], Centre cardiologique du Nord (CCN), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre hospitalier universitaire de Nantes (CHU Nantes), Hospices Civils de Lyon (HCL), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), 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 ), and Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)
Subjects: Heart Valve Prosthesis Implantation, Cardiac Catheterization, [SDV]Life Sciences [q-bio], heart failure, General Medicine, 030204 cardiovascular system & hematology, Surgical Instruments, Severity of Illness Index, Tricuspid Valve Insufficiency, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Treatment Outcome, Humans, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Tricuspid Valve, prognosis, transoesophageal echocardiography, Cardiology and Cardiovascular Medicine, tricuspid regurgitation
Abstract: Aims Tricuspid regurgitation (TR) is associated with significant morbidity and mortality. Its independent prognostic role has been repeatedly demonstrated. However, this valvular heart condition is largely undertreated because of the increased risk of surgical repair. Recently, transcatheter techniques for the treatment of TR have emerged, but their implications for the clinical endpoints are still unknown. Methods and results The Tri.fr trial will be a multicentre, controlled, randomized (1:1 ratio), superior, open-label, and parallel-group study conducted in 300 patients with severe secondary TR that is considered non-surgical by heart teams. Inclusion will be possible only after core laboratory review of transthoracic and transoesophageal echocardiography and after validation by the clinical eligibility committee. A description of the mechanisms of the TR will be conducted by the core laboratory. Atrial or ventricular impacts on the severity of the secondary TR will be taken into account for the randomization. The patients will be followed for 12-month, and the primary outcome will be the Packer composite clinical endpoint [combining New York Heart Association class, patient global assessment (PGA), and major cardiovascular events]. It will test the hypothesis that a tricuspid valve percutaneous repair strategy using a clip dedicated to the tricuspid valve is superior to best guideline-directed medical therapy in symptomatic patients with severe secondary TR. Conclusion Tri.fr will be the first randomized, academic, multicentre study testing the value of percutaneous correction in patients with severe secondary TR.
Published: 2021
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15. Continuous positive airway pressure for respiratory support during COVID-19 pandemic: a frugal approach from bench to bedside

Author: Bilal Badat, Nicolas Mongardon, Keyvan Razazi, C. Deguillard, Frédéric Schlemmer, Mehdi Khellaf, Raphaëlle Huguet, Pascal Lim, Nicolas de Prost, François Templier, Karim Jaffal, Dominique Savary, Francois Morin, Elena Fois, Yvon Deplante, François Beloncle, François Perier, Constance Guillaud, Laurent Brochard, Philippe Grimbert, Armand Mekontso Dessap, Anne-Fleur Haudebourg, Jean-Christophe Richard, Samuel Tuffet, Manuella Pons, Vincent Audard, Arnaud Lesimple, Alain Mercat, Guillaume Carteaux, 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), CHU Henri Mondor [Créteil], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurosciences (CHU Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, University of Toronto, Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-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), 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 ), CHU Henri Mondor, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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 de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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), Chard-Hutchinson, Xavier, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-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)
Subjects: medicine.medical_specialty, medicine.medical_treatment, Continuous positive airway pressure, Context (language use), Respiratory physiology, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, Work of breathing, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anesthesiology, medicine, Intubation, Tidal volume, Acute hypoxemic respiratory failure, Frugal innovation, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, COVID-19, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Oxygenation, 3. Good health, respiratory tract diseases, 030228 respiratory system, Emergency medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: Background We describe a frugal approach (focusing on needs, performance, and costs) to manage a massive influx of COVID-19 patients with acute hypoxemic respiratory failure (AHRF) using the Boussignac valve protected by a filter (“Filter Frugal CPAP”, FF-CPAP) in and out the ICU. Methods (1) A bench study measured the impact of two filters with different mechanical properties on CPAP performances, and pressures were also measured in patients. (2) Non-ICU healthcare staff working in COVID-19 intermediate care units were trained with a video tutorial posted on a massive open online course. (3) A clinical study assessed the feasibility and safety of using FF-CPAP to maintain oxygenation and manage patients out of the ICU during a massive outbreak. Results Bench assessments showed that adding a filter did not affect the effective pressure delivered to the patient. The resistive load induced by the filter variably increased the simulated patient’s work of breathing (6–34%) needed to sustain the tidal volume, depending on the filter’s resistance, respiratory mechanics and basal inspiratory effort. In patients, FF-CPAP achieved pressures similar to those obtained on the bench. The massive training tool provided precious information on the use of Boussignac FF-CPAP on COVID-19 patients. Then 85 COVID-19 patients with ICU admission criteria over a 1-month period were studied upon FF-CPAP initiation for AHRF. FF-CPAP significantly decreased respiratory rate and increased SpO2. Thirty-six (43%) patients presented with respiratory indications for intubation prior to FF-CPAP initiation, and 13 (36%) of them improved without intubation. Overall, 31 patients (36%) improved with FF-CPAP alone and 17 patients (20%) did not require ICU admission. Patients with a respiratory rate > 32 breaths/min upon FF-CPAP initiation had a higher cumulative probability of intubation (p Conclusion Adding a filter to the Boussignac valve does not affect the delivered pressure but may variably increase the resistive load depending on the filter used. Clinical assessment suggests that FF-CPAP is a frugal solution to provide a ventilatory support and improve oxygenation to numerous patients suffering from AHRF in the context of a massive outbreak.
Published: 2021
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16. Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner

Author: Laurent Loufrani, Marine Adlanmerini, Jean-Marie Foidart, Chanaelle Fébrissy, Julie Favre, Jean-Françoise Arnal, Vincent Procaccio, Rana Zahreddine, Léa Réthoré, Coralyne Proux, Emilie Vessieres, Linda Grimaud, Jordan Rivron, Manuela Cl Garcia, Coralie Fontaine, Gilles Flouriot, Anne-Laure Guihot, Daniel Henrion, Morgane Davezac, Françoise Lenfant, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, 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 ), FRM - DPC20171138957, Fondation pour la Recherche Médicale, Equipe FRM DEQ20160334924, Fondation pour la Recherche Médicale, ANR-18-CE14-0016-01, Agence Nationale de la Recherche, Fondation Lefoulon Delalande, Institut National de la Santé et de la Recherche Médicale, Université de Toulouse, Région Occitanie Pyrénées-Méditerranée, Institut Universitaire de France, ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Henrion, Daniel, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Membrane estrogen receptor, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Ligands, medicine.disease_cause, Mice, 0302 clinical medicine, cell biology, blood flow, Biology (General), 0303 health sciences, Chemistry, General Neuroscience, resistance arteries, estrogen receptors, General Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Blood Circulation, Medicine, Female, Acetylcholine, Research Article, medicine.drug, Agonist, medicine.medical_specialty, endothelium, medicine.drug_class, QH301-705.5, Science, Alpha (ethology), General Biochemistry, Genetics and Molecular Biology, shear stress, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, mouse, 030304 developmental biology, General Immunology and Microbiology, Insulin, Estrogen Receptor alpha, Hydrogen Peroxide, Endocrinology, Estrogen receptor alpha, Ex vivo, Oxidative stress
Abstract: Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.
Published: 2021
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17. Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Author: Marianne Burgard, George C. Hartoularos, Martin Castelle, Alice Hadchouel, Laureline Berteloot, Romain Lévy, Bénédicte Neven, Jean-Laurent Casanova, Qian Zhang, Karim Dorgham, Lucy Bizien, Chun Jimmie Ye, Hanène Abid, Tom Toin, Isabelle Melki, Peng Zhang, Nadhira Houhou-Fidouh, Paul Bastard, Emmanuelle Jouanguy, Charlotte Roy, Flore Rozenberg, Guy Gorochov, Service d'immuno-hématologie 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), Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de Pneumologie Allergologie [CHU Necker], University of California (UC), CHU Necker - Enfants Malades [AP-HP], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [CHU Necker], Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service de Génétique Médicale [CHU Necker], Service d'Immunologie [CHU Pitié-Salpétrière], 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), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), Gestionnaire, HAL Sorbonne Université 5, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères - - GENVIR2020 - ANR-20-CE93-0003 - AAPG2020 - VALID, Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19. - - AABIFNCOV2020 - ANR-20-CO11-0001 - COVID-19 - VALID, Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant. - - GenMIS-C2021 - ANR-21-COVR-0039 - COVID-19 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: medicine.drug_class, Viremia, Monoclonal antibody, Antibodies, Monoclonal, Humanized, Virus, Neutralization, 03 medical and health sciences, Immunocompromised Host, 0302 clinical medicine, Interferon, medicine, Genetics, Humans, 030304 developmental biology, Blood type, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, business.industry, SARS-CoV-2, COVID-19, interferon, Viral Load, Biological Sciences, medicine.disease, Antibodies, Neutralizing, Interferon-Stimulated Gene Factor 3, gamma Subunit, 3. Good health, Upper respiratory tract infection, Child, Preschool, inherited primary immunodeficiency, Immunology, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, RNA-seq, business, Viral load, 030215 immunology, medicine.drug
Abstract: Significance Life-threatening COVID-19 pneumonia can be caused by rare inborn errors of type I interferon (IFN) immunity, or by autoantibodies neutralizing IFN-α2 or IFN-ω. In 2018, we reported a girl with critical influenza pneumonia due to inherited IRF9 deficiency, a component of the ISGF-3 transcription factor. We report the course of COVID-19 in the same patient. She was admitted on day 1 of upper respiratory tract infection with viremia. Administration of SARS-CoV-2–specific neutralizing monoclonal antibodies on day 2 prevented the development of pneumonia. SARS-CoV-2–specific monoclonal antibodies were sufficient to overcome a lack of ISGF-3– and IRF9-dependent type I and type III IFN immunity to the virus. They should be considered in selected children at high risk of life-threatening COVID-19., We describe an unvaccinated child at risk for life-threatening COVID-19 due to an inherited deficiency of IRF9, which governs ISGF-3–dependent responses to type I and III interferons (IFN). She was admitted, with a high nasal SARS-CoV-2 load on day 1 of upper respiratory tract infection. She was viremic on day 2 and received casirivimab and imdevimab. Her clinical manifestations and viremia disappeared on days 3 and 4, respectively. Circulating SARS-CoV-2 virus induced the expression of IFN-stimulated genes in leukocytes on day 1, whereas the secretion of blood type I IFNs, which peaked on day 4, did not. Antibody-mediated SARS-CoV-2 neutralization is, therefore, sufficient to overcome a deficiency of antiviral IFNs.
Published: 2021
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18. Adaptation of ED design layout during the COVID-19 pandemic: a national cross-sectional survey

Author: Pauline Ravon, Thomas Saloux, Francois Morin, Bruno Carneiro, Dominique Savary, Pierre-Marie Roy, Delphine Douillet, Thomas Moumneh, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), 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 ), and Chard-Hutchinson, Xavier
Subjects: emergency department, Cross-sectional study, [SDV]Life Sciences [q-bio], emergency care systems, Context (language use), Computer-assisted web interviewing, Critical Care and Intensive Care Medicine, emergency departments, 03 medical and health sciences, 0302 clinical medicine, Pandemic, medicine, Humans, Hospital Design and Construction, 030212 general & internal medicine, Pandemics, Original Research, Health Services Needs and Demand, SARS-CoV-2, business.industry, Staff management, COVID-19, 030208 emergency & critical care medicine, Workload, General Medicine, Emergency department, medicine.disease, Triage, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, efficiency, Health Care Surveys, Emergency Medicine, France, Medical emergency, Emergency Service, Hospital, business
Abstract: BackgroundThe aim was to describe the organisational changes in French EDs in response to the COVID-19 pandemic with regard to architectural constraints and compare with the recommendations of the various bodies concerning the structural adjustments to be made in this context.MethodsAs part of this cross-sectional study, all heads of emergency services or their deputies were contacted to complete an electronic survey. This was a standardised online questionnaire consisting of four parts: characteristics of the responding centre, creation of the COVID-19 zone and activation of the hospital’s emergency operations plan, flow and circulation of patients and, finally, staff management. Each centre was classified according to its workload related to COVID-19 and its size (university hospital centre, high-capacity hospital centre and low-capacity hospital centre). The main endpoint was the frequency of implementation of international guidelines for ED organisation.ResultsBetween 11 May and 20 June 2020, 57 French EDs completed the online questionnaire and were included in the analysis. Twenty-eight EDs were able to separate patient flows into two zones: high and low viral density (n=28/57, 49.1%). Of the centres included, 52.6% set up a specific triage area for patients with suspected COVID-19 (n=30/57). Whereas, in 15 of the EDs (26.3%), the architecture made it impossible to increase the surface area of the ED.ConclusionAll EDs have adapted, but many of the changes recommended for the organisation of ED could not be implemented. ED architecture constrains adaptive capacities in the context of COVID-19.
Published: 2021
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19. Turning up the Green Light

Author: U. Valentin Nägerl, Julien Cassereau, Vincent Courdavault, CCSD, Accord Elsevier, MitoVasc - Équipe MitoLab (Mitochondrial Pathophysiology) (MITOVASC-MITOLAB), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biomolécules et biotechnologies végétales (BBV EA 2106), Université de Tours (UT), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Tours
Subjects: 0303 health sciences, animal structures, fluorescent proteins, Super-resolution microscopy, [SDV]Life Sciences [q-bio], Green Fluorescent Proteins, brain imaging, protein engineering, Cell Biology, Protein engineering, Biology, Green-light, Biochemical Activity, Fluorescence, Green fluorescent protein, [SDV] Life Sciences [q-bio], Folding (chemistry), 03 medical and health sciences, 0302 clinical medicine, super-resolution microscopy, Mutation, Biophysics, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: International audience; Fluorescent proteins (FPs) have become indispensable tools in biological research for labeling cells and proteins and sensing their biochemical activity. By introducing 'folding mutations', Campbell et al. engineered a new GFP variant with dramatically enhanced cellular brightness and stability, facilitating advanced cellular bioimaging applications in neuroscience and beyond.
Published: 2021
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20. Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction

Author: Benjamin Alos, Mariama Akodad, Olivier Dubreuil, Didier Bresson, Gilles Rioufol, Cyril Prieur, Charles De Bourguignon, Florent Boutitie, François Derimay, Loïc Bière, Gérard Finet, Rachel Daw, Ahmad Hayek, Fabrice Prunier, Pierre Croisille, Carole Dhelens, Naoual El Jonhy, Nathan Mewton, Eric Bonnefoy-Cudraz, Gabriel Bidaux, Delphine Maucort-Boulch, Claire Bouleti, Denis Angoulvant, Fabrice Ivanes, Lamis Haider, François Roubille, Thomas Bochaton, Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), 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), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours (UT), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-RHUS-0009,MARVELOUS,MARVELOUS(2016), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, Heart Injury, [SDV]Life Sciences [q-bio], Contrast Media, Inflammation, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, Original Research Articles, medicine, Colchicine, Humans, 030212 general & internal medicine, Myocardial infarction, Ventricular remodeling, Referral and Consultation, ComputingMilieux_MISCELLANEOUS, Aged, Ventricular Remodeling, business.industry, Myocardium, Heart, Heart injuries, Thrombosis, Middle Aged, medicine.disease, 3. Good health, Hospitalization, Clinical trial, chemistry, Ventriculat remodeling, Acute Disease, Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ST Elevation Myocardial Infarction, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Supplemental Digital Content is available in the text., Background: Inflammation is a key factor of myocardial damage in reperfused ST-segment–elevation myocardial infarction. We hypothesized that colchicine, a potent anti-inflammatory agent, may reduce infarct size (IS) and left ventricular (LV) remodeling at the acute phase of ST-segment–elevation myocardial infarction. Methods: In this double-blind multicenter trial, we randomly assigned patients admitted for a first episode of ST-segment–elevation myocardial infarction referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day) or matching placebo from admission to day 5. The primary efficacy outcome was IS determined by cardiac magnetic resonance imaging at 5 days. The relative LV end-diastolic volume change at 3 months and IS at 3 months assessed by cardiac magnetic resonance imaging were among the secondary outcomes. Results: We enrolled 192 patients, 101 in the colchicine group and 91 in the control group. At 5 days, the gadolinium enhancement–defined IS did not differ between the colchicine and placebo groups with a mean of 26 interquartile range (IQR) [16–44] versus 28.4 IQR [14–40] g of LV mass, respectively (P=0.87). At 3 months follow-up, there was no significant difference in LV remodeling between the colchicine and placebo groups with a +2.4% (IQR, –8.3% to 11.1%) versus –1.1% (IQR, –8.0% to 9.9%) change in LV end-diastolic volume (P=0.49). Infarct size at 3 months was also not significantly different between the colchicine and placebo groups (17 IQR [10–28] versus 18 IQR [10–27] g of LV mass, respectively; P=0.92). The incidence of gastrointestinal adverse events during the treatment period was greater with colchicine than with placebo (34% versus 11%, respectively; P=0.0002). Conclusions: In this randomized, placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days did not reduce IS assessed by cardiac magnetic resonance imaging. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03156816.
Published: 2021
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21. Doxorubicin-Induced Autophagolysosome Formation Is Partly Prevented by Mitochondrial ROS Elimination in DOX-Resistant Breast Cancer Cells

Author: Ahmadpour, Seyedeh, Desquiret-Dumas, Valérie, Yikilmaz, Ulku, Dartier, Julie, Domingo, Isabelle, Wetterwald, Celine, Orre, Charlotte, Gueguen, Naïg, Brisson, Lucie, Mahéo, Karine, Dumas, Jean-François, Brisson, Lucie, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: reactive oxygen species, QH301-705.5, Antineoplastic Agents, Apoptosis, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, doxorubicin, Article, mitochondria, Chemistry, mitophagy, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MCF-7 Cells, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, polycyclic compounds, Humans, Female, Biology (General), Lysosomes, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, QD1-999
Abstract: International audience; Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional mitochondria by mitophagy could thus prevent the initiation of the apoptotic cascade. In breast cancer patients, resistance to doxorubicin (DOX), one of the most widely used cancer drugs, is an important cause of poor clinical outcomes. However, the role played by mitophagy in the context of DOX resistance in breast cancer cells is not well understood. We therefore tried to determine whether an increase in mitophagic flux was associated with the resistance of breast cancer cells to DOX. Our first objective was to explore whether DOX-resistant breast cancer cells were characterized by conditions that favor mitophagy induction. We next tried to determine whether mitophagic flux was increased in DOX-resistant cells in response to DOX treatment. For this purpose, the parental (MCF-7) and DOX-resistant (MCF-7dox) breast cancer cell lines were used. Our results show that mitochondrial reactive oxygen species (ROS) production and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression are higher in MCF-7dox in a basal condition compared to MCF-7, suggesting DOX-resistant breast cancer cells are prone to stimuli to induce a mitophagy-related event. Our results also showed that, in response to DOX, autophagolysosome formation is induced in DOX-resistant breast cancer cells. This mitophagic step following DOX treatment seems to be partly due to mitochondrial ROS production as autophagolysosome formation is moderately decreased by the mitochondrial antioxidant mitoTEMPO
Published: 2021
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22. Basic life support training in out-of-hospital cardiac arrest: From the youth to a special 'Senior Force Against Cardiac Arrest'

Author: Alexis Descatha, Thomas Bizouard, Dominique Savary, Francois Morin, Delphine Douillet, Delphine Plard, Suzanne Schunder-Tatzber, Marc Fadel, Pascal Cassan, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), OMV [Vienne], Fédération internationale des Sociétés de la Croix-Rouge et du Croissant-Rouge (IFIRC Global First Aid Reference Centre), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chard-Hutchinson, Xavier, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: medicine.medical_specialty, Emergency Medical Services, Occupational Medicine, Adolescent, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Emergency Nursing, Out of hospital cardiac arrest, Occupational medicine, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Out-of-hospital cardiac arrest, business.industry, Basic life support, 030208 emergency & critical care medicine, Basic life support training, medicine.disease, Cardiopulmonary Resuscitation, [SDV] Life Sciences [q-bio], Emergency Medicine, Medical emergency, Cardiology and Cardiovascular Medicine, business
Abstract: International audience
Published: 2021
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23. Bios2cor: an R package integrating dynamic and evolutionary correlations to identify functionally important residues in proteins

Author: Bruck Taddese, Daniel Henrion, Marie Chabbert, Antoine Garnier, Madeline Deniaud, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and CHABBERT, Marie
Subjects: Statistics and Probability, 0303 health sciences, Sequence, Computer science, [SDV]Life Sciences [q-bio], Computational biology, Protein superfamily, Dihedral angle, Biochemistry, Computer Science Applications, Visualization, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Computational Mathematics, R package, 0302 clinical medicine, Computational Theory and Mathematics, Abstract Summary, Molecular Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Summary Both dynamic correlations in protein sidechain motions during molecular dynamics (MD) simulations and evolutionary correlations in multiple sequence alignments (MSAs) of homologous proteins may reveal functionally important residues. We developed the R package Bios2cor that provides a unique framework to investigate and, possibly, integrate both analyses. Bios2cor starts with an MSA or an MD trajectory and computes correlation/covariation scores between positions in the MSA or between sidechain dihedral angles or rotamers in the MD trajectory. In addition, Bios2cor provides a variety of tools for the analysis, the visualization and the interpretation of the data. Availability and implementation The R package Bios2cor is available from the Comprehensive R Archive Network, at https://CRAN.R-project.org/package=Bios2cor.
Published: 2021
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24. Guidance Level for Brevetoxins in French Shellfish

Author: Arnich, Nathalie, Abadie, Eric, Amzil, Zouher, Dechraoui Bottein, Marie-Yasmine, Comte, Katia, Chaix, Estelle, Delcourt, Nicolas, Hort, Vincent, Mattei, César, Molgó, Jordi, Le Garrec, Raphaele, Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Ecology and Conservation Science for Sustainable Seas (ECOSEAS), Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre antipoison et de toxicovigilance [CHU Toulouse] (CAPTV Toulouse), Pôle Médecine d'urgences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de sécurité des aliments de Maisons-Alfort (LSAl), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut de Recherche pour le Développement (IRD), Centre antipoison et de toxicovigilance (Toulouse) (CAPTV Toulouse), CHU Toulouse [Toulouse]-CHU Purpan, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and GUITTON, SOPHIE
Subjects: guidance level, QH301-705.5, Oxocins, food and beverages, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Article, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, brevetoxins, shellfish, [SDV.TOX.TCA] Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Dinoflagellida, Mediterranean Sea, emerging toxins, Animals, Humans, Shellfish Poisoning, marine biotoxins, Marine Toxins, France, Biology (General), neurotoxic shellfish poisoning, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Environmental Monitoring
Abstract: To prevent health risks associated with the consumption of shellfish contaminated with BTXs in France, a working group was set up by the French Agency for Food, Environmental and Occupational Health & Safety (Anses). One of the aims of this working group was to propose a guidance level for the presence of BTXs in shellfish.; International audience; Brevetoxins (BTXs) are marine biotoxins responsible for neurotoxic shellfish poisoning (NSP) after ingestion of contaminated shellfish. NSP is characterized by neurological, gastrointestinal and/or cardiovascular symptoms. The main known producer of BTXs is the dinoflagellate Karenia brevis, but other microalgae are also suspected to synthesize BTX-like compounds. BTXs are currently not regulated in France and in Europe. In November 2018, they have been detected for the first time in France in mussels from a lagoon in the Corsica Island (Mediterranean Sea), as part of the network for monitoring the emergence of marine biotoxins in shellfish. To prevent health risks associated with the consumption of shellfish contaminated with BTXs in France, a working group was set up by the French Agency for Food, Environmental and Occupational Health & Safety (Anses). One of the aims of this working group was to propose a guidance level for the presence of BTXs in shellfish. Toxicological data were too limited to derive an acute oral reference dose (ARfD). Based on human case reports, we identified two lowest-observed-adverse-effect levels (LOAELs). A guidance level of 180 µg BTX-3 eq./kg shellfish meat is proposed, considering a protective default portion size of 400 g shellfish meat.
Published: 2021
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25. Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom in resolved structures

Author: Tiss, Asma, Ben Boubaker, Rym, Henrion, Daniel, Guissouma, Hajer, Chabbert, Marie, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tunis El Manar (UTM), CHABBERT, Marie, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: [SDV] Life Sciences [q-bio], GPCR, computational biology, loop modeling, [SDV]Life Sciences [q-bio], membrane receptor, MODELLER, Homology modeling, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021
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26. Effects of mean arterial pressure on arousal in sedated ventilated patients with septic shock: a SEPSISPAM post hoc exploratory study

Author: Nicolas Weiss, Peter Radermacher, Frédéric Gonzalez, Fabien Grelon, Christophe Guitton, Thierry Van Der Linden, Valérie Seegers, Antoine Vieillard-Baron, Soizic Gergaud, Marie Conrad, Pierre-François Dequin, Nadia Anguel, Jean-Marie Tonnelier, René Robert, Bruno Mégarbane, Ferhat Meziani, Pierre Guezennec, Youenn Jouan, Jean-Paul Mira, Pierre Asfar, Yves Le Tulzo, Fabienne Tamion, François Legay, Service de Médecine Intensive Réanimation [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Réanimation Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Le Mans Université (UM), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Cochin [AP-HP], Hôpital Saint-Vincent de Paul, Service d'anesthésie et réanimation chirurgicale, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier Saint-Brieuc, Hôpital Yves LE FOLL [Saint-Brieuc], CHU Pontchaillou [Rennes], Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département d'anesthésiologie et de soins intensifs [Institut Paoli-Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Le Mans (CH Le Mans), Service de réanimation médicale [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHRU Brest - Service de Réanimation Médicale (CHU - BREST - Réa Med), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de réanimation [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Saint Philibert [Lomme], Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Medical Intensive Care Unit [Boulogne-Billancourt], Hôpital Ambroise Paré [AP-HP], Universitätsklinikum Ulm - University Hospital of Ulm, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Intensive et Réanimation [Angers], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Univ Angers, Okina, INSERM UMRS-1144, Université Paris Cité, Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: medicine.medical_specialty, Mean arterial pressure, Resuscitation, Vasopressors, medicine.drug_class, Sedation, [SDV]Life Sciences [q-bio], Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Arousal, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anesthesiology, Septic shock, Cerebral perfusion, Medicine, Cerebral perfusion pressure, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, 030228 respiratory system, Anesthesia, Sedative, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, medicine.symptom, business
Abstract: Background It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal. Methods We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a “high-target” level of MAP (80–85 mmHg) versus the recommended “low-target” MAP (65–70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS). Results We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group. Conclusion In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg. Electronic supplementary material The online version of this article (10.1186/s13613-019-0528-5) contains supplementary material, which is available to authorized users.
Published: 2019
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27. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019
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28. Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly

Author: Laurence Faivre, Natáliya Tkachenko, Celia Azevedo Soares, Annick Toutain, Marlène Rio, Anne Boland, Kendra Engleman, Eléonore Viora-Dupont, Kévin Uguen, Cédric Le Maréchal, Yang Cao, Sophie Rondeau, Kilannin Krysiak, Jean-François Deleuze, Caroline Benech, Frédéric Tran Mau-Them, Sylvie Odent, Jorge L. Granadillo, Dominique Bonneau, Claude Férec, Ibrahim Elsharkawi, Séverine Audebert-Bellanger, Julie Neidich, Stéphane Bézieau, Brigitte Gilbert-Dussardier, Elena Repnikova, Sylvia Redon, Shivarajan Manickavasagam Amudhavalli, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), 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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidade do Porto = University of Porto, Centro Hospitalar do Porto, Children's Mercy Hospital [Kansas City], Université Paris-Saclay, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre hospitalier universitaire de Nantes (CHU Nantes), 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], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Heterozygote, Microcephaly, Adolescent, DNA Copy Number Variations, Language delay, [SDV]Life Sciences [q-bio], Karyotype, Inheritance Patterns, chemical and pharmacologic phenomena, 030105 genetics & heredity, Biology, dysmorphic features, loss of function mutation, 03 medical and health sciences, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, HMGB1 Protein, Child, Gene, Genetic Association Studies, In Situ Hybridization, Fluorescence, Genetics (clinical), Loss function, HMGB1, Facies, Exons, developmental disabilities, Microdeletion syndrome, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Female, Haploinsufficiency
Abstract: International audience; 13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Published: 2021
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29. Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation

Author: Karine Duroure, Estelle Colin, Thomas Edouard, Ludovic Martin, Linda Grimaud, Lyndon Gallacher, George McGillivray, Guy Lenaers, Valérie Desquiret-Dumas, Clarisse Billon, Anne Breton, Mohammed Zarhrate, Emmanuel Mas, Dominique Bonneau, Lynn Pais, Daniel Henrion, Thomas Haaf, Reza Maroofian, Marianna Parlato, Frank M. Ruemmele, Anne-Laure Guihot, Anaïs Philippe, Ehsan Ghayoor Karimiani, Pauline E. Schneeberger, Stanislas Lyonnet, Bernadette Bègue, Bruno Moulin, Rémi Duclaux-Loras, Nicolas Cagnard, Michael Frank, Laurence Faivre, Ruben Attali, Yves Alembik, Filippo Del Bene, Kerstin Kutsche, Céline Revenu, Fabienne Charbit-Henrion, Katta M. Girisha, Aboulfazl Rad, Eyal Reinstein, Shalini S. Nayak, Barbara Vona, Nadine Cerf-Bensussan, Caroline Lekszas, Shay Tzur, Alban Ziegler, Susan M. White, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ingénierie Radioprotection Sûreté Démantèlement (IRSD), Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Embryology and genetics of human malformation, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital de Hautepierre [Strasbourg], Nouvel Hôpital Civil de Strasbourg, Tel Aviv University (TAU), Emedgene Technologies [Tel Aviv], Murdoch Children's Research Institute (MCRI), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Kasturba Medical College, Manipal, Massachusetts Institute of Technology (MIT), University College of London [London] (UCL), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, St George's, University of London, University of Würzburg = Universität Würzburg, Fondation Princesse Grace, Fondation Maladies Rares, Harbig Family Foundation, Royal Children's Hospital Foundation, University of Tubingen (2545-1-0), Federal Ministry of Education and Research (01DQ17003 to K.K.), Indian Council of Medical Research (file no. 5/7/1508/2016 to K.M.G), National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, National Human Genome Research Institute grant R01 HG009141, Victorian Government's Operational Infrastructure Support Program, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), European Project: 661527,H2020,H2020-MSCA-IF-2014,NMJALS(2015), European Project: 339407,EC:FP7:ERC,ERC-2013-ADG,IMMUNOBIOTA(2014), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Embryology and genetics of human malformation (Equipe Inserm U1163), SEGUIN, Nathalie, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, In vivo analysis of neuromuscular junction stability in zebrafish models of amyotrophic lateral sclerosis - NMJALS - - H20202015-11-16 - 2017-11-15 - 661527 - VALID, Host-microbiota interactions across the gut immune system:lessons from early onset inflammatory bowel diseases and from gnotobiotic mice - IMMUNOBIOTA - - EC:FP7:ERC2014-03-01 - 2019-02-28 - 339407 - VALID, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Connective Tissue Disorder, Loss of Heterozygosity, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, IPO8, TGF-β signaling, Pathogenesis, 0302 clinical medicine, Loss of Function Mutation, Transforming Growth Factor beta, connective tissue disorder, Child, Connective Tissue Diseases, Zebrafish, Genetics (clinical), Karyopherin, chemistry.chemical_classification, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunity, Cellular, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Middle Aged, beta Karyopherins, Pedigree, arterial dilatation, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, medicine.anatomical_structure, Cardiovascular Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Bone Diseases, Signal Transduction, Adult, Adolescent, Connective tissue, Biology, Importin 8, Young Adult, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Report, Genetics, medicine, Animals, Humans, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Infant, Immune dysregulation, Loeys-Dietz syndrome, biology.organism_classification, joint hyperlaxity, chemistry, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Transforming growth factor
Abstract: International audience; Dysregulated transforming growth factor TGF-beta signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-beta-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-beta signaling, ipo8(-/-) zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8(-/-) zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-beta signaling during development and reinforces the existing link between TGF-beta signaling and connective tissue defects.
Published: 2021
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30. Assessment of physicians’ resilience level during the COVID-19 pandemic

Author: E Riquin, P.-M. Roy, Delphine Douillet, Olivier Hugli, P Miroux, Francois Morin, Thomas Moumneh, Rafael Mahieu, Maxime Léger, M Noizet, F Javaudin, M Oberlin, Dominique Savary, E Thibaud, Jérémie Riou, A Caillaud, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Hôpital pasteur [Colmar], Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), 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 ), Lausanne University Hospital, Chard-Hutchinson, Xavier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )
Subjects: Adult, Male, medicine.medical_specialty, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Specialty, Neurosciences. Biological psychiatry. Neuropsychiatry, Anxiety, Molecular neuroscience, Article, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, law, Intensive care, Anesthesiology, Physicians, Genetics, Medicine, Humans, 030212 general & internal medicine, Resilience (network), Pandemics, Biological Psychiatry, Depression (differential diagnoses), business.industry, SARS-CoV-2, COVID-19, Emergency department, Middle Aged, Resilience, Psychological, Intensive care unit, 3. Good health, Psychiatry and Mental health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Family medicine, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, 030217 neurology & neurosurgery, RC321-571
Abstract: We aim to assess physicians’ level of resilience and define factors that improve or decrease the resilience level during the COVID-19 pandemic. Physicians from hospitals located in areas with different COVID-19 caseload levels, were invited to participate in a national e-survey between April and May 2020. Study participants were mainly emergency physicians, and anaesthesiologists, infectious disease consultants, and intensive care. The survey assessed participant’s characteristics, factors potentially associated with resilience, and resilience using the Connor-Davidson Resilience Scale (RISC-25), with higher scores indicative of greater resilience. Factors associated with the resilience score were assessed using a multivariable linear regression. Of 451 responding physicians involved in the care of COVID-19 patients, 442 were included (98%). Age was 36.1 ± 10.3 years and 51.8% were male; 63% worked in the emergency department (n = 282), 10.4% in anesthesiology (n = 46), 9.9% in infectious disease department (n = 44), 4.8% in intensive care unit (n = 21) or other specialties (n = 49). The median RISC-25 score was at 69 (IQR 62–75). Factors associated with higher RISC scores were anesthesia as a specialty, parenthood, no previous history of anxiety or depression and nor increased anxiety. To conclude, this study is the first to characterize levels of resilience among physicians involved in COVID-19 unit. Our data points to certain protective characteristics and some detrimental factors, such as anxiety or depression, that could be amenable to remediating or preventing strategies to promote resilience and support caregivers in a pandemic.
Published: 2021
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31. Arterial Digital Pulse Photoplethysmography in Patients with Suspected Thoracic Outlet Syndrome: A Study of the 'Ca+Pra' Maneuver

Author: Patrick Saulnier, Pierre Ramondou, Francine Thouveny, Mickael Daligault, Pierre Abraham, Mathieu Feuilloy, Jeanne Hersant, Samir Henni, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ESEO-GSII (GSII), ESEO-Tech, Université Bretagne Loire (UBL)-École supérieure d'électronique de l'ouest [Angers] (ESEO)-Université Bretagne Loire (UBL)-École supérieure d'électronique de l'ouest [Angers] (ESEO), Laboratoire d'Acoustique de l'Université du Mans (LAUM), Le Mans Université (UM)-Centre National de la Recherche Scientifique (CNRS), Jarry, Anne-Flore, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université Bretagne Loire (UBL)-Université Bretagne Loire (UBL)
Subjects: medicine.medical_specialty, Medicine (General), [SPI] Engineering Sciences [physics], [SDV]Life Sciences [q-bio], Clinical Biochemistry, Ischemia, ischemia, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, [SPI]Engineering Sciences [physics], 0302 clinical medicine, R5-920, Internal medicine, Photoplethysmogram, thoracic outlet syndrome, Plethysmograph, Medicine, pathophysiology, Thoracic outlet syndrome, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Pulse (signal processing), arterial inflow, medicine.disease, [SDV] Life Sciences [q-bio], transcutaneous oximetry, Angiography, Cardiology, photoplethysmography, sense organs, business, Sensitivity (electronics), 030217 neurology & neurosurgery
Abstract: The level of pulse amplitude (PA) change in arterial digital pulse plethysmography (A-PPG) that should be used to diagnose thoracic outlet syndrome (TOS) is debated. We hypothesized that a modification of the Roos test (by moving the arms forward, mimicking a prayer position (“Pra”)) releasing an eventual compression that occurs in the surrender/candlestick position (“Ca”) would facilitate interpretation of A-PPG results. In 52 subjects, we determined the optimal PA change from rest to predict compression at imaging (ultrasonography +/− angiography) with receiver operating characteristics (ROC). “Pra”-PA was set as 100%, and PA was expressed in normalized amplitude (NA) units. Imaging found arterial compression in 23 upper limbs. The area under ROC was 0.765 ± 0.065 (p &lt, 0.0001), resulting in a 91.4% sensitivity and a 60.9% specificity for an increase of fewer than 3 NA from rest during “Ca”, while results were 17.4% and 98.8%, respectively, for the 75% PA decrease previously proposed in the literature. A-PPG during a “Ca+Pra” test provides demonstrable proof of inflow impairment and increases the sensitivity of A-PPG for the detection of arterial compression as determined by imaging. The absence of an increase in PA during the “Ca” phase of the “Ca+Pra” maneuver should be considered indicative of arterial inflow impairment.
Published: 2021
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32. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Author: Stéphane Bézieau, Médéric Jeanne, Anne Sophie Denommé-Pichon, Jason Laufman, William B. Dobyns, Sébastien Küry, Judith Halewa, Elliott H. Sherr, Dominique Bonneau, Julie Vogt, Sophie Blesson, Hélène Demory, Jérôme Honnorat, Helene Cox, Séverine Audebert-Bellanger, Marie Laure Vuillaume, Sylviane Marouillat, Estelle Colin, Avgi Andreou, Emanuela Argilli, Bertrand Isidor, Bernhard Lohkamp, Miroslava Hancarova, Rajesh Khanna, Davit Babikyan, Sarka Bendova, Kimberly A. Aldinger, Aubin Moutal, Saskia M. Maas, Marjon van Slegtenhorst, Annick Toutain, Sylvie Odent, Rose Anne Thépault, Natella Kostandyan, Eleina M. England, Zdenek Sedlacek, Richard Redon, M. Mahdi Motazacker, Frédéric Laumonnier, Brigitte Gilbert-Dussardier, Grazia M.S. Mancini, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Arizona, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Birmingham Women's and Children's NHS Foundation Trust, University of Akron, Yerevan State Medical University after Mkhitar Heratsi, Charles University [Prague] (CU), Center for Integrative Brain Research, University of Washington [Seattle], University of California [Los Angeles] (UCLA), University of California (UC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), 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], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], National Human Genome Research Institute, Ministry of Health of the Czech Republic, DGOS, Wellcome Trust, Chard-Hutchinson, Xavier, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Amsterdam UMC, University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-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 )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Human Genetics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis
Subjects: Models, Molecular, Male, 0301 basic medicine, Hydrolases, [SDV]Life Sciences [q-bio], Hippocampal formation, Medical and Health Sciences, 0302 clinical medicine, Neurodevelopmental disorder, Tubulin, Models, Neurotrophic factors, Cerebellum, Intellectual disability, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, dendrite branching, Genetics (clinical), de novo missense variants, Pediatric, Genetics & Heredity, DPYSL5, Biological Sciences, [SDV] Life Sciences [q-bio], corpus callosum agenesis, Mental Health, Child, Preschool, Neurological, Female, Microtubule-Associated Proteins, Adult, Neurite, Intellectual and Developmental Disabilities (IDD), primary neuronal cultures, Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Rare Diseases, Mediator, Report, Intellectual Disability, Genetics, medicine, Humans, Preschool, Corpus Callosum Agenesis, brain malformation, Neurosciences, Molecular, medicine.disease, neurodevelopmental disorder, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Missense, Agenesis of Corpus Callosum, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
Published: 2021
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33. High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts

Author: Cretin, Emma, Lopes, Priscilla, Vimont, Elodie, Tatsuta, Takashi, Langer, Thomas, Gazi, Anastasia, Sachse, Martin, Yu‐Wai‐Man, Patrick, Reynier, Pascal, Wai, Timothy, Cretin, Emma [0000-0002-8423-233X], Tatsuta, Takashi [0000-0003-0003-0587], Langer, Thomas [0000-0003-1250-1462], Gazi, Anastasia [0000-0002-2922-3625], Sachse, Martin [0000-0001-5981-9166], Yu‐Wai‐Man, Patrick [0000-0001-7847-9320], Reynier, Pascal [0000-0003-0802-4608], Wai, Timothy [0000-0002-6770-6222], Apollo - University of Cambridge Repository, Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Max planck Institute for Biology of Ageing [Cologne], Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), University of Cambridge [UK] (CAM), Moorfields Eye Hospital [London], UCL-Institute of Ophthalmology, University College of London [London] (UCL), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), T.W. is supported by the European Research Council (ERC) Starting Grant No. 714472 (Acronym 'Mitomorphosis') and ATIP-AVENIR (INSERM/CNRS). E.C. is supported by a PhD scholarship from the French Ministry of Higher Education, Research, and Innovation (Ministère français de lʼEnseignement supérieur, de la Recherche et de lʼInnovation). T.L. was supported by funds of the German Research Council (CRC1218, project number 269925409. P.YWM. is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK) and also receives funding from Fight for Sight (UK), Moorfields Eye Charity, the Isaac Newton Trust (UK), the Addenbrooke's Charitable Trust, the National Eye Research Centre (UK), the International Foundation for Optic Nerve Disease (IFOND), the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health., We thank Kristin Tsuo and Vincent Guillemot for statistical assistance in R, Etienne Kornobis for Illumina sequencing, and Pierre-Henri Commere and Sandrine Schmutz for flow cytometry services at the Institut Pasteur. Imaging on the Opera Phenix, funded by the Région Ile-de-France program DIM1-Health, was facilitated by Nathalie Aulner. We thank Sylvie Fabrega of the Viral Vector for Gene Transfer core facility of Structure Fédérative de Recherche Necker, Université de Paris for lentiviral particle synthesis. We thank Michael Ryan for providing MEFs lacking MiD49/MiD51/Mff, Nils-Göran Larsson for providing mitoYFP mice, and Guangwei Du for plasmids. We thank Arnaud Echard for critical reading of the manuscript and Marie Lemesle for excellent administrative assistance., European Project: 714472,ERC-2016-STG,Mitomorphosis(2017), Yu-Wai-Man, Patrick [0000-0001-7847-9320], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Institut Pasteur [Paris], Faculty of Brain Sciences of University College London (UCL), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Medicine (General), phospholipid metabolism, QH426-470, DNA, Mitochondrial, OPA1, Article, high‐throughput screening, GTP Phosphohydrolases, EMBO57, R5-920, EMBO16, Optic Atrophy, Autosomal Dominant, Genetics, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], High-throughput screening, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Articles, Fibroblasts, genetic modifiers, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, mitochondrial dynamics, High-Throughput Screening Assays, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, EMBO27, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Abstract: International audience; Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.
Published: 2021
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34. Outpatient Management of Patients With COVID-19: Multicenter Prospective Validation of the Hospitalization or Outpatient Management of Patients With SARS-CoV-2 Infection Rule to Discharge Patients Safely

Author: Douillet, Delphine, Penaloza, A, Mahieu, R, Morin, F, Chauvin, A, Gennai, S, Schotte, T, Montassier, E, Thiebaud, P-C, Ghuysen, A, Dall’acqua, D, Benhammouda, K, Bissokele, P, Violeau, M, Joly, L-M, Andrianjafy, H, Soulie, C, Savary, D, Riou, J, Roy, P-M, Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cliniques Universitaires Saint-Luc [Bruxelles], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital universitaire Robert Debré [Reims], Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Liège (CHU-Liège), CH Vichy, CH Colmar, Centre Hospitalier Libourne, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CHU Rouen, Normandie Université (NU), Groupe Hospitalier Nord Essonne [Longjumeau], CH Cholet, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), 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), None, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Université de 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 ), and Chard-Hutchinson, Xavier
Subjects: [SDV] Life Sciences [q-bio], clinical support decision tool, expert consensus, [SDV]Life Sciences [q-bio], outpatient, rule-based decision-making, COVID-19, rule validation, hospitalization
Abstract: International audience; BACKGROUND: The Hospitalization or Outpatient Management of Patients With SARS-CoV-2 Infection (HOME-CoV) rule is a checklist of eligibility criteria for home treatment of patients with COVID-19, defined using a Delphi method. RESEARCH QUESTION: Is the HOME-CoV rule reliable for identifying a subgroup of COVID-19 patients with a low risk of adverse outcomes who can be treated at home safely? STUDY DESIGN AND METHODS: We aimed to validate the HOME-CoV rule in a prospective, multicenter study before and after trial of patients with probable or confirmed COVID-19 who sought treatment at the ED of 34 hospitals. The main outcome was an adverse evolution, that is, invasive ventilation or death, occurring within the 7 days after patient admission. The performance of the rule was assessed by the false-negative rate. The impact of the rule implementation was assessed by the absolute differences in the rate of patients who required invasive ventilation or who died and in the rate of patients treated at home, between an observational and an interventional period after implementation of the HOME-CoV rule, with propensity score adjustment. RESULTS: Among 3,000 prospectively enrolled patients, 1,239 (41.3%) demonstrated a negative HOME-CoV rule finding. The false-negative rate of the HOME-CoV rule was 4 in 1,239 (0.32%; 95% CI, 0.13%-0.84%), and its area under the receiver operating characteristic curve was 80.9 (95% CI, 76.5-85.2). On the adjusted populations, 25 of 1,274 patients (1.95%) experienced an adverse evolution during the observational period vs 12 of 1,274 patients (0.95%) during the interventional period: -1.00 (95% CI, -1.86 to -0.15). During the observational period, 858 patients (67.35%) were treated at home vs 871 patients (68.37%) during the interventional period: -1.02 (95% CI, -4.46 to 2.26). INTERPRETATION: A large proportion of patients treated in the ED with probable or confirmed COVID-19 have a negative HOME-CoV rule finding and can be treated safely at home with a very low risk of complications. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04338841; URL: www.clinicaltrials.gov.
Published: 2021
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35. Serum Interleukin-26 Is a New Biomarker for Disease Activity Assessment in Systemic Lupus Erythematosus

Author: Benoit Brilland, Maxime Bach-Bunner, Christopher Nunes Gomes, Vincent Larochette, Etienne Foucher, Marc Plaisance, Patrick Saulnier, Nathalie Costedoat-Chalumeau, Pascale Ghillani, Cristina Belizna, Yves Delneste, Jean-François Augusto, Pascale Jeannin, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Dpt Néphrologie Dialyse Transplantation [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Service des maladies du sang [CHU Angers], CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'immunologie et allergologie [CHU Angers], Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, Male, Urine, complement consumption, Gastroenterology, Severity of Illness Index, Serology, chemistry.chemical_compound, 0302 clinical medicine, IL-26, systemic lupus erythematosus, Immunology and Allergy, Lupus Erythematosus, Systemic, skin and connective tissue diseases, Original Research, Proteinuria, biology, Complement C4, Complement C3, Middle Aged, Prognosis, 3. Good health, Biomarker (medicine), Female, medicine.symptom, Antibody, Adult, medicine.medical_specialty, Immunology, Inflammation, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Autoantibodies, Creatinine, SLEDAI, business.industry, Interleukins, Autoantibody, RC581-607, 030104 developmental biology, chemistry, Case-Control Studies, anti-DNA antibodies, biology.protein, Immunologic diseases. Allergy, business, Biomarkers, 030215 immunology
Abstract: ObjectiveInterleukin-26 (IL-26) has a unique ability to activate innate immune cells due to its binding to circulating double-stranded DNA. High levels of IL-26 have been reported in patients with chronic inflammation. We aimed to investigate IL-26 levels in patients with systemic lupus erythematosus (SLE).MethodsIL-26 serum levels were quantified by ELISA for 47 healthy controls and 109 SLE patients previously enrolled in the PLUS study. Performance of IL-26 levels and classical markers (autoantibodies or complement consumption) to identify an active SLE disease (SLE disease activity index (SLEDAI) score > 4) were compared.ResultsIL-26 levels were significantly higher in SLE patients than in controls (4.04 ± 11.66 and 0.74 ± 2.02 ng/mL; p = 0.005). IL-26 levels were also significantly higher in patients with active disease than those with inactive disease (33.08 ± 21.06 vs 1.10 ± 3.80 ng/mL, p < 0.0001). IL-26 levels correlated with SLEDAI score and the urine protein to creatinine ratio (uPCR) (p < 0.001). Patients with high IL-26 levels had higher SLEDAI score, anti-DNA antibodies levels, and uPCR (p < 0.05). They presented more frequently with C3 or C4 complement consumption. Lastly, IL-26 showed stronger performance than classical markers (complement consumption or autoantibodies) for active disease identification.ConclusionsOur results suggest that, in addition to classical SLE serological markers, the measurement of IL-26 levels may be a useful biomarker for active disease identification in SLE patients.
Published: 2021
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36. Splenectomy for haemophagocytic lymphohistiocytosis of unknown origin: risks and benefits in 21 patients

Author: Guillemette Fouquet, G. Urbanski, Claire Larroche, Fabrice Bonnet, Nanthara Sritharan, Charlotte Salmon Gandonnière, Coralie Bloch-Queyrat, Estibaliz Lazaro, Benjamin Carpentier, Antoinette Perlat, Olivier Hermine, Carole Lacout, François Lifermann, Louis Terriou, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier de Dax, Centre Hospitalier de Saint-Denis [Ile-de-France], 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), CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Admin, Oskar, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Splenectomy, Hemophagocytic lymphohistiocytosis, Risk Assessment, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Diagnosis, medicine, Humans, Risks and benefits, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Hematology, Middle Aged, medicine.disease, 3. Good health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030215 immunology
Abstract: International audience; No abstract available
Published: 2021
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37. Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature

Author: Anthony T. Moore, Yann Nadjar, Miodrag Vojcic, Patrick Yu-Wai-Man, F. Lucy Raymond, James Acheson, Anthony G. Robson, Guy Lenaers, Mary M. Reilly, Neringa Jurkute, Andrew R. Webster, Jenny Higgs, Gavin Arno, Priya D. Shanmugarajah, Marios Hadjivassiliou, Valérie Touitou, Iain Horrocks, Roy Poh, University College of London [London] (UCL), NHS Foundation Trust [London], The Royal Marsden, Royal Hallamshire Hospital, Liverpool Women's NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, Royal Hospital for Sick Children, Glasgow, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Service d'Ophtalmologie [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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCL, Institute of Neurology [London], University of Cambridge [UK] (CAM), Institute of Neurology, Queen Square, London, University of California (UC), HAL-SU, Gestionnaire, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), University of California, and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: 0301 basic medicine, Retinal degeneration, Adult, Male, Adolescent, Mutation, Missense, Visual Acuity, Disease, Retina, syndromic optic neuropathy, 03 medical and health sciences, ferredoxin reductase, Young Adult, 0302 clinical medicine, Atrophy, Retinal Dystrophies, Exome Sequencing, medicine, Genetics, Electroretinography, Missense mutation, Humans, retinal dystrophy, Child, Exome sequencing, Retrospective Studies, Whole genome sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Haplotype, medicine.disease, 3. Good health, Pedigree, Ferredoxin-NADP Reductase, 030104 developmental biology, Phenotype, FDXR, iron accumulation, Child, Preschool, Female, business, neurodegenerative disorder, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Author(s): Jurkute, Neringa; Shanmugarajah, Priya D; Hadjivassiliou, Marios; Higgs, Jenny; Vojcic, Miodrag; Horrocks, Iain; Nadjar, Yann; Touitou, Valerie; Lenaers, Guy; Poh, Roy; Acheson, James; Robson, Anthony G; Raymond, F Lucy; Reilly, Mary M; Yu-Wai-Man, Patrick; Moore, Anthony T; Webster, Andrew R; Arno, Gavin; Genomics England Research Consortium | Abstract: PurposeThe purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.MethodsPatients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.ResultsTen individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C g A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.ConclusionsFDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations.
Published: 2021
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38. Hand Strength Deficit in Patients with Neurogenic Thoracic Outlet Syndrome

Author: Alban Fouasson-Chailloux, Bastien Louguet, Pierre Abraham, Pauline Daley, Guillaume Gadbled, Marc Dauty, Yves Bouju, Pierre Menu, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU Nantes - Pôle médecine physique et de réadaptation (CHU Nantes - PHU/MPR), Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Saint-Jacques [CHU Nantes], Département de Médecine du Sport [CHU Nantes], Clinique Chirurgicale Orthopédique et Traumatologique - CCOT [CHU Nantes], Institut Main Atlantique [Saint Herblain] (IMA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Jehan, Frederic, Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Medicine (General), medicine.medical_specialty, Weakness, Clinical Biochemistry, neurogenic, 030204 cardiovascular system & hematology, Asymptomatic, Article, 03 medical and health sciences, Grip strength, R5-920, 0302 clinical medicine, Hand strength, thoracic outlet syndrome, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], In patient, grip, Neurogenic thoracic outlet syndrome, Thoracic outlet syndrome, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Healthy subjects, medicine.disease, body regions, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Physical therapy, medicine.symptom, business, strength, key pinch, 030217 neurology & neurosurgery
Abstract: Neurogenic thoracic outlet syndrome (NTOS) is a chronic painful and disabling condition. Patients complain about upper-limb paresthesia or weakness. Weakness has been considered one of the diagnostic criteria of NTOS, but objective comparisons to healthy controls are lacking. We compared the grip and the key pinch strengths between NTOS patients and healthy controls. Grip strength was evaluated with a hydraulic hand dynamometer and the key pinch with a pinch gauge. All the patients with NTOS completed a QuickDASH. We included prospectively 85 patients with NTOS, 73% female and 27% male. The mean age was 40.4 ± 9.6. They were compared to 85 healthy subjects, 77.6% female and 22.4% male. Concerning the grip, symptomatic hands of NTOS patients had significantly 30% less strength compared to control hands (p ≤ 0.001), and 19% less strength compared to asymptomatic hands (p = 0.03). Concerning the key pinch, symptomatic hands of patients with NTOS had significantly 19.5% less strength compared to control hands (p ≤ 0.001). Grip and key pinch strengths had a significant correlation with the QuickDASH (r = −0.515 and r = −0.403, respectively, p ≤ 0.001). Patients with NTOS presented an objective hand strength deficit compared to healthy controls. This deficit was significantly correlated to the upper-limb disability. These findings confirm the interest of hand strength evaluation in the diagnostic process of patients with NTOS.
Published: 2021
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39. The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells

Author: Hathaichanok Impheng, Christian Legros, Narawut Pakaprot, Philippe Lory, Malik Bouasse, Céline Lemmers, Arnaud Monteil, Nathalie C. Guérineau, 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), LabEx Ion Channels Science and Therapeutics [France], BioCampus (BCM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mahidol University [Bangkok], Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Association Française contre les Myopathies, Fondation Maladies Rares, Naresuan University (NU), Ministère des Affaires Etrangères, ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), Guerineau, Nathalie C., Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, extracellular Ca2+, endocrine system, resting membrane potential, [SDV]Life Sciences [q-bio], Cell, Action Potentials, Enteroendocrine cell, Biochemistry, Membrane Potentials, 03 medical and health sciences, 0302 clinical medicine, Anterior pituitary, Genetics, Extracellular, medicine, Animals, Secretion, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], background conductance, Molecular Biology, Ion channel, Membrane potential, Chemistry, Sodium, Membrane Proteins, ion channels, Prolactin, Rats, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Pituitary Gland, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Endocrine Cells, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Biotechnology
Abstract: International audience; Anterior pituitary endocrine cells that release hormones such as growth hormone and prolactin are excitable and fire action potentials. In these cells, several studies previously showed that extracellular sodium (Na+ ) removal resulted in a negative shift of the resting membrane potential (RMP) and a subsequent inhibition of the spontaneous firing of action potentials, suggesting the contribution of a Na+ background conductance. Here, we show that the Na+ leak channel NALCN conducts a Ca2+ - Gd3+ -sensitive and TTX-resistant Na+ background conductance in the GH3 cell line, a cell model of pituitary endocrine cells. NALCN knockdown hyperpolarized the RMP, altered GH3 cell electrical properties and inhibited prolactin secretion. Conversely, the overexpression of NALCN depolarized the RMP, also reshaping the electrical properties of GH3 cells. Overall, our results indicate that NALCN is functional in GH3 cells and involved in endocrine cell excitability as well as in hormone secretion. Indeed, the GH3 cell line suitably models native pituitary cells that display a similar Na+ background conductance and appears as a proper cellular model to study the role of NALCN in cellular excitability.
Published: 2021
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40. Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Author: Nathalie C. Guérineau, César Mattei, Joohee Park, Frédéric De Nardi, Christian Legros, Claire Legendre, Daniel Henrion, Hélène Tricoire-Leignel, Jennifer Bourreau, Antoine Taly, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Guerineau, Nathalie C.
Subjects: Male, 0301 basic medicine, Insecticides, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Nicotinic, 010501 environmental sciences, Pharmacology, epinephrine secretion, Guanidines, 01 natural sciences, Nicotine, Biology (General), Receptor, α3β4 nAChR, Spectroscopy, Epinephrine secretion, Chemistry, blood pressure, General Medicine, Computer Science Applications, Drug Partial Agonism, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Toxicity Tests, Subacute, medicine.anatomical_structure, Nicotinic agonist, [SDV.TOX]Life Sciences [q-bio]/Toxicology, psychological phenomena and processes, medicine.drug, Agonist, Epinephrine, QH301-705.5, medicine.drug_class, acetamiprid, education, clothianidin, behavioral disciplines and activities, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, mental disorders, medicine, Animals, Arterial Pressure, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, 0105 earth and related environmental sciences, acute intoxication, Organic Chemistry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Rats, Disease Models, Animal, Thiazoles, 030104 developmental biology, Gene Expression Regulation, Adrenal Medulla, Catecholamine, Cholinergic, Ganglia, neonicotinoids, Adrenal medulla, nicotine
Abstract: Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3β4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3β4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 μM, but it was stronger at 500 μM. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3β4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms.
Published: 2021
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41. History of heart failure in patients with coronavirus disease 2019: Insights from a French registry

Author: Iris Ma, Orianne Weizman, Thibaut Pommier, Cyril Zakine, A. Darmon, Melchior Jonveaux, Nacim Ezzouhairi, Théo Pezel, Wassima Marsou, Laura Geneste, Delphine Mika, C Fauvel, Antoine Deney, Thomas Delmotte, Baptiste Duceau, Vassili Panagides, Thomas Levasseur, Julien Ternacle, Clément Karsenty, Guillaume Bonnet, Victor Waldmann, Flavien Vincent, Marine Mevelec, Sabir Attou, Joffrey Cellier, Ariel Cohen, Antonin Trimaille, Diane Chavignier, Willy Sutter, Nathalie Noirclerc, Benjamin Perin, Hôpital Nord [CHU - APHM], CHU Lille, Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Henri Mondor, Nouvel Hôpital Civil de Strasbourg, CHU Strasbourg, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Amiens-Picardie, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Rouen, Normandie Université (NU), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Clinique Saint Gatien, Centre Hospitalier Intercommunal Fréjus - St Raphaël (CHI Fréjus - St Raphaël), Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière-Fernand-Widal [APHP], Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], CHRU de Nancy, Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)], Hôpital Européen Georges Pompidou [APHP] [HEGP], Groupement des Hôpitaux de l'Institut Catholique de Lille [GHICL], Centre Hospitalier Universitaire de Toulouse [CHU Toulouse], Centre Hospitalier Universitaire de Reims [CHU Reims], Université de Bordeaux [UB], Centre Hospitalier Intercommunal Fréjus - St Raphaël [CHI Fréjus - St Raphaël], Centre Hospitalier Régional d'Orléans [CHRO], and Signalisation et physiopathologie cardiovasculaire [UMRS1180]
Subjects: Male, qSOFA, quick sequential organ failure assessment, [SDV]Life Sciences [q-bio], CHF, chronic heart failure, Comorbidity, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, HF, heart failure, 0302 clinical medicine, RAAS, renin-angiotensin-aldosterone system, Risk Factors, LVEF, left ventricular ejection fraction, Clinical endpoint, 030212 general & internal medicine, Hospital Mortality, Registries, Résultats, COVID-19, coronavirus disease 2019, Ejection fraction, Incidence, Hazard ratio, Confounding Factors, Epidemiologic, General Medicine, Stroke volume, Middle Aged, Treatment Outcome, Cardiology, Female, France, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, HFpEF, heart failure with preserved ejection fraction, RT-PCR, real-time reverse transcriptase polymerase chain reaction, Heart failure, ACE2, angiotensin-converting enzyme 2, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, 03 medical and health sciences, Facteurs de risque, Clinical Research, COVID-19, Femme, HFpEF, HFrEF, RAAS inhibitors, SARS-COV 2, Internal medicine, medicine, Intubation, Intratracheal, Humans, HFrEF, heart failure with reduced ejection fraction, Aged, Retrospective Studies, business.industry, SARS-CoV-2, Retrospective cohort study, Stroke Volume, medicine.disease, business, Heart failure with preserved ejection fraction, Procedures and Techniques Utilization
Abstract: Summary Background Although cardiovascular comorbidities seem to be strongly associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), data regarding patients with preexisting heart failure are limited. Aims To investigate the incidence, characteristics and clinical outcomes of patients with COVID-19 with a history of heart failure with preserved or reduced ejection fraction. Methods We performed an observational multicentre study including all patients hospitalized for COVID-19 across 24 centres in France from 26 February to 20 April 2020. The primary endpoint was a composite of in-hospital death or need for orotracheal intubation. Results Overall, 2809 patients (mean age 66.4 ± 16.9 years) were included. Three hundred and seventeen patients (11.2%) had a history of heart failure; among them, 49.2% had heart failure with reduced ejection fraction and 50.8% had heart failure with preserved ejection fraction. COVID-19 severity at admission, defined by a quick sequential organ failure assessment score > 1, was similar in patients with versus without a history of heart failure. Before and after adjustment for age, male sex, cardiovascular comorbidities and quick sequential organ failure assessment score, history of heart failure was associated with the primary endpoint (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.06–1.90; P = 0.02). This result seemed to be mainly driven by a history of heart failure with preserved ejection fraction (HR: 1.61, 95% CI: 1.13–2.27; P = 0.01) rather than heart failure with reduced ejection fraction (HR: 1.19, 95% CI: 0.79–1.81; P = 0.41). Conclusions History of heart failure in patients with COVID-19 was associated with a higher risk of in-hospital death or orotracheal intubation. These findings suggest that patients with a history of heart failure, particularly heart failure with preserved ejection fraction, should be considered at high risk of clinical deterioration.
Published: 2021
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42. LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4

Author: Gilles Simard, Zainab Safiedeen, Arnaud Chevrollier, Sakina Ali, Ramaroson Andriantsitohaina, Luisa Vergori, M. Carmen Martinez, Soazig Le Lay, Xavier Vidal-Gómez, Frédéric Gagnadoux, Marine Malloci, Jérôme Boursier, Charlène Besnard, Raffaella Soleti, Séverine Dubois, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm, Université d'Angers, Centre Hospitalo-Universitaire d'Angers, BOURGEAIS, Véronique, and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Lipopolysaccharides, Male, 0301 basic medicine, Mitochondrial ROS, Endocrinology, Diabetes and Metabolism, viruses, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Exosomes, Cohort Studies, Mice, chemistry.chemical_compound, Cytosol, Endocrinology, 0302 clinical medicine, Medicine, 030212 general & internal medicine, Endothelial dysfunction, Cells, Cultured, chemistry.chemical_classification, Organelle Biogenesis, virus diseases, MESH: Toll-Like Receptor 4, Middle Aged, respiratory system, Metabolic syndrome, Mitochondria, [SDV] Life Sciences [q-bio], Female, MESH: Endothelium, Vascular, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, MESH: Metabolic Syndrome, 030209 endocrinology & metabolism, Nitric Oxide, Nitric oxide, Extracellular Vesicles, 03 medical and health sciences, Insulin resistance, Internal medicine, Animals, Humans, MESH: Extracellular Vesicles, Reactive oxygen species, business.industry, medicine.disease, Toll-Like Receptor 4, Oxidative Stress, 030104 developmental biology, chemistry, Mitochondrial biogenesis, TLR4, Endothelium, Vascular, MESH: Lipopolysaccharides, Reactive Oxygen Species, business, Dyslipidemia
Abstract: Background Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors -hyperglycemia, dyslipidemia, hypertension and obesity- leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction. Methods Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs). Results Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs. Conclusion These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.
Published: 2021
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43. Position paper on stress cardiac magnetic resonance imaging in chronic coronary syndrome: Endorsed by the Société française de radiologie (SFR), the Société française d’imagerie cardiovasculaire (SFICV) and the Société française de cardiologie (SFC)

Author: Laurent Macron, Martine Gilard, Jean-Nicolas Dacher, Florent Le Ven, François Pontana, Gilles Barone-Rochette, Damien Mandry, Louis Boyer, Alain Furber, Alexis Jacquier, Olivier Genée, Jérôme Garot, Luc-Philippe Christiaens, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pole Cardio-vasculaire et pulmonaire [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire [Grenoble] (CHU), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Centre cardiologique du Nord (CCN), Hôpital Privé Jacques Cartier [Massy], Pôle santé Oréliance, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de Radiologie adultes [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de cardiologie [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), and DACHER, Jean Nicolas
Subjects: Adult, Male, Techniques d’imagerie cardiaque, Myocardial ischaemia, Angor, Consensus, Delphi Technique, Vasodilator Agents, Angina pectoris, Myocardial Ischemia, Cardiac imaging techniques, 030204 cardiovascular system & hematology, Coronaropathie stable, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Coronary Circulation, Medicine, Humans, 030212 general & internal medicine, Stress Cardiac Magnetic Resonance Imaging, Aged, medicine.diagnostic_test, business.industry, Hemodynamics, Magnetic resonance imaging, General Medicine, Adrenergic beta-Agonists, Middle Aged, Prognosis, Magnetic Resonance Imaging, 3. Good health, Acquisition Protocol, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk stratification, Chronic Disease, Ischémie myocardique, Position paper, Cardiac Imaging Techniques, Female, Stable coronary artery disease, Cardiology and Cardiovascular Medicine, business, Nuclear medicine
Abstract: International audience; This paper is intended to update the former consensus between the French Societies of Radiology and Cardiology about the use of stress cardiac magnetic resonance imaging in chronic coronary syndrome, published in 2009. The Delphi method was used to build the present consensus. This expert panel consensus includes recommendations for indications, the procedure (with patient preparation), stress-inducing drugs, the acquisition protocol, interpretation and risk stratification by stress magnetic resonance imaging.
Published: 2021
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44. Position paper on stress cardiac MRI in chronic coronary syndrome: Endorsed by the Société Française de Radiologie (SFR) the Société Française d’Imagerie CardioVasculaire (SFICV) and the Société Française de Cardiologie (SFC)

Author: Florent Le Ven, Luc Christiaens, Alexis Jacquier, Martine Gilard, Jérôme Garot, Olivier Genée, François Pontana, Louis Boyer, Alain Furber, Laurent Macron, Damien Mandry, Jean-Nicolas Dacher, Gilles Barone-Rochette, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), 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)-Université de Brest (UBO), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre cardiologique du Nord (CCN), Hôpital Privé Jacques Cartier [Massy], Pôle santé Oréliance, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de Radiologie adultes [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de cardiologie [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 de la Cavale Blanche - CHRU Brest (CHU - BREST ), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and DACHER, Jean Nicolas
Subjects: medicine.medical_specialty, Myocardial ischemia, Angina pectoris, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Stress (linguistics), medicine, Radiology, Nuclear Medicine and imaging, Stable coronary artery disease, Cardiac MRI, Stress Cardiac Magnetic Resonance Imaging, Radiological and Ultrasound Technology, business.industry, General Medicine, 3. Good health, Acquisition Protocol, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030220 oncology & carcinogenesis, Risk stratification, Cardiology, Position paper, business
Abstract: International audience; This position paper was intended to update the former consensus between the French Societies of Radiology and Cardiology about the use of stress cardiac magnetic resonance imaging (MRI) in chronic coronary syndrome published in 2009. The Delphi method was used to build the present consensus. This expert panel consensus includes recommendations for indications, procedure with patient preparation, stress inducing drugs, acquisition protocol, interpretation and risk stratification by stress MRI.
Published: 2021
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45. Secondary coenzyme Q deficiency in neurological disorders

Author: Naïg Gueguen, Guy Lenaers, Pascal Reynier, Olivier R. Baris, Marco Spinazzi, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Baris, Olivier
Subjects: 0301 basic medicine, Mitochondrial Diseases, Ubiquinone, [SDV]Life Sciences [q-bio], Cellular functions, Coenzyme Q Deficiency, Mitochondrion, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Medicine, Humans, Tissue Distribution, Tissue distribution, Secondary coenzyme Q deficiency, Muscle Weakness, business.industry, CoQ Deficiency, Skeletal muscle, food and beverages, Brain, Coenzyme Q, 3. Good health, Mitochondria, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Mitochondrial respiratory chain, Coenzyme Q – cytochrome c reductase, Muscle, Ataxia, business, 030217 neurology & neurosurgery, Neurological diseases
Abstract: International audience; Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.
Published: 2021
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46. Acute, major muscular hematoma associated with antithrombotic agents: A multicenter real-world cohort

Author: Karine Lacut, Marie-Clémence Huet, Emmanuel Oger, Pierre-Marie Roy, Laure Pavageau, Jacques Bouget, Damien Viglino, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Grenoble, CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Centre hospitalier universitaire de Nantes (CHU Nantes), National Clinical Research Hospital Program of the French Ministry of Health, No. PHRC-12-009-0243, Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Jonchère, Laurent
Subjects: Adult, medicine.medical_specialty, Vitamin K, [SDV]Life Sciences [q-bio], Population, Prothrombin complex concentrates, 030204 cardiovascular system & hematology, Fondaparinux, Case management, 03 medical and health sciences, 0302 clinical medicine, Hematoma, Fibrinolytic Agents, Internal medicine, Intensive care, Antithrombotic, Humans, Medicine, Mortality, education, Aged, Retrospective Studies, Aged, 80 and over, education.field_of_study, business.industry, Anticoagulants, Hematology, Emergency department, Heparin, Low-Molecular-Weight, Antithrombotic agents, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cohort, Iliopsoas, business, medicine.drug
Abstract: International audience; BACKGROUND: There is little data on major muscular hematomas and the little there is has mainly focused on patients exposed to oral anticoagulants. OBJECTIVE: To describe the clinical characteristics, management and outcomes of patients admitted to emergency department (ED) for major muscular hematoma associated with an antithrombotic agent, and to identify predictors of in-hospital mortality. PATIENTS AND METHODS: Over a three-year period, all consecutive cases of adult patients admitted to the ED of 5 tertiary care hospitals for major muscular hematoma while exposed to an antithrombotic agent were prospectively collected and medically validated. Clinical and biological data, therapeutic management of the bleeding event, and in-hospital mortality were collected from the medical records and compared across five groups of hematoma locations. Potential confounders were taken in account using a multivariate binomial regression model. RESULTS: Three hundred and seventy-five patients were included (mean age = 81.4 years): 271 were exposed to vitamin K antagonists, 58 to parenteral anticoagulants (heparin, LMWH, fondaparinux), 33 to antiplatelets, and 13 to direct oral anticoagulants. The muscular hematomas were located in the lower limbs (n = 198), the rectus sheath (n = 71), the iliopsoas (n = 45), the upper limbs (n = 33), or elsewhere (n = 28). Reversal therapy was prescribed for 48.5% of patients, red cell transfusions for 63.6%, surgery for 12.3% and embolization for 3.5%. For 84% of patients, hospitalization was required, with a median length of stay of 10 days. Overall, in-hospital mortality was 8.5%. Reversal therapy, the need for intensive care and mortality were significantly more frequent among patients with iliopsoas hematomas. The independent predictors of in-hospital mortality were: decrease in mean arterial pressure (RR = 1.84), decrease in hemoglobin level (RR = 1.37) and the iliopsoas location (RR = 3.06). CONCLUSION: Frail elderly patients with major muscular hematomas linked to antithrombotic agents risk substantial morbidity and in-hospital mortality. The iliopsoas location was the most life-threatening bleeding site. Close observation of this population is warranted to ensure better outcomes.
Published: 2021
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47. Point-of-care ultrasonography for risk stratification of non-critical COVID-19 patients on admission (POCUSCO): a study protocol of an international study

Author: Francois Morin, Pierre-Marie Roy, Christophe Aubé, Vincent Dubée, Delphine Douillet, Dominique Savary, Florence Dupriez, Jean-François Hamel, Josué Rakotonjanahary, Jérémie Riou, UCL - SSS/IRSS - Institut de recherche santé et société, UCL - (SLuc) Service des urgences, HAL UR1, Admin, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cliniques Universitaires Saint-Luc [Bruxelles], 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 ), Université d'Angers (UA), NCT04338100Ministère des Affaires Sociales et de la Santé, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 )
Subjects: medicine.medical_specialty, ARDS, Adolescent, [SDV]Life Sciences [q-bio], Point-of-Care Systems, medicine.medical_treatment, Context (language use), Risk Assessment, 030218 nuclear medicine & medical imaging, respiratory infections, 03 medical and health sciences, Patient Admission, 0302 clinical medicine, accident & emergency medicine, medicine, Humans, Multicenter Studies as Topic, Intubation, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Pandemics, business.industry, COVID-19, accident and emergency medicine, ultrasonography, Emergency department, General Medicine, medicine.disease, virology, 3. Good health, [SDV] Life Sciences [q-bio], Emergency medicine, Good clinical practice, Emergency Medicine, Medicine, Emergency Service, Hospital, business, Risk assessment, Declaration of Helsinki
Abstract: IntroductionIn the context of the COVID-19 pandemic, early identification of patients who are likely to get worse is a major concern. Severity mainly depends on the development of acute respiratory distress syndrome (ARDS) with a predominance of subpleural lesions. Lung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may be appropriate for examining patients with COVID-19. We suggest that L-POCUS performed during the initial examination may identify patients with COVID-19 who are at a high risk of complicated treatment or unfavourable evolution.Methods and analysisPoint-of-care ultrasonography for risk stratification of non-critical COVID-19 patients on admission is a prospective, multicentre study. Adult patients visiting the emergency department (ED) of participating centres for suspected or confirmed COVID-19 are assessed for inclusion. Included patients have L-POCUS performed within 48 hours following ED admission. The severity of lung damage is assessed using the L-POCUS score based on 36 points for ARDS. Apart from the L-POCUS score assessment, patients are treated as recommended by the WHO. For hospitalised patients, a second L-POCUS is performed at day 5±3. A follow-up is carried out on day 14, and the patient’s status according to the Ordinal Scale for Clinical Improvement for COVID-19 from the WHO is recorded.The primary outcome is the rate of patients requiring intubation or who are dead from any cause during the 14 days following inclusion. We will determine the area under the ROC curve of L-POCUS.Ethics and disseminationThe protocol has been approved by the French and Belgian Ethics Committees and is carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study is funding by a grant from the French Health Ministry, and its findings will be disseminated in peer-reviewed journals and at scientific conferences.Trial registration numberNCT04338100.
Published: 2021
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48. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Author: Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], 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 E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Immunology, Central nervous system, Alpha interferon, Aicardi-Goutières syndrome, cerebrospinal fluid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medical microbiology, Downregulation and upregulation, systemic lupus erythematosus, Interferon, Humans, Immunology and Allergy, Medicine, Child, Retrospective Studies, business.industry, Infant, Interferon-alpha, medicine.disease, 3. Good health, Hydrocephalus, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Organ Specificity, Case-Control Studies, Child, Preschool, Interferon Type I, Mutation, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, STING-associated vasculopathy with onset in infancy, business, 030215 immunology, medicine.drug
Abstract: International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
Published: 2021
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49. Urothelial Cancer Associated 1 (UCA1) and miR-193 Are Two Non-coding RNAs Involved in Trophoblast Fusion and Placental Diseases

Author: Apicella, Clara, Ruano, Camino, Jacques, Sébastien, Gascoin, Géraldine, Méhats, Céline, Vaiman, Daniel, Miralles, Francisco, 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 de Paris (UP), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Miralles, Francisco
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], placenta, intra uterine growth restriction, Cell Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, trophoblast, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], preeclampsia, Cell and Developmental Biology, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, syncytialisation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], embryonic structures, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], non-coding RNAs, Original Research, Developmental Biology
Abstract: International audience; A bioinformatics screen for non-coding genes was performed from microarrays analyzing on the one hand trophoblast fusion in the BeWo cell model, and on the other hand, placental diseases (preeclampsia and Intra-Uterine Growth Restriction). Intersecting the deregulated genes allowed to identify two miRNA (mir193b and miR365a) and one long non-coding RNA (UCA1) that are pivotal for trophoblast fusion, and deregulated in placental diseases. We show that miR-193b is a hub for the down-regulation of 135 cell targets mainly involved in cell cycle progression and energy usage/nutrient transport. UCA1 was explored by siRNA knock-down in the BeWo cell model. We show that its down-regulation is associated with the deregulation of important trophoblast physiology genes, involved in differentiation, proliferation, oxidative stress, vacuolization, membrane repair and endocrine production. Overall, UCA1 knockdown leads to an incomplete gene expression profile modification of trophoblast cells when they are induced to fuse into syncytiotrophoblast. Then we performed the same type of analysis in cells overexpressing one of the two major isoforms of the STOX1 transcription factor, STOX1A and STOX1B (associated previously to impaired trophoblast fusion). We could show that when STOX1B is abundant, the effects of UCA1 down-regulation on forskolin response are alleviated.
Published: 2021
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50. Venous Thromboembolic Risk in Patients with Lower Limb Trauma Requiring Immobilization: Towards an Individualized Approach

Author: Douillet, D., Barbere, T., Peintre, M., Moumneh, T., Morin, F., Savary, D., Penaloza, A., Roy, P-M, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), Université d'Angers (UA), Université Catholique de Louvain = Catholic University of Louvain (UCL), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and 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 )
Subjects: [SDV]Life Sciences [q-bio], Immobilisation, Thromboprophylaxis, Trauma, Risk stratification, Venous thromboembolism
Abstract: National audience; Lower limb trauma requiring immobilization is a situation at risk of developing venous thromboembolic (VTE) disease. However, recommendations and practices vary significantly from country to country and from center to center. The aims of this narrative review are to describe the epidemiology, prevention, and prediction algorithms for venous thromboembolic disease in patients with lower limb trauma requiring immobilization. The incidence of VTE varies between studies due to the great heterogeneity of the patients included (from ankle sprains to major injuries requiring surgery) and due to the heterogeneity of the evaluation criteria (consideration of asymptomatic proximal or distal or only symptomatic thrombosis). The estimated incidence of symptomatic venous thromboembolic events is 2.0% (95% confidence interval: 1.3 to 2.7). The efficacy of thromboprophylaxis has been confirmed in two meta-analyses that included randomized controlled trials. However, these results had to be carefully interpreted because many trials had methodological flaws. The largest and most recent study showed no benefit of low molecular weight heparin prevention on symptomatic events in an unselected population. These results suggest adopting a personalized strategy, keeping prophylaxis for at-risk patients. Several scores are currently being proposed to assess individual thromboembolic risk. Considering the characteristics of the patient, the trauma, and the immobilization, it is possible to identify a large subgroup of patients in whom prevention seems useless and a subgroup of high-risk patients in whom prevention should be prescribed or even reinforced. In conclusion, in the case of lower limb trauma requiring immobilization, the indication for thromboprophylaxis should be guided by the individual assessment of thrombotic risk.
Published: 2021
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