Author: "Centre Régional de Pharmacovigilance (CRPV)" - Searchworks@Jio Institute Digital Library Search Results

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1. Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies

Author: Vassilis Koutkias, Agnès Lillo-Le Louët, Marie-Christine Jaulent, Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris 13 (UP13), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé ( LIMICS ), Université Paris 13 ( UP13 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Pharmacovigilance ( CRPV ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Paris 13 (UP13)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Drug-Related Side Effects and Adverse Reactions, Pyridones, social media, Information Storage and Retrieval, joint exploitation, Adverse drug events, 030226 pharmacology & pharmacy, case studies, computational framework, Pharmacovigilance, 03 medical and health sciences, Adverse Event Reporting System, 0302 clinical medicine, Data acquisition, emerging data sources for pharmacovigilance, Robustness (computer science), Adverse Drug Reaction Reporting Systems, Humans, Medicine, Pharmacology (medical), Social media, 030212 general & internal medicine, spontaneous reporting systems, Clozapine, Cerebral Hemorrhage, heterogeneous public data, Safety surveillance, business.industry, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, General Medicine, Data science, Cardiotoxicity, 3. Good health, Visualization, Identification (information), [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Haloperidol, Pyrazoles, bibliographic databases, business, Antipsychotic Agents, Factor Xa Inhibitors
Abstract: International audience; Objective: Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance.Methods: Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage.Results: The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework.Conclusions: This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.
Published: 2016
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2. Changing spectrum of suspected drugs of epidermal necrolysis: A World Health Organization pharmacovigilance database analysis from 1997-2020

Author: N. de Prost, T. Bettuzzi, C. Chinchilla Purtillo, Bénédicte Lebrun-Vignes, P. Maison, Laurence Le Cleach, Emilie Sbidian, Pierre Wolkenstein, S. Ingen-Housz Oro, Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: medicine.medical_specialty, Databases, Factual, Drug-Related Side Effects and Adverse Reactions, business.industry, Database analysis, MEDLINE, Dermatology, Antibodies, Monoclonal, Humanized, World Health Organization, medicine.disease, Toxic epidermal necrolysis, Pharmacovigilance, Pharmaceutical Preparations, Epidermal necrolysis, Stevens-Johnson Syndrome, medicine, Adverse Drug Reaction Reporting Systems, Humans, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Retrospective Studies
Abstract: International audience
Published: 2021
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3. A cell-contact-regulated operon is involved in genetic variability in Neisseria meningitidis

Author: Xavier Nassif, Eric Frapy, Dominique Schneider, Anne Jamet, Patricia Martin, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Universite Paris Descartes, INSERM, Region Ile-De-France, Foundation pour la Recherche Medicale, Centre Régional de Pharmacovigilance ( CRPV ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Pathogénie des infections systémiques ( UMR_S 570 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] ( LAPM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH : Operon, Operon, TOPOISOMERASES, Cell, Neisseria meningitidis, medicine.disease_cause, Bacterial Adhesion, MESH : Host-Pathogen Interactions, Genetics, 0303 health sciences, Mutation, MESH: Gene Expression Regulation, Bacterial, SEROGROUP-A, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], General Medicine, GENOME, [ SDV.BID.EVO ] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], medicine.anatomical_structure, Interaction with host, Meningococcus, ESCHERICHIA-COLI, Host-Pathogen Interactions, MESH : Gene Expression Regulation, Bacterial, MESH: Operon, PHASE VARIATION, OUTER-MEMBRANE PROTEIN, MESH : Bacterial Adhesion, Biology, Microbiology, MESH: Neisseria meningitidis, 03 medical and health sciences, MESH: Gene Expression Profiling, Downregulation and upregulation, medicine, HIGH MUTATION-RATES, Humans, Genetic variability, MESH: Bacterial Adhesion, Molecular Biology, Gene, 030304 developmental biology, MESH: Humans, MESH : Neisseria meningitidis, 030306 microbiology, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Humans, MESH: Host-Pathogen Interactions, Gene Expression Regulation, Bacterial, EVOLUTION, bacteria, HOST-CELLS, SYSTEM
Abstract: International audience; The ability of Neisseria meningitidis to establish efficient interaction with host cells is crucial for its survival. We recently demonstrated that an entire operon containing genes NMA1802 to NMA1806 was overexpressed during the early stage of the colonization process. In this work, we investigated whether upregulation of the expression of this operon facilitated the ability of N. meningitidis to adapt to growth on host cells. Using a strain displaying an inducible operon, we demonstrated that the NMA1802-NMA1806 cell-contact-regulated operon could potentially improve the adaptability of meningococcus during growth on the cell surface through enhanced generation of variants.
Published: 2012
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4. Documentation in pharmacovigilance: using an ontology to extend and normalize Pubmed queries

Author: Delamarre, Denis, Lillo-Le Louët, Agnès, Guillot, Laetitia, Jamet, Anne, Sadou, Eric, Ouazine, Theo, Burgun, Anita, Jaulent, Marie-Christine, Modélisation Conceptuelle des Connaissances Biomédicales, 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 ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Pharmacovigilance ( CRPV ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire de Santé Publique et Informatique Médicale ( SPIM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes (UR)-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 Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de Santé Publique et Informatique Médicale (SPIM), Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: MESH: Terminology as Topic, PubMed, Drug-Related Side Effects and Adverse Reactions, Adverse drug reaction reporting, Adverse drug reaction, MESH: Documentation, Documentation, MESH: Drug Toxicity, MESH: Natural Language Processing, MESH : Database Management Systems, Terminology as Topic, MESH : Vocabulary, Controlled, Data Mining, Humans, Information retrieval, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, Natural Language Processing, MESH: Humans, Ontology, MESH : Data Mining, MESH: Data Mining, MESH : Humans, MESH : Drug Toxicity, MESH: PubMed, MESH: Vocabulary, Controlled, MESH : Natural Language Processing, MESH : PubMed, MESH : Terminology as Topic, Vocabulary, Controlled, Database Management Systems, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH : Documentation, Databases bibliographic, MESH: Database Management Systems
Abstract: International audience; OBJECTIVES: To assess and understand adverse drug reactions (ADRs), a systematic review of reference databases like Pubmed is a necessary and mandatory step in Pharmacovigilance. In order to assist pharmacovigilance team with a computerized tool, we performed a comparative study of 4 different approaches to query Pubmed through ADR-drug terms. The aim of this study is to assess how an ontology of adverse effects, used to normalize and extend queries, could improve this search. MATERIAL AND METHOD: The ontological resource OntoEIM contains 58,000 classes and integrates MedDRA terminology. The entry point is a ADR-Drug term and the four methods are (i) a direct search on Pubmed (ii) a search with a normalized query enhanced with domain-specific Mesh Heading criteria, (iii) a search with the same elaborated query extended to the MeSH sub-hierarchy of the adverse effect entry and (iv) a search with a set of MedDRA terms grouped by subsomption in the OntoEIM ontology. For each of the 16 queries performed and analysed, relevant publications are selected "manually" by two pharmacovigilant experts. RESULTS: The recall is respectively of 63%, 50%, 67% and 74%, the precision of 13%, 26%, 29% and 4%. The best recall is provided by the ontology-based method, for 4 cases out of 16 this method returns relevant publications when the others return no results. CONCLUSION: Results show that an ontology-based search tool improves the recall performance, but other tools and methods are needed to raise the precision.
Published: 2010
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5. Erreurs médicamenteuses en Auvergne Rhône-Alpes : étude pilote descriptive collaborative entre structures régionales de vigilance et d’appui (SRVA)

Author: Pauline Rascle, Nathalie Paret, Marie Zenut, Benjamin Grenier, Michel Roy, Amélie Faudel, Marion Lepelley, Jean-Marc Sapori, Catherine Stamm, Laurence Gilles-Afchain, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hospices Civils de Lyon (HCL), Centre Régional de Pharmacovigilance [CHU Clermont-Ferrand] (CRPV), CHU Gabriel Montpied [Clermont-Ferrand], and CHU Clermont-Ferrand-CHU Clermont-Ferrand
Subjects: business.industry, [SDV]Life Sciences [q-bio], Poison control, medicine.disease, 030226 pharmacology & pharmacy, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pharmacovigilance, Ambulatory, Health care, Medicine, Pharmacology (medical), 030212 general & internal medicine, Medical emergency, business
Abstract: Medication errors (ME) are frequently encountered and present at every step of the therapeutic process. This study's aims were to take stock of the ME reported to the region's pharmacovigilance (CRPV) and poison control centers (CAPTV) and to identify potential regional actions. A 2-months (January and February 2017) prospective gathering of the calls to the CAPTV regarding the ME and of the ME declarations to the region's CRPV (Clermont-Ferrand, Grenoble, Lyon, Saint-Etienne) has been carried out. The place of occurrence, the event's description and its consequences and data regarding the patient were collected. In addition to that, the regional drug observatory OMEDIT analysis has allowed to determine the ME's types (REMED characterization, never event?) and to look for the results of a potential thorough analysis. The study reported 580 calls for 590 ME and 583 patients. ME mostly affected the ambulatory/domicile sector (76%), the medico-social sector (14%) and the healthcare facilities sector (7%). It usually was about dose errors, medication errors and patient errors with a different profile in each sector. The majority of errors (85%) occurred at the administration step. Almost all the observed ME were confirmed errors having reached the patient (99.5%) but only a few had serious consequences. One out of 5 ME was eligible for a thorough analysis but even less were subjected to that kind of analysis. The main never event concerned the unidose in the ambulatory sector. The health products involved were mostly a single medication (75%) and then the patient's full treatment (12%). The CRPV/CAPTV/OMEDIT's skills are complementary for the gathering, the analysis and the management of the ME. Training campaigns and support are to be considered for the professionals and especially within the medico-social facilities.
Published: 2020
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6. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database

Author: Lee S. Nguyen, Leslie T. Cooper, Mathieu Kerneis, Christian Funck-Brentano, Johanne Silvain, Nicolas Brechot, Guillaume Hekimian, Enrico Ammirati, Badr Ben M’Barek, Alban Redheuil, Estelle Gandjbakhch, Kevin Bihan, Bénédicte Lebrun-Vignes, Stephane Ederhy, Charles Dolladille, Javid J. Moslehi, Joe-Elie Salem, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU 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), CMC Ambroise Paré [Neuilly-sur-Seine], Service de Pharmacologie médicale [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), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Mayo Clinic [Jacksonville], Groupe Action, Institut de cardiologie [CHU Pitié-Salpêtrière], Service de Réanimation Médicale [CHU Pitié-Salpétrière], Ospedale Niguarda, Service de Radiologie Polyvalente et Oncologique = Service d'Imagerie Spécialisées et des Urgences [CHU Pitié-Salpêtrière] (SISU), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Cardiologie [CHU Pitié-Salpêtrière], Département de Pharmacologie [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), Vanderbilt University [Nashville], Gestionnaire, Hal Sorbonne Université, and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)
Subjects: Systems Analysis, Databases, Factual, Science, Cardiology, General Physics and Astronomy, Antineoplastic Agents, World Health Organization, Article, General Biochemistry, Genetics and Molecular Biology, Pharmacovigilance, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Adverse Drug Reaction Reporting Systems, Humans, Data Management, Multidisciplinary, Adverse effects, Bayes Theorem, General Chemistry, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Myocarditis, Cross-Sectional Studies, Pharmaceutical Preparations, Risk factors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Immunotherapy, Antipsychotic Agents
Abstract: While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis., Multiple drugs have been in the past associated with myocarditis. Here the authors perform a pharmacovigilance study and analyze 5108 reports of drug-induced myocarditis reporting temporal trends and overall mortality and identifying emerging drug classes among the treatments associated with myocarditis.
Published: 2022
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7. Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: a French population-based study on prostate cancer patients

Author: Boris Campillo-Gimenez, Emmanuel Oger, André Happe, Romain Mathieu, Lucie-Marie Scailteux, Fabien Despas, Sandrine Kerbrat, Sébastien Vincendeau, Emmanuel Nowak, Frédéric Balusson, CHU Pontchaillou [Rennes], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), 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), Pharmaco-Épidémiologie des Produits de Santé (PEPS), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Drugs Agency, National Health Insurance, 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 Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Jonchère, Laurent
Subjects: Male, safety, medicine.medical_specialty, 030204 cardiovascular system & hematology, Rate ratio, QT interval, Brain Ischemia, 03 medical and health sciences, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, abiraterone, Atrial Fibrillation, Nitriles, Phenylthiohydantoin, Pharmacovigilance, medicine, Humans, Enzalutamide, castration-resistant prostate cancer, Pharmacology (medical), liver test monitoring, Adverse effect, Pharmacology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, enzalutamide, business.industry, Atrial fibrillation, medicine.disease, adverse events, 3. Good health, Hospitalization, Stroke, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, chemistry, acute kidney injury, 030220 oncology & carcinogenesis, Heart failure, Benzamides, Androstenes, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business
Abstract: International audience; Aims - Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. Method - Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. Results - Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. Conclusion - Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.
Published: 2022
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8. Psychotic Episode following Treatment with Hydroxychloroquine in a 17- Year-Old Female Adolescent with Cutaneous Lupus Erythematosus: A Drug Causality Supported by a Literature Review and a Worldwide Pharmacovigilance Database Search

Author: Miguel Hie, Bénédicte Lebrun-Vignes, David Cohen, Stéphane Barete, Cora Cravero, Julie Brunelle, Solène Spiers, Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence 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], Service de Dermatologie [CHU Pitié-Salpêtrière], Centre Hospitalier le Vinatier [Bron], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Institut des Systèmes Intelligents et de Robotique (ISIR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], 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)-Institut E3M [CHU Pitié-Salpêtrière]
Subjects: Drug, medicine.medical_specialty, business.industry, Drug Imputability, media_common.quotation_subject, Hydroxychloroquine, Case Report, General Medicine, Female adolescent, Psychosis, Dermatology, Causality, 3. Good health, Suicide Attempt, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Pharmacovigilance, Cutaneous Lupus Erythematosus, Medicine, Database search engine, business, medicine.drug, media_common
Abstract: International audience; Background: Hydroxychloroquine (HCQ), a useful treatment for chronic dermatologic or rheumatologic diseases, has recently gathered widespread attention as a possible treatment for COVID-19 infection. However, its rare et severe neuropsychiatric side effects (NSE), such as psychosis and suicidal tendencies, are poorly documented, especially in youths.Case presentation: We present the first case on a 17-yearold girl of severe acute psychosis with a suicide attempt during HCQ treatment in association with thalidomide for chronic and refractory discoid lupus erythematosus. Drug causality was evaluated using the updated French causality assessment method. We performed a literature review and a worldwide pharmacovigilance database search on psychotic features after HCQ and thalidomide treatment. We found six cases in the literature and 53 cases (psychotic disorder: N=45, 3.7% and acute psychosis: N=8, 0.7%) in the pharmacovigilance database reporting the occurrence of psychotic symptoms under HCQ and none under thalidomide. The intrinsic and extrinsic imputability scores support the hypothesis that HCQ induced psychosis and suicide attempt in our patient. Withdrawing HCQ resulted in a dramatically improved situation, which remained perfectly stable after 3 years of follow-up.Conclusion: In HCQ-induced psychosis, recovery may be obtained with HCQ withdrawal, no future HCQ reintroduction, and, for the most serious manifestations, a short period of antipsychotic medication. Clinicians need to be aware of the NSE of HCQ and the appropriate interventions to be carried out.
Published: 2021
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9. Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study

Author: Javid Moslehi, Dan M. Roden, Christian Funck-Brentano, Paul Gougis, Bénédicte Lebrun-Vignes, Joe-Elie Salem, Stéphane Ederhy, Lee S. Nguyen, Service de pharmacologie médicale [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), Groupe de REcherche en Cardio Oncologie [CHU Saint-Antoine] (GRC 27 GRECO), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Vanderbilt University School of Medicine [Nashville], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CMC Ambroise Paré [Neuilly-sur-Seine], and Service de Cardiologie [CHU Saint-Antoine]
Subjects: medicine.medical_specialty, long QT, medicine.medical_treatment, Concordance, Torsades de pointes, Antineoplastic Agents, 030204 cardiovascular system & hematology, World Health Organization, Sudden death, QT interval, World health, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Torsades de Pointes, Neoplasms, Internal medicine, Pharmacovigilance, medicine, Adverse Drug Reaction Reporting Systems, Humans, Disproportionality analysis, business.industry, ventricular arrhythmias, Bayes Theorem, Immunotherapy, medicine.disease, 3. Good health, Clinical trial, Long QT Syndrome, anticancer drugs, 030220 oncology & carcinogenesis, pharmacovigilance, torsade de pointes, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Aims With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). Methods and results We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P Conclusion This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements. Clinical trial registration NCT03530215.
Published: 2021
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10. Transketolase of Staphylococcus aureus in the Control of Master Regulators of Stress Response During Infection

Author: Elodie Ramond, Xin Tan, Fabiola Tros, Jean-Philippe Barnier, Daniel Euphrasie, Jason Ziveri, Ivan Nemazanyy, Xavier Nassif, Anne Jamet, Baptiste Decaux-Tramoni, Alain Charbit, Marion Dupuis, Mathieu Coureuil, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), SOGIP, SOGIP (ERC 249236)/Laboratoire d'Anthropologie des Institutions et des Organisations Sociales (IIAC-LAIOS), Institut interdisciplinaire d'anthropologie du contemporain (IIAC), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-Institut interdisciplinaire d'anthropologie du contemporain (IIAC), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), U1002, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Charbit, Alain
Subjects: 0301 basic medicine, Staphylococcus aureus, RNAIII, 030106 microbiology, Mutant, pentose phosphate pathway, Transketolase, Biology, Pentose phosphate pathway, Kidney, medicine.disease_cause, Microbiology, Mice, 03 medical and health sciences, Stress, Physiological, sigma B, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Transcription (biology), RpiRc, medicine, Animals, Humans, Metabolomics, Immunology and Allergy, Gene Silencing, Gene, ComputingMilieux_MISCELLANEOUS, Gene Expression Profiling, metabolic adaptation, Gene Expression Regulation, Bacterial, Staphylococcal Infections, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Carbon, 3. Good health, Disease Models, Animal, Phenotype, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Infectious Diseases, Genes, Bacterial, Mutation, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, transketolase, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Intracellular, Signal Transduction
Abstract: Staphylococcus aureus is a leading cause of both acute and chronic infections in humans. The importance of the pentose phosphate pathway (PPP) during S. aureus infection is currently largely unexplored. In the current study, we focused on one key PPP enzyme, transketolase (TKT). We showed that inactivation of the unique gene encoding TKT activity in S. aureus USA300 (∆tkt) led to drastic metabolomic changes. Using time-lapse video imaging and mice infection, we observed a major defect of the ∆tkt strain compared with wild-type strain in early intracellular proliferation and in the ability to colonize kidneys. Transcriptional activity of the 2 master regulators sigma B and RpiRc was drastically reduced in the ∆tkt mutant during host cells invasion. The concomitant increased RNAIII transcription suggests that TKT—or a functional PPP—strongly influences the ability of S. aureus to proliferate within host cells by modulating key transcriptional regulators.
Published: 2019
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11. Immune checkpoint inhibitor–associated hypophysitis—World Health Organisation VigiBase report analysis

Author: Elisa Guerrero, Anne Bachelot, Bénédicte Lebrun-Vignes, Douglas B. Johnson, Javid Moslehi, Joe-Elie Salem, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pharmacologie médicale [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), CIC Paris Est, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: Adult, Male, Cancer Research, Databases, Factual, Hypophysitis, [SDV]Life Sciences [q-bio], Immune checkpoint inhibitors, Programmed Cell Death 1 Receptor, MEDLINE, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, World Health Organization, B7-H1 Antigen, World health, Pharmacovigilance, Young Adult, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, CTLA-4 Antigen, Young adult, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, biology, business.industry, Antibodies, Monoclonal, Middle Aged, medicine.disease, Ipilimumab, 3. Good health, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Monoclonal, Immunology, biology.protein, Female, Antibody, business
Abstract: International audience
Published: 2019
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12. Poor assessment of bone mineral density after a forearm fracture in women aged 50 years or older: Data from a French health insurance database

Author: Delphine Chu Miow Lin, Denis Mulleman, Philippe Goupille, Emmanuel Oger, André Happe, Elsa Cattelain-Lopez, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pontchaillou [Rennes], This work was supported by grants from the Osteoporosis research and information group (GRIO – Groupe de recherche et d’information sur les ostéoporoses) in 2013 and the French league against rheumatism (AFLAR – Association française de lutte anti-rhumatismale) in 2014., Université de Tours, 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)
Subjects: medicine.medical_specialty, MEDLINE, 030209 endocrinology & metabolism, 03 medical and health sciences, Fractures, Bone, 0302 clinical medicine, Absorptiometry, Photon, Rheumatology, Bone Density, medicine, Humans, Osteoporosis, Postmenopausal, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, Bone mineral, Insurance, Health, business.industry, Health insurance database, 3. Good health, Forearm, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Physical therapy, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Forearm fracture, business
Abstract: International audience
Published: 2021
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13. Néphrotoxicité en pédiatrie

Author: Pierre Cochat, J Bacchetta, M Auffret, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 03 medical and health sciences, [SCCO]Cognitive science, 0302 clinical medicine, 030225 pediatrics, Pediatrics, Perinatology and Child Health, 030232 urology & nephrology, 3. Good health
Abstract: Resume L’elimination des medicaments est essentiellement renale et hepatique, et 75 % des medicaments sont principalement elimines par les reins. La nephrotoxicite en pediatrie concerne surtout les medicaments, mais il est important de connaitre d’autres types de nephrotoxicite non medicamenteux, par ingestion accidentelle ou volontaire, ou par contact, avec des produits chimiques, des toxines environnementales, des drogues, des vegetaux ou des animaux. La nephrotoxicite peut etre aigue ou chronique, dose-dependante ou -independante, et peut atteindre tous les compartiments fonctionnels du rein, meme si la necrose tubulaire aigue est le mecanisme le plus frequemment observe. Chez l’enfant, les informations sont souvent extrapolees des observations faites chez l’adulte et parfois a partir de l’experimentation animale ; il importe donc de preciser les particularites de la nephrotoxicite en pediatrie, qui subissent des variations considerables entre la periode fœtale et l’adolescence. Nous proposons donc une mise au point sur la nephrotoxicite en pediatrie, avec des rappels de physiopathologie, le rappel des grandes situations de nephrotoxicite medicamenteuse, et enfin un expose des situations les plus frequentes de nephrotoxicite non medicamenteuse.
Published: 2020
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14. How to interact with medical terminologies? Formative usability evaluations comparing three approaches for supporting the use of MedDRA by pharmacovigilance specialists

Author: Sébastien Ferré, Laura Douze, Carlos Bobed, Cédric Bousquet, Jean-Baptiste Lamy, Bissan Audeh, Romaric Marcilly, Agnès Lillo-Le Louët, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Semantics, Logics, Information Systems for Data-User Interaction ( SemLIS), GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), ANR-16-CE23-0011, Agence Nationale de la Recherche, ANR-16-CE23-0011,PEGASE,Pharmacovigilance Enrichie par des Groupements Améliorant la détection des Signaux Émergents(2016), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Jonchère, Laurent, Pharmacovigilance Enrichie par des Groupements Améliorant la détection des Signaux Émergents - - PEGASE2016 - ANR-16-CE23-0011 - AAPG2016 - VALID, Université de Lille, CHU Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Semantics, Logics, Information Systems for Data-User Interaction [ SemLIS], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé [LIMICS], and Centre Régional de Pharmacovigilance [CRPV]
Subjects: Drug-Related Side Effects and Adverse Reactions, 020205 medical informatics, Cognitive walkthrough, Computer science, MedDRA, Health Informatics, Formative evaluation, 02 engineering and technology, lcsh:Computer applications to medicine. Medical informatics, Health informatics, Formative assessment, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Usability testing, Adverse Drug Reaction Reporting Systems, Humans, Specialization, Systematized Nomenclature of Medicine, 0202 electrical engineering, electronic engineering, information engineering, 030212 general & internal medicine, [SDV.IB] Life Sciences [q-bio]/Bioengineering, SNOMED CT, Information retrieval, business.industry, Health Policy, System usability scale, Usability, 3. Good health, Computer Science Applications, lcsh:R858-859.7, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, Research Article
Abstract: Background Medical terminologies are commonly used in medicine. For instance, to answer a pharmacovigilance question, pharmacovigilance specialists (PVS) search in a pharmacovigilance database for reports in relation to a given drug. To do that, they first need to identify all MedDRA terms that might have been used to code an adverse reaction in the database, but terms may be numerous and difficult to select as they may belong to different parts of the hierarchy. In previous studies, three tools have been developed to help PVS identify and group all relevant MedDRA terms using three different approaches: forms, structured query-builder, and icons. Yet, a poor usability of the tools may increase PVS’ workload and reduce their performance. This study aims to evaluate, compare and improve the three tools during two rounds of formative usability evaluation. Methods First, a cognitive walkthrough was performed. Based on the design recommendations obtained from this evaluation, designers made modifications to their tools to improve usability. Once this re-engineering phase completed, six PVS took part in a usability test: difficulties, errors and verbalizations during their interaction with the three tools were collected. Their satisfaction was measured through the System Usability Scale. The design recommendations issued from the tests were used to adapt the tools. Results All tools had usability problems related to the lack of guidance in the graphical user interface (e.g., unintuitive labels). In two tools, the use of the SNOMED CT to find MedDRA terms hampered their use because French PVS were not used to it. For the most obvious and common terms, the icons-based interface would appear to be more useful. For the less frequently used MedDRA terms or those distributed in different parts of the hierarchy, the structured query-builder would be preferable thanks to its great power and flexibility. The form-based tool seems to be a compromise. Conclusion These evaluations made it possible to identify the strengths of each tool but also their weaknesses to address them before further evaluation. Next step is to assess the acceptability of tools and the expressiveness of their results to help identify and group MedDRA terms.
Published: 2020
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15. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Author: Aurélien Corneau, David Veyer, Tali Anne Szwebel, Nicolas Roche, Bruno Charbit, Darragh Duffy, Laura Barnabei, Hélène Péré, Flore Rozenberg, Nathalie Marin, Vincent Bondet, Benjamin Terrier, Pierre-Louis Tharaux, Solen Kernéis, Nader Yatim, Jeremy Boussier, Nikaïa Smith, Sarah H. Merkling, Alain Fischer, Nicolas Carlier, Frédéric Rieux-Laucat, Jean-Marc Treluyer, Camille Chenevier-Gobeaux, Paul Breillat, Rémy Gauzit, Luc Mouthon, Frédéric Pène, Jérôme Hadjadj, Caroline Morbieu, Catherine Blanc, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunogenetics of pediatric autoimmune diseases (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), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Laboratoire de Virologie [Hôpital Européen Georges Pompidou - APHP], 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), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Diagnostic biologique automatisé [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité Equipe mobile d'Infectiologie [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Unité de Soins Intensifs [CHU Cochin], Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Virologie [CHU Cochin], Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Institut Pasteur, by a government grant managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (ANR-10-IAHU-01 and the Laboratoire d’Excellence ‘‘Milieu Intérieur', grant no. ANR-10-LABX-69-01), and by a grant from the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). J.H. is a recipient of an Institut Imagine MD-PhD fellowship program supported by the Fondation Bettencourt Schueller. L.B. is supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) program of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program., We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Cochin Hospital, especially C. Azoulay L. Beaudeau, E. Canoui, P. Cohen, A. Contejean, B. Dunogué, D.Journois, P. Legendre, J. Marey and A. Régent. We thank Y. Gaudin for his advices on viral mechanism. We thank all the patients, supporters and our families for their confidence in our work., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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 de Paris (UP), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Chaire Médecine expérimentale (A. Fischer)
Subjects: Male, 0302 clinical medicine, Interferon, T-Lymphocyte Subsets, 0303 health sciences, Multidisciplinary, biology, NF-kappa B, Interleukin, Middle Aged, Viral Load, 3. Good health, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, Female, medicine.symptom, Coronavirus Infections, Viral load, medicine.drug, Signal Transduction, Adult, Critical Illness, Pneumonia, Viral, Alpha interferon, Inflammation, Interferon alpha-2, 03 medical and health sciences, Betacoronavirus, Immune system, medicine, Humans, Interleukin 6, Pandemics, 030304 developmental biology, Aged, business.industry, Interleukin-6, SARS-CoV-2, Tumor Necrosis Factor-alpha, Gene Expression Profiling, COVID-19, Interferon-alpha, Interferon-beta, Immunity, Innate, Cross-Sectional Studies, Immunology, biology.protein, business
Abstract: Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626
Published: 2020
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16. Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study

Author: Dan M. Roden, Marie Bretagne, Javid Moslehi, Antoine Pariente, Camille Potey, Pauline Dureau, Christian M. Shaffer, Gabriel G. Malouf, Joe-Elie Salem, Bénédicte Lebrun-Vignes, Christian Funck-Brentano, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [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), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], CHU Strasbourg, Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine
Subjects: Male, Time Factors, Databases, Factual, 030204 cardiovascular system & hematology, Androgen deprivation therapy, chemistry.chemical_compound, Prostate cancer, Pharmacovigilance, 0302 clinical medicine, Risk Factors, Tachycardia, Supraventricular, Medicine, 030212 general & internal medicine, Abiraterone, Aged, 80 and over, Atrial fibrillation, General Medicine, Middle Aged, 3. Good health, Benzamides, Androstenes, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Abiratérone, Heart failure, [SDV.CAN]Life Sciences [q-bio]/Cancer, Risk Assessment, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Nitriles, Phenylthiohydantoin, Enzalutamide, Adverse Drug Reaction Reporting Systems, Humans, Aged, Retrospective Studies, PharmacoEpi-Drugs, business.industry, Prostatic Neoplasms, Androgen Antagonists, Odds ratio, medicine.disease, Cardiotoxicity, Insuffisance cardiaque, Fibrillation auriculaire, chemistry, Anti-androgène, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Observational study, business
Abstract: International audience; Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.Aim: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.Methods: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.Results: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P
Published: 2020
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17. Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study

Author: Bretagne, Marie, Lebrun-Vignes, Bénédicte, Pariente, Antoine, Shaffer, Christian M, Malouf, Gabriel G, Dureau, Pauline, Potey, Camille, Funck-Brentano, Christian, Roden, Dan M, Moslehi, Javid J, Salem, Joe-Elie, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [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), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], CHU Strasbourg, Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine
Subjects: Insuffisance cardiaque, Fibrillation auriculaire, Anti-androgène, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Abiratérone, Enzalutamide, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Heart failure, [SDV.CAN]Life Sciences [q-bio]/Cancer, Androgen deprivation therapy, Abiraterone, Atrial fibrillation
Abstract: International audience; Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.Aim: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.Methods: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.Results: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P
Published: 2020
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18. Informativité des forums de discussion français pour l’évaluation des effets indésirables du baclofène

Author: Pierre Karapetiantz, Agnès Lillo-Le Louët, Cédric Bousquet, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 03 medical and health sciences, 0302 clinical medicine, Political science, [SDV]Life Sciences [q-bio], Pharmacology (medical), 030226 pharmacology & pharmacy, Humanities, 3. Good health
Abstract: Resume Objectif Evaluer l’informativite et la qualite des descriptions d’effets indesirables susceptibles d’etre lies au baclofene, dans les forums de discussion francais. Methodes Nous avons evalue la qualite des cas de pharmacovigilance potentiels associes au baclofene dans 22 forums de discussion. Nous avons ensuite compare ces donnees aux cas de pharmacovigilance issus de la base nationale de pharmacovigilance (BNPV), en termes d’informativite concernant le patient, le traitement et l’effet indesirable ainsi que la gravite et le caractere inattendu des effets. Resultats Nous avons identifie 782 cas de pharmacovigilance potentiels parmi 2621 messages issus de forums francais. L’informativite des messages des forums etait significativement inferieure a celle des cas issus de la BNPV, pour l’ensemble des donnees concernant le patient (3 %/6 % vs 88 % pour l’âge/la classe d’âge et 46 % vs 99 % pour le sexe, respectivement), pour la duree de traitement (9 % vs 24 %) et pour l’evolution de l’effet indesirable (1 % vs 64 %, respectivement). Mais l’indication du traitement et sa posologie etaient plus frequemment renseignees dans les forums que dans la BNPV (67 % vs 24 % et 27 % vs 9 %, respectivement). Les cas d’effets indesirables issus des forums sont tres majoritairement non graves, contrairement a ceux issus de la BNPV (38 % vs 0,7 %). La proportion de cas rapportant des effets indesirables inattendus est significativement plus importante dans les forums que dans la BNPV (43,8 % vs 11,6 %). Conclusion L’indication et la posologie etaient plus souvent renseignees dans les messages que dans la BNPV, ce qui fait des forums une ressource interessante pour etudier les conditions d’utilisation du baclofene. Bien que les forums comportent plus d’effets inattendus, leur moindre informativite rend difficile l’evaluation de l’imputabilite. Nous estimons que les forums et la BNPV sont deux sources de donnees complementaires pour la securite d’emploi du baclofene.
Published: 2019
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19. Critical Role of a Sheath Phosphorylation Site On the Assembly and Function of an Atypical Type VI Secretion System

Author: Mathieu Coureuil, Ida Chiara Guerrera, Guénolé Prigent, Claire Lays, Monique Barel, Fabiola Tros, Nicholas H. Keep, Jason Ziveri, Alain Charbit, Anne Jamet, Cerina Chhuon, Héloïse Rytter, Thomas Henry, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Necker - Enfants Malades [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Pathogénie des infections systémiques (UMR_S 570), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Inflammasome, Bacterial Infections and Autoinflammation (I2BA), 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), University of London [London], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), U1002, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Charbit, Alain
Subjects: Proteomics, Stimulation, Biochemistry, Gas Chromatography-Mass Spectrometry, Analytical Chemistry, Cell Line, Potassium Chloride, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Tandem Mass Spectrometry, Humans, Secretion, Phosphorylation, Francisella tularensis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Type VI secretion system, Alanine, 0303 health sciences, Electronic Data Processing, Phosphomimetics, biology, Molecular Structure, Research, Macrophages, 030302 biochemistry & molecular biology, Type VI Secretion Systems, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Mutagenesis, Site-Directed, Francisella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Processing, Post-Translational, Biogenesis
Abstract: The bacterial pathogen Francisella tularensis possesses a noncanonical type VI secretion system (T6SS) that is required for phagosomal escape in infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the T6SS in culture. By differential proteomics, we found here that the amounts of the T6SS proteins remained unchanged upon KCl stimulation, suggesting involvement of post-translational modifications in T6SS assembly. A phosphoproteomic analysis indeed identified a unique phosphorylation site on IglB, a key component of the T6SS sheath. Substitutions of Y139 with alanine or phosphomimetics prevented T6SS formation and abolished phagosomal escape whereas substitution with phenylalanine delayed but did not abolish phagosomal escape in J774-1 macrophages. Altogether our data demonstrated that the Y139 site of IglB plays a critical role in T6SS biogenesis, suggesting that sheath phosphorylation could participate to T6SS dynamics. Data are available via ProteomeXchange with identifier PXD013619; and on MS-Viewer, key lkaqkllxwx.
Published: 2019
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20. Molecular interactions between Neisseria meningitidis and its human host

Author: Xavier Nassif, Sandrine Bourdoulous, Hervé Lécuyer, Anne Jamet, Mathieu Coureuil, Emmanuelle Bille, U1002, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Panthéon-Assas (UP2), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Virulence Factors, [SDV]Life Sciences [q-bio], Immunology, Bacterial Toxins, Virulence, Inflammation, Neisseria meningitidis, medicine.disease_cause, Microbiology, 03 medical and health sciences, Inovirus, Virology, Nasopharynx, medicine, Extracellular, Humans, Pathogen, Special Issue ‐ Review, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Disseminated intravascular coagulation, 0303 health sciences, Special Issue ‐ Reviews, biology, Host Microbial Interactions, 030306 microbiology, Endothelial Cells, Epithelial Cells, biology.organism_classification, medicine.disease, 3. Good health, Colonisation, Meningococcal Infections, Blood Vessels, medicine.symptom, Bacteria
Abstract: Neisseria meningitidis is a Gram‐negative bacterium that asymptomatically colonises the nasopharynx of humans. For an unknown reason, N. meningitidis can cross the nasopharyngeal barrier and invade the bloodstream where it becomes one of the most harmful extracellular bacterial pathogen. This infectious cycle involves the colonisation of two different environments. (a) In the nasopharynx, N. meningitidis grow on the top of mucus‐producing epithelial cells surrounded by a complex microbiota. To survive and grow in this challenging environment, the meningococcus expresses specific virulence factors such as polymorphic toxins and MDAΦ. (b) Meningococci have the ability to survive in the extra cellular fluids including blood and cerebrospinal fluid. The interaction of N. meningitidis with human endothelial cells leads to the formation of typical microcolonies that extend overtime and promote vascular injury, disseminated intravascular coagulation, and acute inflammation. In this review, we will focus on the interplay between N. meningitidis and these two different niches at the cellular and molecular level and discuss the use of inhibitors of piliation as a potent therapeutic approach.
Published: 2019
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21. Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

Author: Pierre Bataille, Pierre Cochat, Olivier Traxer, Saïd Lebbah, Agnés Lillo‐Le Louët, Caroline Prot-Bertoye, Michel Normand, Hung Viet N’Guyen, Franck Bridoux, Isabelle Tostivint, Clément Pontoizeau, Pierre Brignon, Bertrand Doré, Marie Courbebaisse, Marie Essig, Bertrand Knebelmann, Sophie Le Toquin-Bernard, Gérard Friedlander, Pierre Conort, Christian Combe, Christian Saussine, Stéphane Decramer, Arnaud Mejean, Michel Daudon, Jean-Philippe Jais, Paul Meria, Denis Morin, M. Pietak, Bertrand Dussol, Christian Choquenet, Marie Frimat, Pierre Ronco, Dominique Joly, Michel Tsimaratos, Nicolas Gaunez, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), CHU Tenon [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CH Boulogne sur Mer, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Louis Pasteur [Colmar] (CH Colmar), Hôpital Princesse Grace [Monaco], Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Urologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse], Université de Poitiers, Chirurgie urologique et transplantation rénale [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Évolution, génomes, comportement et écologie (EGCE), Université Paris-Sud - Paris 11 (UP11)-IRD-Centre National de la Recherche Scientifique (CNRS), Hôpital Privé Saint Martin Caen, 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), Hopital Saint-Louis [AP-HP] (AP-HP), 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), Qualité et fonctionnement hydrologique des systèmes aquatiques (UR QHAN), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), CHU Strasbourg, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'urologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Service de néphrologie pédiatrique [CHU Necker], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Toulouse [Toulouse]-Hôpital des Enfants, 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Drug-Related Side Effects and Adverse Reactions, Urology, 030232 urology & nephrology, Urine, Urinalysis, Gastroenterology, Potassium bicarbonate, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Crystalluria, Humans, Child, Adverse effect, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Cystinuria, Sodium bicarbonate, business.industry, Urine specific gravity, Penicillamine, Tiopronin, Infant, Hydrogen-Ion Concentration, Middle Aged, medicine.disease, 3. Good health, Sodium Bicarbonate, Treatment Outcome, chemistry, Child, Preschool, 030220 oncology & carcinogenesis, Female, France, medicine.symptom, business, medicine.drug
Abstract: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0pH ≤7.5, P = 0.03; OR 0.26 [95% CI 0.13-0.53] for 7.5pH ≤8.0, P0.001; OR 1 for specific gravity ≤1.005 OR 5.76 [95% CI 1.45-22.85] for 1.006 ≤ specific gravity ≤1.010, P = 0.01; and OR 11.06 [95% CI 2.76-44.26] for 1.011 ≤ specific gravity ≤ 1.014, P0.001). Increased urine pH significantly increased the risk of calcium phosphate crystalluria (OR 1 for pH≤ 6.5; OR 6.09 [95% CI 2.15-17.25] for pH8.0, P0.001).Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.
Published: 2019
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22. Cytopenia induced by low-dose methotrexate: An analysis of 433 cases from the French pharmacovigilance database

Author: Laurence Fardet, Bénédicte Lebrun-Vignes, Delphine Laugier, Corinne Simon, Sophie Lalevée, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: musculoskeletal diseases, Male, Databases, Factual, Pancytopenia, 030204 cardiovascular system & hematology, computer.software_genre, Low dose methotrexate, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal Medicine, medicine, Humans, Medication Errors, heterocyclic compounds, In patient, 030212 general & internal medicine, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, Cytopenia, Leukopenia, Database, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Methotrexate, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, France, medicine.symptom, business, computer, medicine.drug
Abstract: Up to 5% of individuals exposed to low-dose methotrexate (MTX) (i.e., ≤30 mg/week) may develop cytopenia. However, MTX-induced cytopenia have been poorly described.All cases of cytopenia (i.e., anaemia, leukopenia, thrombocytopenia, bi- or pancytopenia) in patients receiving low-dose MTX reported to the French pharmacovigilance database during 2006-2016 were analysed. Three groups were defined: cytopenia due to MTX medication errors (e.g., daily rather than weekly administration), cytopenia in people receiving several medications including MTX, cytopenia in people receiving only MTX.433 cases were analysed. Eighty-four cases (19.4%) were due to medication errors, 180 (41.6%) occurred in individuals exposed both to MTX and other drugs, and 169 (39.0%) occurred in individuals only exposed to MTX. By comparison to other patients, those with cytopenia due to medication errors were older (74 ± 13 vs 69 ± 15 years, p = 0.002), received more frequently MTX orally (92.9% vs 65.3%, p0.001) and had more frequently pancytopenia (71.4% vs 54.4%, p = 0.005). By comparison to individuals exposed to multiple drugs (n = 180), those exposed only to MTX (n = 169) were older (71 ± 15 vs 67 ± 14, p = 0.02), and had more often pancytopenia (62.7% vs 46.7%, p = 0.001). Among those only exposed to MTX, most cases (n = 140, 82.8%) were considered as toxic rather than idiosyncratic reactions and a trigger (e.g. diarrhoea) was found in 59.3% of those cases. Overall 30 (6.9%) deaths occurred, including 8 in the "medication error" group and 8 in the "MTX only" group.These data may be useful for defining optimal biological monitoring of patients prescribed low-dose MTX.
Published: 2019
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23. Methylprednisolone-related liver injury: A descriptive study using the French pharmacovigilance database

Author: Aurore Gouraud, Jérôme Dumortier, Véronique Pizzoglio, Corinne Simon, Geneviève Durrieu, Nathalie Bleyzac, Sabrina Pierre, Judith Cottin, Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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), CHU Toulouse [Toulouse], Hôpital Edouard Herriot [CHU - HCL], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Liver injury, Gastroenterology, Methylprednisolone, 03 medical and health sciences, Route of administration, Pharmacovigilance, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Adverse effect, Child, Aged, Autoimmune disease, Aged, 80 and over, Hepatology, business.industry, Multiple sclerosis, Infant, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Concomitant, Child, Preschool, 030211 gastroenterology & hepatology, Female, France, Safety, Chemical and Drug Induced Liver Injury, business, medicine.drug
Abstract: International audience; Purpose: Hepatotoxicity associated with methylprednisolone (MP) is rarely reported in the literature. The aim of the present study was to review the characteristics of acute liver injury associated with intravenous (IV) or oral MP registered in the French pharmacovigilance database (FPD).Methods: All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as the adverse effect reported up to May 2016 were extracted from the FPD. Cases were identified using the "Drug related hepatic disorders" Standard Medical Query.Results: A total of 97 cases of liver injury associated with MP were analysed; 58.8% were women and the median age was 46 years (range: 1-91). MP was used for an autoimmune disease in 47.6% of cases including 26 cases of multiple sclerosis, and was IV in 79.4% of cases. Nearly three-quarters of patients (73,2%) had a hepatocellular type of injury, the severity of which was mainly mild (45%) or moderate (31%). Most patients (92%) spontaneously and fully recovered within a mean 38.4 days. A rechallenge using the IV route was performed in 13 patients and for 10 (76.9%) this was positive (the initial type of injury was hepatocellular for all these cases). Regarding IV route of administration (n=77), MP was coded as the only suspected drug in 22% of cases.Discussion: The results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient; systematic liver monitoring for high-dose IV MP may be recommended.
Published: 2019
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24. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database

Author: Franck Morschhauser, Chouki Chenaf, Alexis B. Cortot, Nicolas Etienne, Laurent Mortier, Aurélie Grandvuillemin, Christine Le Beller, Delphine Staumont-Sallé, David Launay, Solenn Brousseau, Guillaume Lefèvre, Matthieu Groh, Johana Béné, Sophie Gautier, Jean-Emmanuel Kahn, Eric Hachulla, Alexandra Forestier, Myriam Labalette, Quentin Scanvion, service de médecine interne et immunologie clinique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord Ouest [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centre Régional de Pharmacovigilance, de Renseignement sur le Médicament et de Pharmaco épidémiologie de Bourgogne [Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Régional de Pharmacovigilance [CHU Clermont-Ferrand] (CRPV), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Foch [Suresnes], Institut d'Immunologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Ambroise Paré [AP-HP], The authors would like to thank all the physicians who contributed adverse drug reaction reports to the French pharmacovigilance system., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER
Subjects: 0301 basic medicine, Moderate to severe, medicine.medical_specialty, Databases, Factual, Immune checkpoint inhibitors, Immunology, Early detection, emergent adverse event, immune checkpoint inhibitors, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, Hypereosinophilic Syndrome, Eosinophilia, Immunology and Allergy, Medicine, Humans, Adverse effect, RC254-282, business.industry, Brief Report, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, RC581-607, respiratory system, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, immune-related adverse events, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Immunologic diseases. Allergy, business
Abstract: International audience; A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median [range] time to the absolute eosinophil count (AEC) peak was 15 [4─139] weeks. The median AEC was 2.7 [0.8─90.9] G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.
Published: 2019
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25. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Author: Javid Moslehi, Justin M. Balko, Joe-Elie Salem, Ali Manouchehri, Alexandra M Haugh, Bénédicte Lebrun-Vignes, Henry T. Quach, Andrew L. Mammen, Douglas B. Johnson, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [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), National Institutes of Health [Bethesda] (NIH), Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, MedDRA, [SDV]Life Sciences [q-bio], Guillain-Barre syndrome, Pharmacovigilance, 0302 clinical medicine, PD-1, Immunology and Allergy, Myasthenia gravis, Incidence (epidemiology), lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Encephalitis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Immunotherapy, Meningitis, Research Article, PD-L1, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Drug-Related Side Effects and Adverse Reactions, Immunology, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, medicine, Neurotoxicity, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adverse effect, Retrospective Studies, Pharmacology, business.industry, Odds ratio, medicine.disease, Neuropathy, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, CTLA-4, Nervous System Diseases, business, 030215 immunology
Abstract: Background Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. Methods We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5–18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2–11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5–3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6–12%), later onset (median 61–80 days), and were non-overlapping. Conclusions ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations. Electronic supplementary material The online version of this article (10.1186/s40425-019-0617-x) contains supplementary material, which is available to authorized users.
Published: 2019
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26. Fulminant arterial vasculitis as an unusual complication of disseminated staphylococcal disease due to the emerging CC1 methicillin-susceptible Staphylococcus aureus clone: a case report

Author: Xavier Nassif, Alain Charbit, Delphine Borgel, Charles Vidal, Anne Jamet, Louise Galmiche, Florence Moulin, Capucine Picard, Olivier Lortholary, Julie Toubiana, Jean-Paul Mira, Department of Microbiology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatric Intensive Care Unit [Paris], Pathology Department [Paris], Department of Hematology [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for the Study of Primary Immunodeficiencies [Paris], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), 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), Medical Intensive Care Unit [Paris], Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], [Institut Cochin] Departement Infection, immunité, inflammation, 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Infectious Diseases and Tropical Medicine [Paris], Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], 'Personal Protection Against Vectors' working group (PPAV), PPAV working group, Université Paris Descartes - Paris 5 (UPD5), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service de Réanimation Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Cochin [AP-HP], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], and Bodescot, Myriam
Subjects: Male, 0301 basic medicine, Fulminant, Cefotaxime, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Methicillin, 0302 clinical medicine, Medical microbiology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Gangrene, Virulence, Clindamycin, Brain, Staphylococcal Infections, Magnetic Resonance Imaging, Shock, Septic, Anti-Bacterial Agents, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Staphylococcus aureus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Vasculitis, medicine.medical_specialty, Adolescent, 030106 microbiology, Amputation, Surgical, lcsh:Infectious and parasitic diseases, Sepsis, 03 medical and health sciences, Case report, medicine, Genetic susceptibility, Humans, lcsh:RC109-216, Polymorphism, Leg, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, S. aureus, Immunology, Methicillin Susceptible Staphylococcus Aureus, business
Abstract: International audience; BACKGROUND:Staphylococcus aureus has emerged as a leading cause of invasive severe diseases with a high rate of morbidity and mortality worldwide. The wide spectrum of clinical manifestations and outcome observed in staphylococcal illness may be a consequence of both microbial factors and variability of the host immune response.CASE PRESENTATION:A 14-years old child developed limb ischemia with gangrene following S. aureus bloodstream infection. Histopathology revealed medium-sized arterial vasculitis. The causing strain belonged to the emerging clone CC1-MSSA and numerous pathogenesis-related genes were identified. Patient's genotyping revealed functional variants associated with severe infections. A combination of virulence and host factors might explain this unique severe form of staphylococcal disease.CONCLUSION:A combination of virulence and genetic host factors might explain this unique severe form of staphylococcal disease.
Published: 2019
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27. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database

Author: Laurent Arnaud, Thierry Martin, Philippe Mertz, Aude Lambert, François Chasset, Martine Tebacher-Alt, Joe-Elie Salem, Jean Sibilia, P.E. Gavand, Charlotte Muller, Bénédicte Lebrun-Vignes, CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Service de dermatologie et allergologie [CHU Tenon], CHU Tenon [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 Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], and CHU Pitié-Salpêtrière [AP-HP]
Subjects: Male, 0301 basic medicine, Databases, Factual, [SDV]Life Sciences [q-bio], computer.software_genre, Etanercept, 0302 clinical medicine, systemic lupus erythematosus, Lupus Erythematosus, Systemic, Immunology and Allergy, skin and connective tissue diseases, media_common, Systemic lupus erythematosus, Database, Middle Aged, Hydralazine, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Female, medicine.drug, Adult, Drug, media_common.quotation_subject, Immunology, Procainamide, World Health Organization, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, Pharmacovigilance, medicine, Adalimumab, Humans, Adverse effect, Retrospective Studies, 030203 arthritis & rheumatology, business.industry, drug-induced lupus, medicine.disease, Infliximab, 030104 developmental biology, adverse-drug reaction, pharmacovigilance, business, computer, Adverse drug reaction
Abstract: ObjectiveDrug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL.MethodsWe analysed all ICSRs classified as ‘systemic lupus erythematosus’ according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting.ResultsA total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine.ConclusionThis study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases.Trial registration numberNCT03480529.
Published: 2019
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28. Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

Author: Cormier-Dequaire, Florence, Bekadar, Samir, Anheim, Mathieu, Lebbah, Saïd, Pelissolo, Antoine, Krack, Paul, Lacomblez, Lucette, Lhommée, Eugénie, Castrioto, Anna, Azulay, Jean-Philippe, Defebvre, Luc, Kreisler, Alexandre, Durif, Franck, Marques-Raquel, Ana, Brefel-Courbon, Christine, Grabli, David, Roze, Emmanuel, Llorca, Pierre-Michel, Ory-Magne, Fabienne, Benatru, Isabelle, Ansquer, Solène, Maltête, David, Tir, Fazia Mélissa, Krystkowiak, Pierre, Tranchant, Christine, Lagha-Boukbiza, Ouhaid, Lebrun-Vignes, Bénédicte, Mangone, Graziella, Vidailhet, Marie, Charbonnier-Beaupel, Fanny, Rascol, Olivier, Lesage, Suzanne, Brice, Alexis, Tezenas Du Montcel, Pierre, Corvol, Jean-Christophe, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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), Département de Neurologie [Hôpitaux Universitaires de Strasbourg] (HUS), Les Hôpitaux Universitaires de Strasbourg (HUS), INSERM U955, équipe 15, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Réseau de coopération scientifique en santé mentale, Fondation FondaMental [Créteil]-Fondation FondaMental [Créteil]-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), ANTE-INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Unité de Désordres du Mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UM des troubles du mouvement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Unité Médicale des Troubles du Mouvement, CHU Grenoble-Clinique de Neurologie, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Pharmacologie, PRES Université Lille Nord de France, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de pharmacologie clinique, CHU Toulouse [Toulouse], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Amiens-Picardie, Service de neurologie [Amiens], Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse]
Subjects: Adult, Male, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Opioid, mu, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, Disruptive, Impulse Control, and Conduct Disorders, Levodopa, Risk Factors, Dopamine Agonists, Gambling, Humans, Female, ComputingMilieux_MISCELLANEOUS, Aged
Abstract: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD.We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset.The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105).Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.
Published: 2018
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29. Immune Checkpoint Inhibitor-Associated Myositis: A CharacteristicPhenotype with a Poor Outcome Related to Concomitant Myocarditis

Author: Anquetil, Céline, Salem, Joe-Elie, Lebrun-Vignes, Benedicte, Johnson, Douglas B, Mammen, Andrew, Stenzel, Werner, Léonard-Louis, Sarah, Benveniste, Olivier, Moslehi, Javid J, Allenbach, Yves, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), National Institutes of Health [Bethesda] (NIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University Medical Center [Nashville], and Vanderbilt University [Nashville]
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2018
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30. Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase

Author: Laurent Arnaud, Joe-Elie Salem, Philippe Mertz, Bénédicte Lebrun-Vignes, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Université de Strasbourg (UNISTRA), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de pharmacologie médicale [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), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Drug, Male, medicine.medical_specialty, Databases, Factual, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Immunology, MEDLINE, Antineoplastic Agents, 030204 cardiovascular system & hematology, World Health Organization, World health, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, Immunologic Factors, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, media_common, Retrospective Studies, 030203 arthritis & rheumatology, business.industry, Retrospective cohort study, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.IMM]Life Sciences [q-bio]/Immunology, Observational study, business, Capillary Leak Syndrome
Abstract: International audience
Published: 2018
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31. Mining Patients' Narratives in Social Media for Pharmacovigilance: Adverse Effects and Misuse of Methylphenidate

Author: Xiaoyi Chen, Carole Faviez, Stéphane Schuck, Agnès Lillo-Le-Louët, Nathalie Texier, Badisse Dahamna, Charles Huot, Pierre Foulquié, Suzanne Pereira, Vincent Leroux, Pierre Karapetiantz, Armelle Guenegou-Arnoux, Sandrine Katsahian, Cédric Bousquet, Anita Burgun, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Kappa, 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), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Expert Systems, VIDAL S.A., Institut de Santé Urbaine, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Service d'informatique biomédicale [Rouen], CHU Rouen, Normandie Université (NU), Département d’informatique médicale, de biostatistique et de santé publique [AP-HP Hôpital européen Georges-Pompidou], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), and 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)
Subjects: Topic model, drug misuse, 020205 medical informatics, social media, methylphenidate, 02 engineering and technology, computer.software_genre, [INFO.INFO-SI]Computer Science [cs]/Social and Information Networks [cs.SI], 03 medical and health sciences, 0302 clinical medicine, Text mining, Named-entity recognition, Pharmacovigilance, 0202 electrical engineering, electronic engineering, information engineering, Pharmacology (medical), Social media, [INFO]Computer Science [cs], 030212 general & internal medicine, natural language processing, Adverse effect, ComputingMilieux_MISCELLANEOUS, Original Research, Pharmacology, business.industry, lcsh:RM1-950, data mining, Relationship extraction, 3. Good health, [INFO.INFO-TT]Computer Science [cs]/Document and Text Processing, Identification (information), lcsh:Therapeutics. Pharmacology, pharmacovigilance, drug-related side effects and adverse reactions, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Artificial intelligence, business, Psychology, computer, Natural language processing
Abstract: International audience; Background: The Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) have recognized social media as a new data source to strengthen their activities regarding drug safety. Objective: Our objective in the ADR-PRISM project was to provide text mining and visualization tools to explore a corpus of posts extracted from social media. We evaluated this approach on a corpus of 21 million posts from five patient forums, and conducted a qualitative analysis of the data available on methylphenidate in this corpus. Methods: We applied text mining methods based on named entity recognition and relation extraction in the corpus, followed by signal detection using proportional reporting ratio (PRR). We also used topic modeling based on the Correlated Topic Model to obtain the list of the matics in the corpus and classify the messages based on their topics. Results: We automatically identified 3443 posts about methylphenidate published between 2007 and 2016, among which 61 adverse drug reactions (ADR) were automatically detected. Two pharmacovigilance experts evaluated manually the quality of automatic identification, and a f-measure of 0.57 was reached. Patient's reports were mainly neuro-psychiatric effects. Applying PRR, 67% of the ADRs were signals, including most of the neuro-psychiatric symptoms but also palpitations. Topic modeling showed that the most represented topics were related to Childhood and Treatment initiation, but also Side effects. Cases of misuse were also identified in this corpus, including recreational use and abuse. Conclusion: Named entity recognition combined with signal detection and topic modeling have demonstrated their complementarity in mining social media data. An in-depth analysis focused on methylphenidate showed that this approach was able to detect potential signals and to provide better understanding of patients' behaviors regarding drugs, including misuse.
Published: 2018
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32. Antibacterial Toxins: Gram-Positive Bacteria Strike Back!

Author: Anne Jamet, Alain Charbit, Xavier Nassif, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 0301 basic medicine, Microbiology (medical), Firmicutes, Virulence Factors, media_common.quotation_subject, Gram-positive bacteria, 030106 microbiology, Bacterial Toxins, medicine.disease_cause, Gram-Positive Bacteria, Microbiology, Competition (biology), 03 medical and health sciences, Bacterial Proteins, Protein Domains, Virology, Gram-Negative Bacteria, medicine, Secretion, Bacterial Secretion Systems, ComputingMilieux_MISCELLANEOUS, media_common, biology, Toxin, biology.organism_classification, Anti-Bacterial Agents, 030104 developmental biology, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Bacteria
Abstract: Bacteria live in communities where strains compete with each other by deploying an arsenal of antibacterial toxins. While the past decade revealed the vast array of antibacterial toxins secreted by Gram-negative bacteria, several recent studies have begun to uncover the ability of Gram-positive bacteria to battle with their own weapons.
Published: 2018
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33. Severe cutaneous adverse reactions due to inappropriate medication use

Author: Laurence Fardet, G. Chaby, Laurence Valeyrie-Allanore, Tu Anh Duong, Bénédicte Lebrun-Vignes, F. Tetart, Bruno Sassolas, Olivier Chosidow, B. Milpied, Pierre Wolkenstein, Chaire Avenir Santé Numérique [Créteil] (CASN), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), AP-HP. Université Paris Saclay, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE)
Subjects: Drug, Adult, Male, medicine.medical_specialty, media_common.quotation_subject, Allopurinol, Inappropriate Prescribing, Dermatology, Self Medication, Severity of Illness Index, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Severity of illness, Trimethoprim, Sulfamethoxazole Drug Combination, medicine, Humans, 030212 general & internal medicine, Medical prescription, ComputingMilieux_MISCELLANEOUS, media_common, Aged, Retrospective Studies, business.industry, Incidence (epidemiology), Incidence, Anti-Inflammatory Agents, Non-Steroidal, Retrospective cohort study, Middle Aged, Confidence interval, Anti-Bacterial Agents, Population study, Anticonvulsants, Female, Drug Eruptions, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Self-medication
Abstract: Background The proportion of severe cutaneous adverse reactions (SCARs) that could be avoided if medication use was consistent with good medical practice is unknown. Objectives To estimate the proportion of SCARs related to inappropriate medication use. Methods We carried out a retrospective study of all validated SCARs collected in a French registry between 2003 and 2016. For each case, all plausible drugs suspected of inducing SCARs (i.e. not just the drug regarded as 'the most probable') were considered with regard to (i) prescription for an inappropriate indication, (ii) unintentional rechallenge despite a previous allergy to the drug or (iii) self-medication with prescription medicines. Results In total, 602 cases were included in the analyses. Antibiotics, anticonvulsants and allopurinol were the drugs most frequently involved, accounting for more than 50% of all cases. All suspected medications were considered to have been appropriately used for 417 of the 602 individuals included in the study population [69·3%, 95% confidence interval (CI) 65·6-73·0] and inappropriately used for 144 individuals (23·9%, 95% CI 20·5-27·3). These inappropriate uses were due mainly to prescriptions for an inappropriate indication (65·8%, 95% CI 58·4-73·2) or unintentional rechallenge (20·9%, 95% CI 14·6-27·2). Allopurinol and co-trimoxazole were the drugs most frequently involved in inappropriate indications. Antibiotics were the largest group involved in unintentional rechallenge. Nonsteroidal anti-inflammatory drugs, available on prescription, were most frequently involved in inappropriate self-medication. Conclusions Our results underline the need for respecting the appropriate indication for drugs in order to reduce the incidence of SCARs. Reducing unintentional rechallenge also seems to be a necessary preventive measure.
Published: 2018
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34. Cyclosporine for Epidermal Necrolysis: Absence of Beneficial Effect in a Retrospective Cohort of 174 Patients-Exposed/Unexposed and Propensity Score-Matched Analyses

Author: Camille Hua, Tu Anh Duong, A. Colin, Laurence Fardet, L. Le Cleach, Emilie Sbidian, Olivier Chosidow, Pierre Wolkenstein, O. Gaudin, Claire Hotz, Florence Poizeau, Ouidad Zehou, Nicolas de Prost, Saskia Ingen-Housz-Oro, Bénédicte Lebrun-Vignes, CHU Pontchaillou [Rennes], Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Dermatologie, Hopital Mondor, Assistance Publique des Hôpitaux de Paris, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance Publique des Hôpitaux de Paris, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), PRES Université Paris-Est, Service de réanimation médicale, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Département de dermatologie, hôpital Henri Mondor, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), and VO, alexandra
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Randomization, Palliative care, Dermatology, Biochemistry, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Re-Epithelialization, Internal medicine, Epidemiology, medicine, Humans, Treatment Failure, Propensity Score, Molecular Biology, Survival analysis, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Skin, Body surface area, business.industry, Palliative Care, Retrospective cohort study, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, Acute Kidney Injury, Middle Aged, medicine.disease, Survival Analysis, Toxic epidermal necrolysis, 030104 developmental biology, Stevens-Johnson Syndrome, Propensity score matching, Cyclosporine, Disease Progression, Female, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Immunosuppressive Agents
Abstract: Cyclosporine has shown promising results for mortality in patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. However, available studies included only a small number of patients and did not include a validated and homogenous control group. We present the results from a retrospective monocentric study including 174 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis during 2005–2016. Among them, 95 received cyclosporine (3 mg/kg/day) plus supportive care, and 79 received supportive care only. Both a traditional exposed/unexposed method and a propensity score-matching method were used to compare the progression of skin detachment between day 0 and day 5, the proportion of patients with cutaneous re-epithelialization starting on day 5 or mucosal re-epithelialization on day 10, the duration of progression, and the number of deaths between the two groups. None of these outcomes significantly favored cyclosporine, either by the exposed/unexposed method or the propensity score method. Acute renal failure affected more patients receiving cyclosporine (P = 0.05). Overall, the results of this epidemiological study did not show a beneficial effect of cyclosporine in patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. They are discordant with those previously published. The large number of patients and the use of a propensity score method provide valuable insights. The main limitation of the study is the lack of randomization.
Published: 2017
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35. Phénotype et pronostic des atteintes systémiques induites sous inhibiteurs de check-points immunitaires

Author: Olivier Lambotte, Michelle Rosenzwajg, Joe-Elie Salem, David Klatzmann, Céline Anquetil, Ali Manouchehri, Bruno Fautrel, Jean-Philippe Spano, Douglas B. Johnson, Y. Allenbach, Javid Moslehi, Jacques Cadranel, Bénédicte Lebrun-Vignes, Olivier Benveniste, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules (GRC 4 - Theranoscan), and Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Gastroenterology, Internal Medicine
Abstract: Introduction Actuellement, les inhibiteurs de check-points immunitaires (ICI) sont recommandes pour le traitement de plus de 16 types de cancers differents et le nombre de patients eligibles ne cesse d’augmenter notamment avec l’approbation recente dans le cancer du sein. La gestion des toxicites immunitaires induites par ces anticorps monoclonaux anti-cytotoxic-T-lymphocyte-associated protein-4 (CTLA4) ou anti-programme cell death 1/programme cell death ligand 1 (PD1/PDL1) devient cruciale. En effet, en restaurant l’immunite cellulaire T antitumorale, les ICI peuvent induire des effets indesirables dont la frequence, le tropisme et la severite dependent notamment des schemas therapeutiques utilises. Une etude recente des toxicites cardiovasculaires immuno-induites a montre un risque de mortalite majeur lie aux myocardites. Cependant, les effets indesirables rhumatologiques sont a ce jour peu decrits. Objectifs Identifier et caracteriser les toxicites rhumatologiques induites par les ICI a l’aide de la base internationale de pharmacovigilance de l’OMS. Materiels et methodes A l’aide de la base de pharmacovigilance de l’OMS, nous avons compare par une analyse de disproportionnalite bayesienne la declaration des effets indesirables rhumatologiques chez les patients exposes aux ICI a la declaration de ces effets dans la base de donnees complete a partir de 2008 (date de la premiere declaration d’evenement indesirable sous ICI). Toutes les pathologies systemiques rhumatologiques (a l’exception de la vascularite) ont ete incluses selon la definition des termes Medical Dictionary for Regulatory Activities (MedDRA). Les molecules suivantes ont ete prises en compte : pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, tremelimumab, cemiplimab et ipilimumab. L’association entre effet indesirable et medicament est calculee par l’information component (IC) ou le reporting odds ratio (ROR). La borne inferieure de l’intervalle de confiance a 95 % de l’IC : IC0,25 est significatif si positif. Resultats Nous avons identifie 54 416 effets indesirables rapportes sous ICI (14 988 450 effets indesirables rapportes dans la base depuis 2008). Comparativement a l’ensemble de la base, une association significative entre ICI et effets indesirables rhumatologiques a ete mise en evidence pour 6 pathologies : les arthrites (n = 606/121 811, ROR 1,4 [1,3–1,5] ; IC0,25 0,45), les myosites (n = 465/26 722, ROR 4,9 [4,5–5,4] ; IC0,25 2,12), la sarcoidose (n= 94/2772, ROR 9,6 [7,9–11,9] ; IC0,25 2,85), la pseudopolyarthrite rhizomelique (n= 76/1504, ROR 14,6 [11,6–18,4] ; IC0,25 3,34), le syndrome de Gougerot-Sjogren (n = 49/2000, ROR 6,9 [5,2–9,2] ; IC0,25 2,24) et le sclerodermie (n =17/2385 vs 17, ROR 2,0 [1,2–3,2] ; IC0,25 0,17). Les patients atteints de myosite etaient plus souvent des hommes (70,4 % ; p Conclusion Parmi les toxicites rhumatologiques, les myosites sont les plus precoces et les plus graves. Le phenotype des toxicites rhumatologiques differe des pathologies auto-immunes spontanees et leur type varie selon l’ICI (PD1 ou CTLA-4), ce qui suggere des mecanismes physiopathologiques distincts. Une meilleure connaissance de ces effets indesirables est necessaire pour si possible les prevenir et ameliorer leur prise en charge therapeutique.
Published: 2019
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36. The Adverse Drug Reactions from Patient Reports in Social Media Project: Five Major Challenges to Overcome to Operationalize Analysis and Efficiently Support Pharmacovigilance Process

Author: Cedric, Bousquet, Badisse, Dahamna, Sylvie, Guillemin-Lanne, Stefan J, Darmoni, Carole, Faviez, Charles, Huot, Sandrine, Katsahian, Vincent, Leroux, Suzanne, Pereira, Christophe, Richard, Stéphane, Schück, Julien, Souvignet, Agnès, Lillo-Le Louët, Nathalie, Texier, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Temis, Kappa, IBM France (IBM), IBM, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: Original Paper, big data, pharmacovigilance, social media, medical terminology, [INFO]Computer Science [cs], natural language processing
Abstract: Background Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Classical Pharmacovigilance process is limited by underreporting which justifies the current interest in new knowledge sources such as social media. The Adverse Drug Reactions from Patient Reports in Social Media (ADR-PRISM) project aims to extract ADRs reported by patients in these media. We identified 5 major challenges to overcome to operationalize the analysis of patient posts: (1) variable quality of information on social media, (2) guarantee of data privacy, (3) response to pharmacovigilance expert expectations, (4) identification of relevant information within Web pages, and (5) robust and evolutive architecture. Objective This article aims to describe the current state of advancement of the ADR-PRISM project by focusing on the solutions we have chosen to address these 5 major challenges. Methods In this article, we propose methods and describe the advancement of this project on several aspects: (1) a quality driven approach for selecting relevant social media for the extraction of knowledge on potential ADRs, (2) an assessment of ethical issues and French regulation for the analysis of data on social media, (3) an analysis of pharmacovigilance expert requirements when reviewing patient posts on the Internet, (4) an extraction method based on natural language processing, pattern based matching, and selection of relevant medical concepts in reference terminologies, and (5) specifications of a component-based architecture for the monitoring system. Results Considering the 5 major challenges, we (1) selected a set of 21 validated criteria for selecting social media to support the extraction of potential ADRs, (2) proposed solutions to guarantee data privacy of patients posting on Internet, (3) took into account pharmacovigilance expert requirements with use case diagrams and scenarios, (4) built domain-specific knowledge resources embeding a lexicon, morphological rules, context rules, semantic rules, syntactic rules, and post-analysis processing, and (5) proposed a component-based architecture that allows storage of big data and accessibility to third-party applications through Web services. Conclusions We demonstrated the feasibility of implementing a component-based architecture that allows collection of patient posts on the Internet, near real-time processing of those posts including annotation, and storage in big data structures. In the next steps, we will evaluate the posts identified by the system in social media to clarify the interest and relevance of such approach to improve conventional pharmacovigilance processes based on spontaneous reporting.
Published: 2017
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37. Diagnostics: Cluster headache and misuse of paracetamol

Author: C. Egloff, Kazutoyo Yasukawa, J. Scala-Bertola, E. Pape, C. Clément, F. Camelot, Faculté de Pharmacie [Nancy], Université de Lorraine (UL), Eco-Anthropologie et Ethnobiologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), ANTEA Group, and ANTEA
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Cluster headache, [SDV]Life Sciences [q-bio], medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, business, General Dentistry, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2016
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38. Interpretation of idarucizumab clinical trial data based on spontaneous reports of dabigatran adverse effects in the French pharmacovigilance database

Author: Trinh-Duc, Albert, Lillo-Le Louët, Agnès, Tellier, Éric, Viard, Thibault, Le Gal, Grégoire, Smadja, David M, Calvez, Ghislaine, Service d'Accueil des Urgences (AGEN - SAU), Centre Hospitalier d'Agen, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Bordeaux (UB), 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), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université de Brest (UBO)
Subjects: [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV]Life Sciences [q-bio], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience
Published: 2016

39. A randomized investigator-masked double-bind placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis

Author: Jacqueline Chevrant-Breton, Caroline Juillard, Michel Rybojad, Nicolas Dupin, Raphaël Porcher, Michel d’Incan, Jean Revuz, Anne Cosnes, Laurent Misery, Abdellatif Tazi, Catherine Droitcourt, Jean-Philippe Lacour, Alain Dupuy, Kristell Desseaux, Bénédicte Lebrun-Vignes, Pascal Joly, Dominique Valeyre, Bruno Sassolas, Olivier Chosidow, Centre d'Investigation Clinique [Rennes] (CIC), 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), Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Modèles, Dynamiques, Corpus (MoDyCo), Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Hôtel-Dieu, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Service de dermatologie, Laboratoire de Neurosciences de Brest (LNB), Université de Brest (UBO), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'informatique médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service des maladies respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de pneumologie [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-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), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service de Dermatologie [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri-Mondor, CHU Cochin [AP-HP], Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Sarcoidosis, Cutaneous Sarcoidosis, Population, Placebo-controlled study, Context (language use), Critical Care and Intensive Care Medicine, Placebo, Skin Diseases, law.invention, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, medicine, Humans, education, Aged, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, Intention-to-treat analysis, business.industry, Remission Induction, Middle Aged, Thalidomide, 3. Good health, Surgery, Treatment Outcome, 030228 respiratory system, Female, France, Cardiology and Cardiovascular Medicine, business, Immunosuppressive Agents, medicine.drug
Abstract: International audience; Abstract: Context:Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. Objective:To evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis. Design, Setting and Participants:Randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicentre trial lasting 3 months, and an open-label study from month 3 to month 6. Adults with clinical and histological diagnosis of cutaneous sarcoidosis were included in nine hospital centres in France. Intervention:Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for three months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide 100 mg to 200 mg daily. Main outcome measures:The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement of 3 target lesions scored for area and infiltration, were compared across randomisation groups. Results:The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients (20%) in the thalidomide group vs 4 out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% (95% CI -26% to +24%) for thalidomide vs placebo; p=1.0). Eight patients with side effects were recorded in the thalidomide group vs 3 in the placebo group. We observed a large number of adverse event-related discontinuations in patients under thalidomide in the first 3 months (4 patients with thalidomide, 0 with placebo), and in the 3 following months (5 patients). Conclusion:At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. Trial registration:NCT0030552 (ClinicalTrial.gov). Context: Thalidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. Objective: To evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis. Design, Setting and Participants: Randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicentre trial lasting 3 months, and an open-label study from month 3 to month 6. Adults with clinical and histological diagnosis of cutaneous sarcoidosis were included in nine hospital centres in France. Intervention: Patients were randomized 1:1 to oral thalidomide (100 mg once daily) or to a matching oral placebo for three months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide 100 mg to 200 mg daily. Main outcome measures: The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement of 3 target lesions scored for area and infiltration, were compared across randomisation groups. Results: The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients (20%) in the thalidomide group vs 4 out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of -1% (95% CI -26% to +24%) for thalidomide vs placebo; p=1.0). Eight patients with side effects were recorded in the thalidomide group vs 3 in the placebo group. We observed a large number of adverse event-related discontinuations in patients under thalidomide in the first 3 months (4 patients with thalidomide, 0 with placebo), and in the 3 following months (5 patients). Conclusion: At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis. Trial registration: NCT0030552 (ClinicalTrial.gov).
Published: 2014
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40. Phenome-wide association studies on a quantitative trait: application to TPMT enzyme activity and thiopurine therapy in pharmacogenomics

Author: Paul Avillach, P. Degoulet, Anita Burgun, Denis Roche, Georgia Malamut, Christine Le Beller, Laurent Chouchana, Antoine Neuraz, Marie-Anne Loriot, Philippe Beaune, Biomedical Informatics and Public Health Department [Paris], 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), Équipe 22 - Information Sciences to support Personalized Medicine [Paris], Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Régional de Pharmacovigilance (CRPV), Biochemistry, Pharmacogenetics and Molecular Oncology Unit [Paris], This study was partly funded by the BioIntelligence collaborative program for the Institut National de la Recherche Médicale (INSERM)., and Bodescot, Myriam
Subjects: Quantitative Trait Loci, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Phenome, Quantitative trait locus, Bioinformatics, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, International Classification of Diseases, Genetics, Humans, lcsh:QH301-705.5, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Ecology, Thiopurine methyltransferase, biology, Methyltransferases, 3. Good health, Phenotype, lcsh:Biology (General), Computational Theory and Mathematics, Pharmacogenetics, Purines, 030220 oncology & carcinogenesis, Modeling and Simulation, Pharmacogenomics, biology.protein, Diagnosis code, Genome-Wide Association Study, Research Article
Abstract: Phenome-Wide Association Studies (PheWAS) investigate whether genetic polymorphisms associated with a phenotype are also associated with other diagnoses. In this study, we have developed new methods to perform a PheWAS based on ICD-10 codes and biological test results, and to use a quantitative trait as the selection criterion. We tested our approach on thiopurine S-methyltransferase (TPMT) activity in patients treated by thiopurine drugs. We developed 2 aggregation methods for the ICD-10 codes: an ICD-10 hierarchy and a mapping to existing ICD-9-CM based PheWAS codes. Eleven biological test results were also analyzed using discretization algorithms. We applied these methods in patients having a TPMT activity assessment from the clinical data warehouse of a French academic hospital between January 2000 and July 2013. Data after initiation of thiopurine treatment were analyzed and patient groups were compared according to their TPMT activity level. A total of 442 patient records were analyzed representing 10,252 ICD-10 codes and 72,711 biological test results. The results from the ICD-9-CM based PheWAS codes and ICD-10 hierarchy codes were concordant. Cross-validation with the biological test results allowed us to validate the ICD phenotypes. Iron-deficiency anemia and diabetes mellitus were associated with a very high TPMT activity (p = 0.0004 and p = 0.0015, respectively). We describe here an original method to perform PheWAS on a quantitative trait using both ICD-10 diagnosis codes and biological test results to identify associated phenotypes. In the field of pharmacogenomics, PheWAS allow for the identification of new subgroups of patients who require personalized clinical and therapeutic management., Author Summary The use of underlying molecular mechanisms and other factors to describe and classify diseases is a major challenge for future treatment strategies. New methods are needed to achieve this goal. The phenome wide association study (PheWAS) methodology was initially developed to unveil unknown associations between a specific genetic status and phenotypic features (e.g. diagnoses from electronic health records). We initially propose to extend this method to assessment of the relationships between the levels of a quantitative trait and diagnosis codes. We also assess the relationships between this quantitative trait and the biological test results. We tested this method using the levels of enzymatic activity of thiopurine S-methyltransferase (TPMT) that is involved in the metabolism of thiopurine drugs used in inflammatory bowel diseases for example. We discovered an association between a very high TPMT activity and nutritional anemia and diabetes. These results could be used to describe a new subgroup of patients in order to optimize drug treatments.
Published: 2013
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41. Adverse Drug Reaction Mining in Pharmacovigilance data using Formal Concept Analysis

Author: Yannick Toussaint, Agnès Lillo-Le Louet, Jean Villerd, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adverse Drug Reactions, Computer science, Association (object-oriented programming), Formal Concept Analysis, Population, 02 engineering and technology, 030226 pharmacology & pharmacy, Health informatics, Task (project management), [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, Pharmacovigilance, 0202 electrical engineering, electronic engineering, information engineering, Formal concept analysis, medicine, Adverse effect, education, Data mining, education.field_of_study, business.industry, medicine.disease, Data science, 020201 artificial intelligence & image processing, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Adverse drug reaction
Abstract: International audience; In this paper we discuss the problem of extracting and evaluating associations between drugs and adverse effects in pharmacovigilance data. Approaches proposed by the medical informatics community for mining one drug - one effect pairs perform an exhaustive search strategy that precludes from mining high-order associations. Some specificities of pharmacovigilance data prevent from applying pattern mining approaches proposed by the data mining community for similar problems dealing with epidemiological studies. We argue that Formal Concept Analysis (FCA) and concept lattices constitute a suitable framework for both identifying relevant associations, and assisting experts in their evaluation task. Demographic attributes are handled so that the disproportionality of an association is computed w.r.t. the relevant population stratum to prevent confounding. We put the focus on the understandability of the results and provide evaluation facilities for experts. A real case study on a subset of the French spontaneous reporting system shows that the method identifies known adverse drug reactions and some unknown associations that has to be further investigated.
Published: 2010
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42. Modeling, building and evaluating an ontology for the automatic characterization of adverse drug effects during pharmacovigilance

Author: Duclos, Catherine, Soualmia, Lina F, Krivine, Sonia, Jamet, Anne, Lillo-Louët, Agnes, Soualmia, Lina F, Laboratoire d'Informatique Médicale et de BIOinformatique (LIM&BIO), Université Paris 13 (UP13), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Databases, Factual, Drug-Related Side Effects and Adverse Reactions, Adverse Drug Reaction Reporting Systems, Humans, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience; BACKGROUND: The characterization of spontaneous reported cases is fundamental for pharmacovigilance. This task is time consuming and its reproducibility is low. OBJECTIVE: To develop a system founded on an ontology that automatically instantiates spontaneous reported cases as "known" adverse drug effects (ADE) only if the reported ADEs are described in drug compendia. METHODS: A simple ontology of drugs and their related adverse effects represented in description logics was developed from a drug database. Manual evaluation was carried out on 378 spontaneous reported cases instantiated as "known ADE of a chemical class". The initial manual characterization was reviewed by a pharmacovigilance expert to validate the generated automatic characterization. RESULTS: The ontology is composed by 57,04 concepts and 5 relations. It was successfully validated thanks to Pellet reasoner and it contains neither inconsistencies nor cycles. In this validation, 86% of the instantiated spontaneous reported cases effectively concerned notorious ADEs, whereas only 75% were initially identified manually as related to notorious ADEs. CONCLUSION: This system can assist characterization by applying a reasoning process similar to that used by experts in the search for ADEs.
Published: 2010

43. Complémentarité des méthodes numériques et symboliques en pharmacovigilance

Author: Jean Villerd, Yannick Toussaint, Agnès Lillo-Le Louet, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sylvie Desprès, and Villerd, Jean
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Pharmacovigilance, Extraction de connaissances, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], Fouille de données, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: National audience; La pharmacovigilance a pour objet la surveillance du risque d'effet indésirable résultant de l'utilisation des médicaments et produits à usage humain. Elle consiste à détecter des « signaux » correspondant à des corrélations suspectes entre la prise d'un médicament et l'observation d'un effet indésirable. Les professionnels de santé sont tenus de signaler tout effet indésirable inattendu en envoyant un rapport a leur centre régional de pharmacovigilance, alimentant ainsi une base nationale. Pour faire face à la quantité de rapports stockés, des méthodes numériques fondées sur des mesures de disproportionnalité été proposées ; elles extraient efficacement les couples (médicament, effet indésirable) sur-représentés dans la base, en vue de leur evaluation par un expert. Toutefois, ces approches fournissent peu d'information aux experts pour leur permettre de comprendre pour quelles raisons ces signaux ont eté retenus. De plus, aucune information ne leur est transmise concernant la spécificité eventuelle d'un signal qui concernerait plus particulièrement une sous-population (sexe, âge). L'utilisation d'une approche symbolique comme l'Analyse de Concepts Formels (ACF), en complément des méthodes numériques existantes, nous a permis d'obtenir une meilleure « tracabilité » des signaux extraits en fournissant aux experts une vue synthétique du contenu de la base. De plus, l'utilisation d'une approche fondée sur les treillis permet de réduire l'espace de recherche, de détecter des associations complexes impliquant plusieurs médicaments et effets indésirables et d'identifier les spécificités liées aux diverses sous-populations. Nous illustrons ces atouts par une expérimentation sur la base régionale HEGP.
Published: 2010

44. VigiTermes : une plateforme de recherche et d'analyse des publications scientifiques au service de la pharmacovigilance

Author: Thebault, Mathilde, Amardeilh, Florence, Delamarre, Denis, Guillemin-Lanne, Sylvie, Jamet, Anne, Lillo-Le Louet, Agnès, Thebault, Mathilde, Technologies pour la santé - Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance - - VigiTermes2007 - ANR-07-TECS-0026 - TECSAN - VALID, Sylvie DESPRES, Temis, Mondeca, Modélisation Conceptuelle des Connaissances Biomédicales, 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)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Vigitermes ANR-07-TECSAN-026, ANR-07-TECS-0026,VigiTermes,Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance(2007), and Université de Rennes (UR)-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: [INFO.INFO-TT]Computer Science [cs]/Document and Text Processing, recherche PubMed, [INFO.INFO-CL] Computer Science [cs]/Computation and Language [cs.CL], [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], annotation sémantique, pharmacovigilance, [INFO.INFO-TT] Computer Science [cs]/Document and Text Processing, bases de connaissance, text mining, modélisations des connaissances, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], [INFO.INFO-CL]Computer Science [cs]/Computation and Language [cs.CL]
Abstract: National audience; La réglementation impose une identification systématique des effets indésirables des médicaments. La plupart des pays se sont dotés de systèmes d'information d'aide à la documentation de ces effets. La tâche est rendue difficile par la multiplicité des sources et le peu d'outils fédérateurs existant pour accéder, rechercher et analyser l'information autour des médicaments. L'objectif du projet VigiTermes est de développer une plateforme pour améliorer la documentation des rapports de cas de pharmacovigilance et de proposer des outils d'accès et d'analyse pour les experts pharmacovigilants, dont l'objectif est d'enquêter sur la détection de nouveaux cas (signaux). Dans ce cadre, nous avons développé un prototype qui reproduit et standardise les stratégies de recherche documentaire formulées par les pharmacovigilants, récupère les résumés PubMed pertinents et en extrait de l'information autour des médicaments et de leurs effets secondaires potentiels.
Published: 2010

45. A Knowledge Management Platform for Documentation of Case Reports in Pharmacovigilance

Author: Amardeilh, Florence, Bousquet, Cédric, Guillemin-Lanne, Sylvie, Wiss-Thébault, Mathilde, Guillot, Laetitia, Delamarre, Denis, Lillo-Le Louet, Agnès, Burgun, Anita, Mondeca Recherche & Développement (MONDECA R&D), Mondeca, Département de Santé Publique et Information Médicale (DSPIM), Université Jean Monnet [Saint-Étienne] (UJM), Temis, Modélisation Conceptuelle des Connaissances Biomédicales, 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)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), VigiTermes, ANR-07-TECS-0026,VigiTermes,Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance(2007), Amardeilh, Florence, Technologies pour la santé - Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance - - VigiTermes2007 - ANR-07-TECS-0026 - TECSAN - VALID, Service de santé publique et d'information médicale [CHU Saint-Etienne] (SSPIM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Université de Rennes (UR)-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 Jean Monnet - Saint-Étienne (UJM)
Subjects: databases, [INFO.INFO-CL] Computer Science [cs]/Computation and Language [cs.CL], knowledge bases, text mining, information storage and retrieval, drug adverse effects, systems integration, semantic annotation, [INFO.INFO-CL]Computer Science [cs]/Computation and Language [cs.CL]
Abstract: Most countries have developed information systems to report drug adverse effects. However, as in other domains where systematic reviews are needed, there is little guidance on how systematic documentation of drug adverse effects should be performed. The objective of the VigiTermes project is to develop a platform to improve documentation of pharmacovigilance case reports for the pharmaceutical industry and regulatory authorities. In order to improve systematic reviews of adverse drug reactions, we developed a prototype that first reproduces and standardizes search strategies, then extracts information from the Medline abstracts which were retrieved and annotates them. The platform aims at providing transparent access and analysis tools to pharmacovigilance experts investigating relevance of safety signals related to drugs. The platform's architecture consists in the integration of two vendor tools ITM® and Luxid® and one academic web service for knowledge extraction from medical literature. Whereas a manual search performed by a pharmacovigilance expert retrieved 578 publications, the system proposed a list of 229 publications thus decreasing time required for review by 60%. Recall was 70% and additional developments are required in order to improve exhaustivity.
Published: 2009

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