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1. Organoids in domestic animals: with which stem cells?

Author

Pain, Bertrand, BMC, BMC, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult stem cells, lcsh:Veterinary medicine, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Cell Culture Techniques, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Review, Organoids, Induced pluripotent stem cells, Pluripotent stem cells, Animals, Domestic, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, lcsh:SF600-1100
Abstract

International audience; AbstractOrganoids are three-dimensional structures that are derived from the self-organization of stem cells as they differentiate in vitro. The plasticity of stem cells is one of the major criteria for generating organoids most similar to the tissue structures they intend to mimic. Stem cells are cells with unique properties of self-renewal and differentiation. Depending on their origin, a distinction is made between pluripotent (embryonic) stem cells (PSCs), adult (or tissue) stem cells (ASCs), and those obtained by somatic reprogramming, so-called induced pluripotent stem cells (iPSCs). While most data since the 1980s have been acquired in the mouse model, and then from the late 1990s in humans, the process of somatic reprogammation has revolutionized the field of stem cell research. For domestic animals, numerous attempts have been made to obtain PSCs and iPSCs, an approach that makes it possible to omit the use of embryos to derive the cells. Even if the plasticity of the cells obtained is not always optimal, the recent progress in obtaining reprogrammed cells is encouraging. Along with PSCs and iPSCs, many organoid derivations in animal species are currently obtained from ASCs. In this study, we present state-of-the-art stem cell research according to their origins in the various animal models developed.

Published
2021

2. Liver organoids in domestic animals: an expected promise for metabolic studies

Author

Baquerre, Camille, Montillet, Guillaume, Pain, Bertrand, Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-11-INBS-0003,CRB-Anim,Réseau de Centres de Ressources Biologiques pour les animaux domestiques(2011), BMC, BMC, and Infrastructures - Réseau de Centres de Ressources Biologiques pour les animaux domestiques - - CRB-Anim2011 - ANR-11-INBS-0003 - INBS - VALID

Subjects
Mammals, lcsh:Veterinary medicine, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Sus scrofa, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Review, Domestic species, Organoids, Birds, Ducks, Liver, Pluripotent stem cells, Animals, Metabolomics, lcsh:SF600-1100, Chickens, Liver organoids
Abstract

International audience; The liver is one of the most important organs, both in terms of the different metabolic processes (energy, lipid, ferric, uric, etc.) and of its central role in the processes of detoxification of substances of food origin or noxious substances (alcohol, drugs, antibiotics, etc.). The development of a relevant model that reproduces some of the functions of this tissue has become a challenge, in particular for human medicine. Thus, in recent years, most studies aimed at producing hepatocytes in vitro with the goal of developing hepatic 3D structures have been carried out in the human model. However, the tools and protocols developed using this unique model can also be considered to address physiological questions specific to this tissue in other species, such as the pig, chicken, and duck. Different strategies are presently being considered to carry out in vitro studies of the hepatic metabolism of these agronomic species.

Published
2021

3. Intestinal organoids in farm animals

Author

Beaumont, Martin, Blanc, Fany, Cherbuy, Claire, EGIDY, Giorgia, Giuffra, Elisabetta, Lacroix-Lamandé, Sonia, Wiedemann, Agnès, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INRAE (PHASE division :'Minigut' project, Animal Genetics Branch : 'SNOOPY' project), Institut Carnot (France Futur Elevage: 'Organopig' project, Qualiment: 'Model_gut' project), Fédération de recherche en infectiologie de la Région Centre Val de Loire (FeRi), Région Centre within the 'ANIMALT' project granted by the Délégation Régionale à la Recherche et à la Technologie du Centre (FEDER) and by the Région Centre, BMC, BMC, and Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
[SDV]Life Sciences [q-bio], Culture, Cell Culture Techniques, Review, Rabbit, Horse, Epithelium, Intestine, Small, Animals, Gut, Intestine, Large, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, Cryopreservation, Pig, lcsh:Veterinary medicine, Polarity, [SDV.BA]Life Sciences [q-bio]/Animal biology, Monolayer, Epithelial Cells, Bovine, Chicken, [SDV] Life Sciences [q-bio], Organoids, Animals, Domestic, Enteroids, lcsh:SF600-1100
Abstract

International audience; AbstractIn livestock species, the monolayer of epithelial cells covering the digestive mucosa plays an essential role for nutrition and gut barrier function. However, research on farm animal intestinal epithelium has been hampered by the lack of appropriate in vitro models. Over the past decade, methods to culture livestock intestinal organoids have been developed in pig, bovine, rabbit, horse, sheep and chicken. Gut organoids from farm animals are obtained by seeding tissue-derived intestinal epithelial stem cells in a 3-dimensional culture environment reproducing in vitro the stem cell niche. These organoids can be generated rapidly within days and are formed by a monolayer of polarized epithelial cells containing the diverse differentiated epithelial progeny, recapitulating the original structure and function of the native epithelium. The phenotype of intestinal organoids is stable in long-term culture and reflects characteristics of the digestive segment of origin. Farm animal intestinal organoids can be amplified in vitro, cryopreserved and used for multiple experiments, allowing an efficient reduction of the use of live animals for experimentation. Most of the studies using livestock intestinal organoids were used to investigate host-microbe interactions at the epithelial surface, mainly focused on enteric infections with viruses, bacteria or parasites. Numerous other applications of farm animal intestinal organoids include studies on nutrient absorption, genome editing and bioactive compounds screening relevant for agricultural, veterinary and biomedical sciences. Further improvements of the methods used to culture intestinal organoids from farm animals are required to replicate more closely the intestinal tissue complexity, including the presence of non-epithelial cell types and of the gut microbiota. Harmonization of the methods used to culture livestock intestinal organoids will also be required to increase the reproducibility of the results obtained in these models. In this review, we summarize the methods used to generate and cryopreserve intestinal organoids in farm animals, present their phenotypes and discuss current and future applications of this innovative culture system of the digestive epithelium.

Published
2021

4. Charles Henry Turner and the cognitive behavior of bees

Author

Anaclara Giurfa de Brito, Tiziana Giurfa de Brito, Martin Giurfa, Maria Gabriela de Brito Sanchez, Fujian Agriculture and Forestry University (FAFU), 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), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), University College of London [London] (UCL), Sciences Po Toulouse - Institut d'études politiques de Toulouse (IEP Toulouse), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, and BMC, BMC

Subjects
0106 biological sciences, cognition, Psychoanalysis, media_common.quotation_subject, 050109 social psychology, Review Article, Biology, 010603 evolutionary biology, 01 natural sciences, social bees, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, [SCCO]Cognitive science, solitary bees, cognition, Charles Henry Turner, [SHS.HISPHILSO] Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Perception, 0501 psychology and cognitive sciences, Animal cognition, Black Lives Matter, Social movement, media_common, African american, Charles Henry Turner, Black Lives Matter, 05 social sciences, Cognition, [SCCO] Cognitive science, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, Graduate degree, Insect Science, [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, solitary bees
Abstract

Social movements in several countries are stimulating a reconsideration of academic structures and historic figures and promoting reparation and recognition of marginalized and forgotten black scientists. A paradigmatic case in that sense is Charles Henry Turner (1867–1923) who was the first African American to receive a graduate degree at the University of Cincinnati and one of the first in earning a PhD degree of the University of Chicago. He performed numerous experiments on sensory perception, orientation, and mating of solitary and social bees, most of which have been unjustly forgotten despite the fact that they anticipated fundamental concepts of animal cognition. We review these studies and highlight the importance of his ideas for modern views of animal cognition and the study of bee behavior. We conclude that besides his scientific contributions, Turner is an inspiration for scientists fighting against social adversity and prejudices.

Published
2020

5. Whole exome sequencing in three families segregating a pediatric case of sarcoidosis

Author

Annick Clement, Yves Pacheco, Jean-François Bernaudin, Gilles Devouassoux, Adrien Buisson, Clarice X. Lim, Dominique Valeyre, Vincent Cottin, Claire Bardel, Alain Calender, Serge Lebecque, Pascal Sève, Pierre Antoine Rollat Farnier, Stéphane Pinson, Harriet Corvol, Abderrazzaq Bentaher, Pascal Roy, Rola Abou Taam, Thomas Weichhart, Nadia Nathan, Véronique Houdouin, Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de Biostatistiques [Lyon], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA Necker), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de Pneumologie [Hôpital Croix Rousse, CHU Lyon], Hôpital de la Croix-Rousse [CHU Lyon], Service de Pneumologie [Hôpital Louis Pradel – CHU Lyon] (Centre de Référence des Maladies Pulmonaires Rares), CHU Lyon-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Médecine Interne [Hôpital Croix Rousse, CHU Lyon], CHU Lyon-Hôpital de la Croix-Rousse [CHU - HCL], Service d'histologie et biologie des tumeurs [CHU Tenon] (ER2-UPMC), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Center for Pathobiochemistry and Genetics [Vienna, Austria], Institute of Medical Genetics [Vienna, Austria]-Medizinische Universität Wien = Medical University of Vienna, Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), Université Paris 13 (UP13)-UFR SMBH, Communautés d’universités et établissements Sorbonne Paris Cité (COMUE Sorbonne Paris Cité), Université Sorbonne Paris Cité (USPC)-Chimie ParisTech-Université Paris sciences et lettres (PSL), Service de Pneumologie [AP-HP Hôpital Avicenne, Bobigny], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), This study was performed with the grant named ‘High Throughput sequencing and rare disease’ from the 'Fondation Maladies Rares' (FMR - France) and financial support from the INNOVARC - DGOS ref. 12–027-0309., GSF (Groupe Sarcoïdose France), CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris 13 (UP13), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-CHU Lyon, Medizinische Universität Wien = Medical University of Vienna-Institute of Medical Genetics [Vienna, Austria], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, BMC, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP]

Subjects
Male, 0301 basic medicine, Proband, Candidate gene, lcsh:Internal medicine, Sarcoidosis, lcsh:QH426-470, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Candidate genes, 03 medical and health sciences, Exome Sequencing, Genetics, Humans, Allele, Child, lcsh:RC31-1245, Gene, Exome, Genetics (clinical), Exome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genetic Variation, Whole-exome sequencing (WES), Human genetics, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], lcsh:Genetics, 030104 developmental biology, Female, Genome-Wide Association Study, Research Article
Abstract

Background Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. Methods From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) (https://clinicaltrials.gov) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). Results We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Conclusions Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants. Electronic supplementary material The online version of this article (10.1186/s12920-018-0338-x) contains supplementary material, which is available to authorized users.

Published
2018

6. CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer

Author

Raphael Lis, Arash Rafii, Massoud Mirshahi, Jennifer Pasquier, Cyril Touboul, Audrey Chevrot, Caroline Geyl, Marc Pocard, Jessica Hoarau-Véchot, Marie Gosset, Stem cell and microenvironment laboratory, Weill Cornell Medicine [Qatar], Department Genetic Medicine, Weill Medical College of Cornell University [New York], 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), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHI Créteil], CHI Créteil-Faculté de médecine de Créteil UPEC – Paris XII, and BMC, BMC

Subjects
0301 basic medicine, Cancer Research, Il-6, Mouse, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mice, 0302 clinical medicine, Cell Movement, Chemokine CCL5, Chemokine CCL2, Ovarian Neoplasms, biology, Mesenchymal stromal cell, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Chemoresistance, Signal Transduction, [SDV.CAN]Life Sciences [q-bio]/Cancer, CCL2, Antibodies, Monoclonal, Humanized, lcsh:RC254-282, CCL5, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, Ovarian cancer, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Interleukin 6, Chemotherapy, Interleukin-6, Research, Mesenchymal stem cell, medicine.disease, Minimal residual disease, Coculture Techniques, 030104 developmental biology, Focal Adhesion Kinase 2, Cancer research, biology.protein
Abstract

Background Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemotherapy. In vitro study confirmed that MSC could induce OCC chemoresistance without contact using transwell setting. Further experiments showed that this induced chemoresistance was dependent on IL-6 OCC stimulation. Methods We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions. Results We demonstrated that Tocilizumab® (anti-IL-6R therapy) in association with chemotherapy significantly reduced the peritoneal carcinosis index (PCI) than chemotherapy alone in mice xenografted with OCCs+MSCs. Further experiments showed that CCL2 and CCL5 are released by MSC in transwell co-culture and induce OCCs IL-6 secretion and chemoresistance. Finally, we found that IL-6 induced chemoresistance was dependent on PYK2 phosphorylation. Conclusions These findings highlight the potential key role of the stroma in protecting minimal residual disease from chemotherapy, thus favoring recurrences. Future clinical trials targeting stroma could use anti-IL-6 therapy in association with chemotherapy. Electronic supplementary material The online version of this article (10.1186/s12943-018-0787-z) contains supplementary material, which is available to authorized users.

Published
2018

7. Systematic quantitative analysis of H2A and H2B variants by targeted proteomics

Author

El Kennani, Sara, Adrait, Annie, Permiakova, Olga, Hesse, Anne-Marie, Ialy-Radio, Côme, Ferro, Myriam, Brun, Virginie, Cocquet, Julie, Govin, Jérôme, Pflieger, Delphine, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), This work was supported by CEA by a PhD fellowship to SEK, by the Fondd’Intervention of the Univ. Grenoble Alpes (to JG), the French NationalResearch Agency (ANR-11-PDOC-0011 EpiGam to JG, ANR-14-CE19-0014-01 toDP, ANR-12-JSV2-0005-01 to JC, ANR-10-INBS-08 ProFI and ANR-10-LABX-49-01GRAL) and the European Union FP7 Marie Curie Action 'Career IntegrationGrant' (304003 to JG), BMC, BMC, Etude de la dynamique des protéomes (EDyP), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
Male, Proteomics, SRM, lcsh:QH426-470, [SDV]Life Sciences [q-bio], PRM, Mass Spectrometry, Epigenesis, Genetic, Histones, Mice, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Testis, Animals, Humans, Amino Acid Sequence, Spermatogenesis, Targeted proteomics, ComputingMilieux_MISCELLANEOUS, Histone variants, Methodology, Chromatin, [SDV] Life Sciences [q-bio], lcsh:Genetics, Organ Specificity, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Peptides
Abstract

Background Histones organize DNA into chromatin through a variety of processes. Among them, a vast diversity of histone variants can be incorporated into chromatin and finely modulate its organization and functionality. Classically, the study of histone variants has largely relied on antibody-based assays. However, antibodies have a limited efficiency to discriminate between highly similar histone variants. Results In this study, we established a mass spectrometry-based analysis to address this challenge. We developed a targeted proteomics method, using selected reaction monitoring or parallel reaction monitoring, to quantify a maximum number of histone variants in a single multiplexed assay, even when histones are present in a crude extract. This strategy was developed on H2A and H2B variants, using 55 peptides corresponding to 25 different histone sequences, among which a few differ by a single amino acid. The methodology was then applied to mouse testis extracts in which almost all histone variants are expressed. It confirmed the abundance profiles of several testis-specific histones during successive stages of spermatogenesis and the existence of predicted H2A.L.1 isoforms. This methodology was also used to explore the over-expression pattern of H2A.L.1 isoforms in a mouse model of male infertility. Conclusions Our results demonstrate that targeted proteomics is a powerful method to quantify highly similar histone variants and isoforms. The developed method can be easily transposed to the study of human histone variants, whose abundance can be deregulated in various diseases. Electronic supplementary material The online version of this article (10.1186/s13072-017-0172-y) contains supplementary material, which is available to authorized users.

Published
2018

8. Neighborhood walk score and selected Cardiometabolic factors in the French RECORD cohort study

Author

Dustin T. Duncan, Bruno Pannier, Basile Chaix, Leonardo Trasande, Jessica K. Athens, Gbenga Ogedegbe, Julie Méline, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), IPC Medical Center [Paris], Department of Population Health [New York, NY, USA], New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Departments of Pediatrics and Environmental Medicine [New York], Department of Population Health [New York, NY, USA] (Spatial Epidemiology Lab), NYU Global Public Health Research Challenge Fund., and BMC, BMC

Subjects
Adult, Male, Built environment, Paris, Waist, [SDV]Life Sciences [q-bio], Poison control, Context (language use), Walkability, Walking, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Walk score, Heart Rate, Residence Characteristics, Risk Factors, Heart rate, Medicine, Humans, 030212 general & internal medicine, Obesity, Aged, 2. Zero hunger, Aged, 80 and over, business.industry, lcsh:Public aspects of medicine, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Middle Aged, Cardiovascular disease, 3. Good health, [SDV] Life Sciences [q-bio], Blood pressure, Cardiovascular Diseases, Hypertension, Environment Design, Female, business, Body mass index, human activities, Demography, Cohort study, Research Article
Abstract

International audience; AbstractBackgroundWalkable neighborhoods are purported to impact a range of cardiometabolic outcomes through increased walking, but there is limited research that examines multiple cardiometabolic outcomes. Additionally, few Walk Score (a novel measure of neighborhood walkability) studies have been conducted in a European context. We evaluated associations between neighborhood Walk Score and selected cardiometabolic outcomes, including obesity, hypertension and heart rate, among adults in the Paris metropolitan area.Methods and resultsWe used data from the second wave of the RECORD Study on 5993 participants recruited in 2011–2014, aged 34–84 years, and residing in Paris (France). To this existing dataset, we added Walk Score values for participants’ residential address. We used multilevel linear models for the continuous outcomes and modified Poisson models were used for our categorical outcomes to estimate associations between the neighborhood Walk Score (both as a continuous and categorical variable) (0–100 score) and body mass index (BMI) (weight/height2 in kg/m2), obesity (kg/m2), waist circumference (cm), systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), hypertension (mmHg), resting heart rate (RHR) (beats per minute), and neighborhood recreational walking (minutes per week). Most participants lived in Walker’s Paradise (48.3%). In multivariate models (adjusted for individual variables, neighborhood variables, and risk factors for cardiometabolic outcomes), we found that neighborhood Walk Score was associated with decreased BMI (β: -0.010, 95% CI: -0.019 to −0.002 per unit increase), decreased waist circumference (β: -0.031, 95% CI: -0.054 to −0.008), increased neighborhood recreational walking (β: +0.73, 95% CI: +0.37 to +1.10), decreased SBP (β: -0.030, 95% CI: -0.063 to −0.0004), decreased DBP (β: -0.028, 95% CI: -0.047 to −0.008), and decreased resting heart rate (β: -0.026 95% CI: -0.046 to −0.005).ConclusionsIn this large population-based study, we found that, even in a European context, living in a highly walkable neighborhood was associated with improved cardiometabolic health. Designing walkable neighborhoods may be a viable strategy in reducing cardiovascular disease prevalence at the population level.

Published
2017

9. THBD sequence variants potentially related to recurrent pregnancy loss

Author

Daniel Vaiman, Clara Esteban-Pérez, Paula Quintero-Ronderos, Dora Janeth Fonseca, Jean-Christophe Gris, Harold Moreno-Ortiz, Elkin Lucena, Paul Laissue, Eric Mercier, Center For Research in Genetics and Genomics-CIGGUR [Bogotá, Colombia] (GENIUROS Research Group), School of Medicine and Health Sciences [Bogotá, Colombia]-Universidad del Rosario [Bogotá, Colombia], Service d'Hématologie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Reproductive Genetics [Bogotá, Colombia], The Colombian Center of Fertility and Sterility [Bogotá, Colombia] (CECOLFES), 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), This study was supported by the Universidad del Rosario (grant: CS/ABN062/GENIUROS 017)., and BMC, BMC

Subjects
single nucleotide, 0301 basic medicine, Candidate gene, Pregnancy disorder, Thrombomodulin, [SDV]Life Sciences [q-bio], THBD, Mestizo, Gene sequence, 030204 cardiovascular system & hematology, Gene mutation, Molecular marker, Bioinformatics, Gene, Computational biology, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Gene Frequency, Pregnancy, habitual, Databases, Genetic, Coding region, lcsh:Reproduction, Female infertility, Thbd protein, Thbd, Obstetrics and Gynecology, Thbd gene, Polymerase chain reaction, [SDV] Life Sciences [q-bio], Recurrent pregnancy loss, Female, Adult, Abortion, Habitual, lcsh:QH471-489, Short Communication, Case control study, Genetic database, Genetic predisposition to disease, Single-nucleotide polymorphism, Major clinical study, Case-control studies, Caucasian, Biology, Polymorphism, Single Nucleotide, lcsh:Gynecology and obstetrics, Article, Databases, 03 medical and health sciences, Genetics, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic variation, human, Polymorphism, Allele frequency, lcsh:RG1-991, Spontaneous abortion, Abortion, Computational Biology, Genetic Variation, Recurrent abortion, Gene frequency, Single nucleotide polymorphism, 030104 developmental biology, Reproductive Medicine, chemistry, Case-Control Studies, genetic, Controlled study, Developmental Biology
Abstract

International audience; AbstractRecurrent pregnancy loss (RPL) is a frequently occurring disease, which is classified as idiopathic in more than 50% of cases. THBD, the endothelial cell receptor for thrombin, has been associated with distinct biological processes and considered a coherent RPL-related candidate gene. In the present study, we have sequenced the complete coding region of THBD in 262 patients affected by RPL. Bioinformatics analysis and screening of controls strongly suggested that the THBD-p.Trp153Gly mutation might be related to RPL aetiology. It could be used, after its validation by functional assays, as a molecular marker for diagnostic/prognostic purposes.

Published
2017

10. The C3HeB/FeJ mouse model recapitulates the hallmark of bovine tuberculosis lung lesions following Mycobacterium bovis aerogenous infection

Author

Nathalie Winter, Mélodie Bouté, Christelle Rossignol, Mathieu Epardaud, Emilie Doz, Florence Carreras, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Department of Agriculture and Food (Ministère de l’Agriculture et de l’Alimentation, DGAL): 'RFSA project: M. Bovis'#2017-325 (04-09-2017), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), INRA : UR1282 Infectiologie animale et santé publique (INRA), Institut National de la Recherche Agronomique (INRA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and BMC, BMC

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Tuberculosis, [SDV]Life Sciences [q-bio], Immunology, Mice, Inbred Strains, souris, Mycobacterium tuberculosis, Lesion, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Immunopathology, Immunologie, medicine, animal modèle, Animals, immunopathologie, Lung, 2. Zero hunger, Mycobacterium bovis, Granuloma, lcsh:Veterinary medicine, General Veterinary, biology, biology.organism_classification, medicine.disease, Virology, Pathophysiology, 3. Good health, [SDV] Life Sciences [q-bio], Vaccinology, Disease Models, Animal, mycobacterium bovis, 030104 developmental biology, medicine.anatomical_structure, Vaccinologie, 030220 oncology & carcinogenesis, tuberculose bovine, lcsh:SF600-1100, Cattle, medicine.symptom, Tuberculosis, Bovine, Research Article
Abstract

Present Adress : Mélodie Bouté, U1019, UMR8204, Université Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France Remerciements : Plateforme @BRIDGE, UMR GABI, INRA de Jouy-en-Josas; International audience; AbstractAchieving the control of bovine tuberculosis (bTB) would require the discovery of an efficient combined immunodiagnostic and vaccine strategy. Since in vivo experiments on cattle are not ethically and economically acceptable there is a need for a cost-effective animal model capable of reproducing, as closely as possible, the physiopathology of bTB to (i) better characterize the cellular and molecular features of bTB immunopathogenesis and (ii) screen preclinical vaccine candidates. To develop such a model, we focused on the C3HeB/FeJ Kramnik’s mouse forming hypoxic, encapsulated granulomas with a caseous necrotic center following Mycobacterium tuberculosis infection. Our work represents the first investigation on C3HeB/FeJ interaction with M. bovis, the main agent of bTB. Detailed histopathological analysis of C3HeB/FeJ lung lesions development following aerogenous M. bovis infection unraveled a bimodal evolution of the pathology. The C3HeB/FeJ recapitulated all the hallmarks of classical bovine lung granulomas but also developed, to some extend, lethal necrotic large lesions characterized by high mycobacterial and neutrophil load, and an inefficient collagen-driven lesion encapsulation. Interestingly these rapidly invasive pneumonia lesions, occurring in a constant percentage of the mice, shared all features with some exacerbated lung lesions that we and others have observed in lungs of cattle naturally or experimentally infected with M. bovis. Together, our findings demonstrate the relevance of the C3HeB/FeJ mouse as a comprehensive model to study bTB immunopathology that could be used for further vaccine therapies in the future.

Published
2017

11. Early screening for Chlamydia trachomatis in young women for primary prevention of pelvic inflammatory disease (i-Predict): study protocol for a randomised controlled trial

Author

Jeanne, Tamarelle, Anne C M, Thiébaut, Bénédicte, Sabin, Cécile, Bébéar, Philippe, Judlin, Arnaud, Fauconnier, Delphine, Rahib, Layidé, Méaude-Roufai, Jacques, Ravel, Servaas A, Morré, Bertille, de Barbeyrac, Elisabeth, Delarocque-Astagneau, Nathalie, Lydié, BMC, BMC, Biostatistique, Biomathématique, Pharmacoépidémiologie et Maladies Infectieuses (B2PHI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), USC EA 3671 Mycoplasmal and chlamydial infections in humans, Université de Bordeaux (UB), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], CHI Poissy-Saint-Germain, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Hôpital Ambroise Paré [AP-HP], University of Maryland [Baltimore County] (UMBC), University of Maryland System, VU University Medical Center [Amsterdam], School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], The i-Predict trial was funded by the Programme Hospitalier de Recherche Clinique National (PHRC-N) 2015 (reference number PHRC-15-0063). Preliminary work for this trial was financed by 2013 Institut National du Cancer- Institut de Recherche en Santé Publique (INCa-IReSP) call for projects 'Recherche Prévention Primaire' (reference number A15012LS)., RS: GROW - R4 - Reproductive and Perinatal Medicine, Institute for Public Health Genomics, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Time Factors, Adolescent, [SDV]Life Sciences [q-bio], GENITAL-INFECTION, FRANCE, Chlamydia trachomatis, SUSCEPTIBILITY, Young Adult, Study Protocol, Sex Factors, Clinical Protocols, Predictive Value of Tests, Risk Factors, chlamydia trachomatis, clearance, immunogenetics, infection, natural course of infection, pelvic inflammatory disease, prevention, reinfection, screening, students, Prevalence, Immunogenetics, Humans, Single-Blind Method, Students, Vaginal Smears, RISK, Bacteriological Techniques, lcsh:R5-920, Incidence, Prevention, Age Factors, Chlamydia Infections, Anti-Bacterial Agents, Primary Prevention, [SDV] Life Sciences [q-bio], Early Diagnosis, Treatment Outcome, Natural course of infection, Research Design, Reinfection, Screening, Clearance, Female, NEISSERIA-GONORRHOEAE, Infection, lcsh:Medicine (General), Pelvic inflammatory disease
Abstract

Background Genital infection with Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection, especially among young women. Mostly asymptomatic, it can lead, if untreated, to pelvic inflammatory disease (PID), tubal factor infertility and ectopic pregnancy. Recent data suggest that Ct infections are not controlled in France and in Europe. The effectiveness of a systematic strategy for Ct screening in under-25 women remains controversial. The main objective of the i-Predict trial (Prevention of Diseases Induced by Chlamydia trachomatis) is to determine whether early screening and treatment of 18- to-24-year-old women for genital Ct infection reduces the incidence of PID over 24 months. Methods/design This is a randomised prevention trial including 4000 eighteen- to twenty-four-year-old sexually active female students enrolled at five universities. The participants will provide a self-collected vaginal swab sample and fill in an electronic questionnaire at baseline and at 6, 12 and 18 months after recruitment. Vaginal swabs in the intervention arm will be analysed immediately for Ct positivity, and participants will be referred for treatment if they have a positive test result. Vaginal swabs from the control arm will be analysed at the end of the study. All visits to general practitioners, gynaecologists or gynaecology emergency departments for pelvic pain or other gynaecological symptoms will be recorded to evaluate the incidence of PID, and all participants will attend a final visit in a hospital gynaecology department. The primary endpoint measure will be the incidence of PID over 24 months. The outcome status (confirmed, probable or no PID) will be assessed by two independent experts blinded to group assignment and Ct status. Discussion This trial is expected to largely contribute to the development of recommendations for Ct screening in young women in France to prevent PID and related complications. It is part of a comprehensive approach to gathering data to facilitate decision-making regarding optimal strategies for Ct infection control. The control group of this randomised trial, following current recommendations, will allow better documentation of the natural history of Ct infection, a prerequisite to evaluating the impact of Ct screening. Characterisation of host immunogenetics will also allow identification of women at risk for complications. Trial registration ClinicalTrials.gov, NCT02904811. Registered on September 14, 2016. World Health Organisation International Clinical Trials Registry, NCT02904811. AOM, 15-0063 and P150950. Registered on September 26, 2016. A completed Standard Protocol Items : Recommendations for International Trials (SPIRIT) Checklist is available in additional file 1. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2211-1) contains supplementary material, which is available to authorized users.

Published
2017

12. Respective contribution of the cephalic neural crest and mesoderm to SIX1-expressing head territories in the avian embryo

Author

Bárbara de Faria da Fonseca, Gérard Couly, Elisabeth Dupin, Institut de la Vision, 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), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Centre National de la Recherche Scientifique (CNRS, France) and Institut National de la Santé et de la Recherche Médicale (INSERM, France). B.F.F was supported by a Ph.D. fellowship from 'Ciências sem Fronteiras' program (CNPq, Brazil)., BMC, BMC, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, SIX1, Mesoderm, Cell type, Embryo, Nonmammalian, animal structures, Mesenchyme, [SDV]Life Sciences [q-bio], Branchial arch, Biology, Quail, 03 medical and health sciences, Neural crest, 0302 clinical medicine, medicine, Animals, Quail-chick chimera, lcsh:QH301-705.5, Mesenchymal stem cell, Anatomy, Embryonic stem cell, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), embryonic structures, Developmental biology, 030217 neurology & neurosurgery, Research Article, Developmental Biology
Abstract

Background Vertebrate head development depends on a series of interactions between many cell populations of distinct embryological origins. Cranial mesenchymal tissues have a dual embryonic source: - the neural crest (NC), which generates most of craniofacial skeleton, dermis, pericytes, fat cells, and tenocytes; and - the mesoderm, which yields muscles, blood vessel endothelia and some posterior cranial bones. The molecular players that orchestrate co-development of cephalic NC and mesodermal cells to properly construct the head of vertebrates remain poorly understood. In this regard, Six1 gene, a vertebrate homolog of Drosophila Sine Oculis, is known to be required for development of ear, nose, tongue and cranial skeleton. However, the embryonic origin and fate of Six1-expressing cells have remained unclear. In this work, we addressed these issues in the avian embryo model by using quail-chick chimeras, cephalic NC cultures and immunostaining for SIX1. Results Our data show that, at early NC migration stages, SIX1 is expressed by mesodermal cells but excluded from the NC cells (NCC). Then, SIX1 becomes widely expressed in NCC that colonize the pre-otic mesenchyme. In contrast, in the branchial arches (BAs), SIX1 is present only in mesodermal cells that give rise to jaw muscles. At later developmental stages, the distribution of SIX1-expressing cells in mesoderm-derived tissues is consistent with a possible role of this factor in the myogenic program of all types of head muscles, including pharyngeal, extraocular and tongue muscles. In NC derivatives, SIX1 is notably expressed in perichondrium and chondrocytes of the nasal septum and in the sclera, although other facial cartilages such as Meckel’s were negative at the stages considered. Moreover, in cephalic NC cultures, chondrocytes and myofibroblasts, not the neural and melanocytic cells express SIX1. Conclusion The present results point to a dynamic tissue-specific expression of SIX1 in a variety of cephalic NC- and mesoderm-derived cell types and tissues, opening the way for further analysis of Six1 function in the coordinated development of these two cellular populations during vertebrate head formation.

Published
2017

13. Specific barriers to the conduct of randomised clinical trials on medical devices

Author

Michaela Eikermann, Janus Christian Jakobsen, Vittorio Bertele, Séverine Pitel, Dawid Pieper, Christian Gluud, Snezana Djurisic, Jacques Demotes-Mainard, Esther Jacobs, Cecilia Martinho, Christine Kubiak, Carsten Koenen, Silvio Garattini, Martine Laville, Doerthe Seidel, Edmund Neugebauer, Sunya Lee Antoine, Ana Rath, Brandenburg Medical School Theodor Fontane & Health Services Research Witten [Neuruppin, Germany], Universität Witten - Herdecke [Germany], Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research in Operative Medicine [Cologne, Germany], Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Unité de Recherche en Diabétologie et Nutrition [Marseille] (QUALISSIMA Marseille Laboratoires pharmaceutiques), Qualissima (SARL) [Marseille], Association for Innovation and Biomedical Research on Light and Image (AIBILI), Copenhagen Trial Unit (CTU), Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, European Clinical Research Infrastructures Network [Paris] (ECRIN), Ecrin, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Department of Cardiology [Holbaek, Denmark], Holbæk Hospital [Denmark], The present review is founded by the European Commission through funding of the project European Clinical Research Infrastructures Network-Integrated Activity, Project reference: 284395, Funded under: FP7-INFRASTRUCTURES., European Project: 284395,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2011-1,ECRIN-IA(2012), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Associação para Investigação Biomédica em Luz e Imagem [Coimbra, Portugal] (AIBILI), University of Coimbra [Portugal] (UC)-Institute for Biomedical Imaging and Life Sciences [Coimbra, Portugal], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), BMC, BMC, European Clinical Research Infrastructures Network - Integrating Activity - ECRIN-IA - - EC:FP7:INFRA2012-01-01 - 2017-12-31 - 284395 - VALID, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
medicine.medical_specialty, Evidence-based medicine, Blinding, Time Factors, Endpoint Determination, [SDV]Life Sciences [q-bio], Alternative medicine, Medicine (miscellaneous), Context (language use), Review, Assessment, Risk Assessment, Evidence-based clinical practice, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Randomized Controlled Trials as Topic, Specific barriers, lcsh:R5-920, business.industry, Clinical study design, European Clinical Research Infrastructure Network, Randomised clinical trials, medicine.disease, Clinical trial, [SDV] Life Sciences [q-bio], Clinical research, Treatment Outcome, Equipment and Supplies, Learning curve, Research Design, Medical devices, Medical emergency, business, lcsh:Medicine (General), 030217 neurology & neurosurgery
Abstract

Background Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. Methods Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Results In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. Conclusions The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2168-0) contains supplementary material, which is available to authorized users.

Published
2017

14. Neuroscience in the third dimension: shedding new light on the brain with tissue clearing

Author

Alain Chédotal, Morgane Belle, Robin J. Vigouroux, Institut de la Vision, 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), and BMC, BMC

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Review, Fluorescence, Field (computer science), lcsh:RC346-429, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, law, Research community, Clearing, Animals, Humans, Orchestration (computing), Dimension (data warehouse), Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Protocol (science), Clarity, Tissue clearing, Tissue-clearing, Neurosciences, Brain, 3DISCO, [SDV] Life Sciences [q-bio], 030104 developmental biology, CLARITY, RNA, Psychology, Neuroscience, iDISCO
Abstract

International audience; AbstractFor centuries analyses of tissues have depended on sectioning methods. Recent developments of tissue clearing techniques have now opened a segway from studying tissues in 2 dimensions to 3 dimensions. This particular advantage echoes heavily in the field of neuroscience, where in the last several years there has been an active shift towards understanding the complex orchestration of neural circuits. In the past five years, many tissue-clearing protocols have spawned. This is due to varying strength of each clearing protocol to specific applications. However, two main protocols have shown their applicability to a vast number of applications and thus are exponentially being used by a growing number of laboratories. In this review, we focus specifically on two major tissue-clearing method families, derived from the 3DISCO and the CLARITY clearing protocols. Moreover, we provide a “hands-on” description of each tissue clearing protocol and the steps to look out for when deciding to choose a specific tissue clearing protocol. Lastly, we provide perspectives for the development of tissue clearing protocols into the research community in the fields of embryology and cancer.

Published
2017

15. Synaptoimmunology - roles in health and disease

Author

Robert Nisticò, Graham L. Collingridge, Dalila Mango, Celine S Nicolas, Zuner A. Bortolotto, Pierre Gressens, Stéphane Peineau, Eric W Salter, Marco Feligioni, Department of Biology [Rome, Italy], Università degli Studi di Roma Tor Vergata [Roma], Pharmacology of Synaptic Disease Lab [Rome, Italy], European Brain Research Institute [Rome, Italy] (EBRI), Department of Physiology [Toronto, ON, Canada], Mount Sinai Hospital [Toronto, Canada] (MSH)-Lunenfeld-Tanenbaum Research Institute [Toronto, Canada]-Université de Toronto [Canada], Centre for Synaptic Plasticity [Bristol, UK] (School of Physiology, Pharmacology & Neuroscience), University of Bristol [Bristol], Centre for the Developing Brain [London], King‘s College London-St Thomas' Hospital [London], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM ERi 24 - GRAP, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), SP is supported by Medical Research Coucil (MR/K023098/1) and is holder of the chair of excellence 'Synaptic Plasticity' funded by Région Hauts de France., Université de Toronto [Canada]-Mount Sinai Hospital [Toronto, Canada] (MSH)-Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], BMC, BMC, University of Toronto-Mount Sinai Hospital [Toronto, Canada] (MSH)-Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], and Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Nervous system, medicine.medical_specialty, Neurology, [SDV]Life Sciences [q-bio], Review, Disease, Biology, Models, Biological, Synaptic Transmission, Synaptic plasticity, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Immune system, Neuroinflammation, medicine, Animals, Humans, Microglia, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Brain Diseases, Settore BIO/14, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Health, Synapses, Psychopharmacology, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction
Abstract

International audience; AbstractMounting evidence suggests that the nervous and immune systems are intricately linked. Many proteins first identified in the immune system have since been detected at synapses, playing different roles in normal and pathological situations. In addition, novel immunological functions are emerging for proteins typically expressed at synapses. Under normal conditions, release of inflammatory mediators generally represents an adaptive and regulated response of the brain to immune signals. On the other hand, when immune challenge becomes prolonged and/or uncontrolled, the consequent inflammatory response leads to maladaptive synaptic plasticity and brain disorders. In this review, we will first provide a summary of the cell signaling pathways in neurons and immune cells. We will then examine how immunological mechanisms might influence synaptic function, and in particular synaptic plasticity, in the healthy and pathological CNS. A better understanding of neuro-immune system interactions in brain circuitries relevant to neuropsychiatric and neurological disorders should provide specific biomarkers to measure the status of the neuroimmunological response and help design novel neuroimmune-targeted therapeutics.

Published
2017

16. Atypical sound discrimination in children with ASD as indicated by cortical ERPs

Author

Bidet-Caulet, Aurélie, Latinus, Marianne, Roux, Sylvie, Malvy, Joëlle, Bonnet-Brilhault, Frédérique, Bruneau, Nicole, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédopsychiatrie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Regional Clinical Research Program (PHRI06-VHA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BMC, BMC, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
genetic structures, Research, [SDV]Life Sciences [q-bio], Autism, Development, behavioral disciplines and activities, FTPV, lcsh:RC321-571, [SDV] Life Sciences [q-bio], mental disorders, otorhinolaryngologic diseases, Voice, Speech, Auditory, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Abstract

International audience; Background: Individuals with autism spectrum disorder (ASD) show a relative indifference to the human voice. Accordingly, and contrarily to their typically developed peers, adults with autism do not show a preferential response to voices in the superior temporal sulcus; this lack of voice-specific response was previously linked to atypical processing of voices. In electroencephalography, a slow event-related potential (ERP) called the fronto-temporal positivity to voice (FTPV) is larger for vocal than for non-vocal sounds, resulting in a voice-sensitive response over right fronto-temporal sites. Here, we investigated the neurophysiological correlates of voice perception in children with and without ASD.Methods: Sixteen children with autism and 16 age-matched typically developing children heard vocal (speech and non-speech) and non-vocal sounds while their electroencephalographic activity was recorded; overall IQ was smaller in the group of children with ASD. ERP amplitudes were compared using non-parametric statistical tests at each electrode and in successive 20-ms time windows. Within each group, differences between conditions were assessed using a non-parametric Quade test between 0 and 400 ms post-stimulus. Inter-group comparisons of ERP amplitudes were performed using non-paired Kruskal-Wallis tests between 140 and 180 ms post-stimulus.Results: Typically developing children showed the classical voice-sensitive response over right fronto-temporal electrodes, for both speech and non-speech vocal sounds. Children with ASD did not show a preferential response to vocal sounds. Inter-group analysis showed no difference in the processing of vocal sounds, both speech and non-speech, but significant differences in the processing of non-vocal sounds over right fronto-temporal sites.Conclusions: Our results demonstrate a lack of voice-preferential response in children with autism spectrum disorders. In contrast to observations in adults with ASD, the lack of voice-preferential response was attributed to an atypical response to non-vocal sounds, which was overall more similar to the event-related potentials evoked by vocal sounds in both groups. This result suggests atypical maturation processes in ASD impeding the specialization of temporal regions in voice processing.

Published
2017

17. Icatibant as an early rescue therapy in hypovolemic shock with converting enzyme inhibitor treatment

Author

Hélène Charbonneau, Marie Buléon, Benoit Richard, Nicolas Mayeur, BMC, BMC, Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d’Anesthésie-Réanimation Chirurgie cardio-thoracique et vasculaire [Toulouse], Clinique Pasteur [Toulouse], Pôle d'Anesthésie-Réanimation [CHU Rangueil], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
Letter, [SDV]Life Sciences [q-bio], Hypovolemia, Bradykinin, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Rescue therapy, Icatibant, Bradykinin B2 Receptor Antagonists, medicine, Animals, Humans, Arterial Pressure, ComputingMilieux_MISCELLANEOUS, biology, business.industry, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, Enzyme inhibitor, Shock (circulatory), Anesthesia, biology.protein, medicine.symptom, business
Abstract

International audience; No abstract available

Published
2017

18. Lipid profiles in French West Indies sickle cell disease cohorts, and their general population

Author

Benoît Tressières, Marc Romana, Yann Lamarre, Philippe Connes, Marie-Laure Lalanne-Mistrih, Marie-Dominique Hardy-Dessources, Vanessa Tarer, Nathalie Lemonne, Dominique Mougenel, Maryse Etienne-Julan, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Unité Transversale de la Drépanocytose [Pointe-à-Pitre, Guadeloupe], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Protéines de la membrane érythrocytaire et homologues non-érythroides, Université des Antilles et de la Guyane (UAG)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Transversale de la Drépanocytose, CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Hôpital Ricou, Centre de référence maladies rares pour la drépanocytose aux Antilles-Guyane, Laboratory of Excellence GR-Ex 'The red cell: from genesis to death', PRES Sorbonne Paris Cité, Université des Antilles et de la Guyane (UAG), and BMC, BMC

Subjects
Male, 0301 basic medicine, Epidemiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Gastroenterology, 0302 clinical medicine, Endocrinology, Genotype, Medicine, Guadeloupe, lcsh:RC620-627, Abdominal obesity, ComputingMilieux_MISCELLANEOUS, Body mass index, education.field_of_study, Osteonecrosis, Middle Aged, Lipids, Sickle cell anemia, 3. Good health, Non HDL-cholesterol, [SDV] Life Sciences [q-bio], lcsh:Nutritional diseases. Deficiency diseases, Female, medicine.symptom, Adult, medicine.medical_specialty, Lipoproteins, Population, Anemia, Sickle Cell, Clinical nutrition, Hemolysis, 03 medical and health sciences, Internal medicine, Acute Chest Syndrome, Genetics, Humans, Vascular Diseases, education, Triglycerides, Retrospective Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, Sickle cell disease, Biochemistry (medical), Case-control study, medicine.disease, Acute chest syndrome, 030104 developmental biology, Apolipoproteins, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

International audience; AbstractBackgroundThe pathophysiology of sickle cell disease (SCD) and the variability of its clinical expression remain not fully understood, whether within or between different SCD genotypes. Recent studies have reported associations between lipid levels and several SCD complications. If lipid levels have been previously described as low in sickle cell anemia (SCA), few data have been provided for sickle cell SC disease (SCC). We designed our epidemiological study to isolate lipid levels and profiles by genotype in Guadeloupian cohorts of SCA and SCC adult patients, at steady state. We compared SCD lipid levels with those of the Guadeloupian general population (GGP), and analyzed potential associations between lipid levels and SCD complications (vaso-occlusive crises, acute chest syndrome and osteonecrosis).MethodsLipids, apolipoproteins, biological variables and anthropometric evaluation, were collected at steady state from medical files for 62 SCC and 97 SCA adult patients. Clinical SCD complications were collected from the clinical files. Analysis was conducted by genotype for all variables.ResultsDifferent SCC and SCA lipid profiles, both distinct from their GGP’s, were identified. Compared to SCC and GGP, higher triglyceride (TG) levels were observed in SCA patients, independent of hydroxyurea, hemolysis, gender, age, body mass index (BMI), abdominal obesity and clinical nutritional status. Our survey highlights also subsequent anthropometrical phenotypes, with an over-representation of abdominal obesity with normal BMI in SCA patients, and affecting almost exclusively females in both genotypes. Moreover, more frequent positive history of acute chest syndrome (ACS) was observed in SCA patients with TG level higher than 1.50 g/l, and of osteonecrosis in SCC patients having non high-density lipoprotein-cholesterol level (Non HDL-C) higher than 1.30 g/l.ConclusionsThis study reveals that SCA and SCC patients exhibit distinct lipid profiles and suggests that high TG and Non HDL-C levels are associated with past histories of ACS and osteonecrosis in SCA and SCC patients, respectively.

Published
2018

19. Risk assessment of occupational exposure to heavy metal mixtures: a study protocol

Author

Imed Gargouri, Fatma Omrane, Moncef Khadhraoui, Boubaker Elleuch, Denis Zmirou-Navier, Laboratory of Environmental Engineering and EcoTechnology [Sfax, Tunisia], Université de Sfax - University of Sfax-École Nationale d'Ingénieurs de Sfax | National School of Engineers of Sfax (ENIS), Interactions Gènes-Risques environnementaux et Effets sur la Santé (INGRES), Université de Lorraine (UL), École des Hautes Études en Santé Publique [EHESP] (EHESP), Faculté de médecine - Faculty of Medicine [Sfax, Tunisie] (FMS), Université de Sfax - University of Sfax, 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 ), The study was funded by Sfax University, Tunisia in collaboration with EHESP (Ecole des Hautes Etudes en Santé Publique, France)., Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and BMC, BMC

Subjects
0301 basic medicine, Pollution, Tunisia, [SDV]Life Sciences [q-bio], media_common.quotation_subject, 010501 environmental sciences, Risk Assessment, 01 natural sciences, Study Protocol, 03 medical and health sciences, Metals, Heavy, Environmental health, Biomonitoring, Mixture, Humans, Industry, Medicine, Indoor pollution, 0105 earth and related environmental sciences, Exposure assessment, media_common, Protocol (science), business.industry, lcsh:Public aspects of medicine, Modeling, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, Heavy metals, Models, Theoretical, Occupational exposure, [SDV] Life Sciences [q-bio], Air monitoring, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 13. Climate action, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Biostatistics, Risk assessment, business
Abstract

International audience; Background - Sfax is a very industrialized city located in the southern region of Tunisia where heavy metals (HMs) pollution is now an established matter of fact. The health of its residents mainly those engaged in industrial metals-based activities is under threat. Indeed, such workers are being exposed to a variety of HMs mixtures, and this exposure has cumulative properties. Whereas current HMs exposure assessment is mainly carried out using direct air monitoring approaches, the present study aims to assess health risks associated with chronic occupational exposure to HMs in industry, using a modeling approach that will be validated later on.Methods - To this end, two questionnaires were used. The first was an identification/descriptive questionnaire aimed at identifying, for each company: the specific activities, materials used, manufactured products and number of employees exposed. The second related to the job-task of the exposed persons, workplace characteristics (dimensions, ventilation, etc.), type of metals and emission configuration in space and time. Indoor air HMs concentrations were predicted, based on the mathematical models generally used to estimate occupational exposure to volatile substances (such as solvents). Later on, and in order to validate the adopted model, air monitoring will be carried out, as well as some biological monitoring aimed at assessing HMs excretion in the urine of workers volunteering to participate. Lastly, an interaction-based hazard index HI and a decision support tool will be used to predict the cumulative risk assessment for HMs mixtures.Discussion - One hundred sixty-one persons working in the 5 participating companies have been identified. Of these, 110 are directly engaged with HMs in the course of the manufacturing process. This model-based prediction of occupational exposure represents an alternative tool that is both time-saving and cost-effective in comparison with direct air monitoring approaches. Following validation of the different models according to job processes, via comparison with direct measurements and exploration of correlations with biological monitoring, these estimates will allow a cumulative risk characterization.

Published
2018

20. Body mass index and lung cancer risk: a pooled analysis based on nested case-control studies from four cohort studies

Author

Gary E. Goodman, Lesley M. Butler, Paolo Vineis, Woon-Puay Koh, Mattias Johansson, Isabelle Stücker, Harinakshi Sanikini, Jian-Min Yuan, Chu Chen, Annika Steffen, Rayjean J. Hung, Matt J. Barnett, Yu-Tang Gao, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Duke-NUS Medical School [Singapore], Saw Swee Hock School of Public Health, National University of Singapore (NUS), Department of Epidemiology, Shanghai Cancer Institute, School of Medicine [Shanghai Jiaotong University], Shanghai Jiaotong University, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Department of Epidemiology and Biostatistics [Imperial College London], Imperial College London, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], This work was supported by the Fondation de France and Ecole doctarale de Sante Publique (ED420). The EPIC study has been supported by the Europe Against Cancer Program of the European Commission. The SCHS and SCS were supported by NCI, NIH grants U01-CA63673, UM1-CA167462 and R01-CA111703. The CARET was supported by the National Institute of Health (U01 CA63673) and the Fred Hutchinson Cancer Research Center, Seattle, WA., BMC, BMC, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Overweight, Body Mass Index, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, 2. Zero hunger, Smoking, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Female, Lung cancer, medicine.symptom, Underweight, Life Sciences & Biomedicine, Research Article, Cohort study, Adult, medicine.medical_specialty, HYPOXIA-INDUCIBLE FACTOR, [SDV.CAN]Life Sciences [q-bio]/Cancer, SECULAR TRENDS, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, medicine, Humans, Oncology & Carcinogenesis, Obesity, METAANALYSIS, Aged, Science & Technology, HISTOLOGIC TYPE, business.industry, MORTALITY, Case-control study, Odds ratio, medicine.disease, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Nested case-control study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, WEIGHT, SINGAPORE CHINESE HEALTH, business, 1112 Oncology And Carcinogenesis, Body mass index
Abstract

Background Obesity has been proposed as a potential protective factor against lung cancer. We examined the association between BMI and lung cancer risk in a pooled analysis based on nested case-control studies from four cohort studies. Methods A case-control study was nested within four cohorts in USA, Europe, China and Singapore that included 4172 cases and 8471 control subjects. BMI at baseline was calculated as weight in kilograms divided by height in meters squared (kg/m2), and classified into 4 categories: underweight (BMI

Published
2018

21. The role of RICTOR downstream of receptor tyrosine kinase in cancers

Author

Ahlem Jebali, Nicolas Dumaz, Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), This work was funded by INSERM, Université Paris Diderot, Société Française de Dermatologie and Ligue Nationale contre le Cancer. Ahlem Jebali was supported by Ligue Nationale contre le Cancer, and BMC, BMC

Subjects
mTOR inhibitors, PDGFR, RTK, TOR Serine-Threonine Kinases, EGFR, [SDV]Life Sciences [q-bio], fungi, digestive, oral, and skin physiology, Receptor Protein-Tyrosine Kinases, Antineoplastic Agents, Review, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, PI3K, [SDV] Life Sciences [q-bio], VEGFR, Rapamycin-Insensitive Companion of mTOR Protein, Neoplasms, HER2, mTOR, Animals, Humans, RICTOR, mTORC2, Signal Transduction
Abstract

International audience; AbstractThe importance of the network defined by phosphatidylinositol-3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) downstream of Receptor Tyrosine Kinase (RTK) has been known for many years but the central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway is only starting to emerge. RICTOR is critical for mTORC2 (the mammalian target of rapamycin complex 2) kinase activity and as such plays a key role downstream of RTK. Alterations of RICTOR have been identified in a number of cancer cell types and its involvement in tumorigenesis has begun to be unraveled recently. Here, we summarize new research into the biology of RICTOR signaling in cancers focusing on tumors with altered RTK. We show that, as a key signaling node and critical effector of RTKs, RICTOR is becoming a valuable therapeutic target in cancer with altered RTK.

Published
2018

22. Cyclosporine A does not prevent second-eye involvement in Leber’s hereditary optic neuropathy

Author

Marie-Bénédicte Rougier, Patrizia Amati-Bonneau, Caroline Tilikete, Dominique Bonneau, Vincent Procaccio, Pascal Reynier, Guy Lenaers, Stéphanie Leruez, Xavier Zanlonghi, Christophe Verny, Dan Milea, Adriana Prundean, Christophe Orssaud, Clarisse Scherer, BMC, BMC, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'ophtalmologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de neurologie [Angers], Unité Fonctionnelle d’Ophtalmologie [AP-HP HEGP, 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)-Centre de référence des Maladies Rares en Ophtalmologie [CHU HEGP] (OPHTARA), 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 de Compétence Maladies Rares [Nantes], Centre Ophtalmologique de la Clinique Jules Verne, Service d'ophtalmologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Unité de Neuro-Ophtalmologie [Bron], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Pierre Wertheimer - HCL [Bron], Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), Financial support for this work was provided by a French national clinical research grant (PHRC 2010–05)., and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
Adult, Male, medicine.medical_specialty, genetic structures, [SDV]Life Sciences [q-bio], Nerve fiber layer, lcsh:Medicine, Pilot Projects, Optic Atrophy, Hereditary, Leber, Optic neuropathy, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ophthalmology, medicine, Clinical endpoint, Humans, Pharmacology (medical), 10. No inequality, Genetics (clinical), business.industry, Eye involvement, Research, lcsh:R, Leber's hereditary optic neuropathy, Retinal, General Medicine, medicine.disease, eye diseases, 3. Good health, Visual field, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Retinal ganglion cell, chemistry, Cyclosporine, 030221 ophthalmology & optometry, Female, sense organs, Leber’s hereditary optic neuropathy, business, Immunosuppressive Agents, Second-eye involvement, 030217 neurology & neurosurgery
Abstract

International audience; AbstractBackrgroundEvaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber’s hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes.ResultsAmong the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11–65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected.ConclusionsOral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber’s hereditary optic neuropathy.Trial registrationClinicalTrials.gov Identifier: NCT02176733. Registrated June 25, 2014.

Published
2018

23. Non-invasive differentiation of idiopathic inflammatory myopathy with cardiac involvement from acute viral myocarditis using cardiovascular magnetic resonance imaging T1 and T2 mapping

Author

Adrian T. Huber, Marine Bravetti, Jérôme Lamy, Tania Bacoyannis, Charles Roux, Alain de Cesare, Aude Rigolet, Olivier Benveniste, Yves Allenbach, Mathieu Kerneis, Philippe Cluzel, Nadjia Kachenoura, Alban Redheuil, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de radiologie cardiovasculaire et interventionnelle [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), University of Bern, 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], Service de médecine interne [CHU Pitié-Salpétrière], Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Cardiologie [CHU Pitié-Salpêtrière], AH received a research grant from the Helmut-Hartweg-Foundation of the Swiss Academy of Medical Sciences (SAMS). JL received a research grant from the Institute of Cardiometabolism and Nutrition (ICAN). The project was financially supported by the Institut Universitaire d’Ingénierie en Santé (IUIS)., BMC, BMC, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-Sorbonne Université (SU), and Centre de recherche en Myologie – U974 SU-INSERM

Subjects
Adult, Male, lcsh:Diseases of the circulatory (Cardiovascular) system, [SDV]Life Sciences [q-bio], Magnetic Resonance Imaging, Cine, Skeletal muscle, 610 Medicine & health, Diagnosis, Differential, Young Adult, Predictive Value of Tests, CMR T1/T2 mapping, Humans, Muscle, Skeletal, Aged, Retrospective Studies, Myositis, Research, Heart, Middle Aged, Thorax, Systemic myositis, [SDV] Life Sciences [q-bio], Myocarditis, Cardiac inflammation, lcsh:RC666-701, Female, Extracellular volume
Abstract

International audience; BACKGROUND:Idiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases with systemic myositis which may involve the myocardium. Cardiac involvement in IIM, although often subclinical, may mimic clinical manifestations of acute viral myocarditis (AVM). Our aim was to investigate the usefulness of the combined analysis of cardiovascular magnetic resonance (CMR) T1 and T2 mapping parameters measured both in the myocardium and in the thoracic skeletal muscles to differentiate AVM from IIM cardiac involvement.METHODS:Sixty subjects were included in this retrospective study (36 male, age 45 ± 16 years): twenty patients with AVM, twenty patients with IIM and cardiac involvement and twenty healthy controls. Study participants underwent CMR imaging with modified Look-Locker inversion-recovery (MOLLI) T1 mapping and 3-point balanced steady-state-free precession T2 mapping. Relaxation times were quantified after endocardial and epicardial delineation on basal and medial short-axis slices, as well as in different thoracic skeletal muscle groups present in the CMR field-of-view. ROC-Analysis was performed to assess the ability of mapping indices to discriminate the study groups.RESULTS:Mapping parameters in the thoracic skeletal muscles were able to discriminate between AVM and IIM patients. Best skeletal muscle parameters to identify IIM from AVM patients were reduced post-contrast T1 and increased extracellular volume (ECV), resulting in an area under the ROC curve (AUC) of 0.95 for post-contrast T1 and 0.96 for ECV. Conversely, myocardial mapping parameters did not discriminate IIM from AVM patients but increased native T1 (AUC 0.89 for AVM; 0.84 for IIM) and increased T2 (AUC 0.82 for AVM; 0.88 for IIM) could differentiate both patient groups from healthy controls.CONCLUSION:CMR myocardial mapping detects cardiac inflammation in AVM and IIM compared to normal myocardium in healthy controls but does not differentiate IIM from AVM. However, thoracic skeletal muscle mapping was able to accurately discern IIM from AVM.

Published
2018

24. Factors associated with breast cancer recurrences or mortality and dynamic prediction of death using history of cancer recurrences: the French E3N cohort

Author

Mathilde His, Marie-Christine Boutron-Ruault, Virginie Rondeau, Alexandre Lafourcade, Laure Dossus, Laura Baglietto, 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), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Nutrition et métabolisme, International Agency for Cancer Research (IACR), The E3N study is being conducted with financial support from the FrenchLeague against Cancer, the Mutuelle Générale de l’Education Nationale, theGustave Roussy Institute, and the National Institute of Health and MedicalResearch. Laura Baglietto is supported by a Marie Curie International . MathildeHis was supported by a PhD fellowship from the French League against Cancer.This work was partly supported by a grant from INCA (2014–1-PL SHS-03)., BMC, BMC, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Cancer Research, [SDV]Life Sciences [q-bio], 01 natural sciences, Metastasis, Cohort Studies, 010104 statistics & probability, Breast cancer, 0302 clinical medicine, Risk Factors, Surgical oncology, E3N cohort, Joint frailty model, Prospective cohort study, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, 3. Good health, [SDV] Life Sciences [q-bio], Death, Local, 030220 oncology & carcinogenesis, Cohort, Female, France, Research Article, Cohort study, Adult, medicine.medical_specialty, Prognostic factors, Recurrences, Aged, Breast Neoplasms, Humans, Life Style, Neoplasm Recurrence, Local, Genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Cancer recurrence, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, 0101 mathematics, business.industry, Cancer, medicine.disease, Neoplasm Recurrence, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences. Methods The E3N (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l’Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model. Results The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively. Conclusions Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient’s survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output. Electronic supplementary material The online version of this article (10.1186/s12885-018-4076-4) contains supplementary material, which is available to authorized users.

Published
2018

25. Value of information methods to design a clinical trial in a small population to optimise a health economic utility function

Author

Martin Posch, Frank Miller, Nigel Stallard, Sarah Zohar, Jason Madan, Simon Day, Michael Pearce, Siew Wan Hee, University of Warwick [Coventry], Medizinische Universität Wien = Medical University of Vienna, Clinical Trials Consulting and Training Limited [Buckingham], Stockholm University, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was conducted as part of the InSPiRe (Innovative methodology for small populations research) project funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number FP HEALTH 2013-602144., BMC, BMC, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)

Subjects
Value of information, Epidemiology, Cost-Benefit Analysis, [SDV]Life Sciences [q-bio], Population, Decision Making, Health Informatics, 01 natural sciences, Decision theory, law.invention, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Outcome Assessment, Health Care, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, 0101 mathematics, education, Statistical hypothesis testing, Randomized Controlled Trials as Topic, education.field_of_study, lcsh:R5-920, Actuarial science, business.industry, Population size, Patient Selection, Regulator, R1, 3. Good health, Clinical trial, [SDV] Life Sciences [q-bio], Sample size determination, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Research Design, Sample Size, Power, Type I error, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, lcsh:Medicine (General), Health economics, Rare disease, Research Article
Abstract

Background Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. Methods We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. Results The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. Conclusions Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population. Electronic supplementary material The online version of this article (10.1186/s12874-018-0475-0) contains supplementary material, which is available to authorized users.

Published
2018

26. Unearthing new genomic markers of drug response by improved measurement of discriminative power

Author

Antonio Peón, Pedro J. Ballester, Cuong Cao Dang, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), BMC, BMC, and INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID

Subjects
0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, computer.software_genre, 0302 clinical medicine, Discriminative model, Drug response, False Negative Reactions, Genetics (clinical), media_common, 0303 health sciences, Discriminant Analysis, Genomics, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Identification (biology), Data mining, DNA microarray, Research Article, Genetic Markers, Drug, lcsh:Internal medicine, lcsh:QH426-470, media_common.quotation_subject, Antineoplastic Agents, Computational biology, Statistics, Nonparametric, 03 medical and health sciences, Genetics, medicine, False Positive Reactions, lcsh:RC31-1245, 030304 developmental biology, Statistical hypothesis testing, Analysis of Variance, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Computational Biology, Cancer, medicine.disease, Human genetics, In vitro, Clinical trial, lcsh:Genetics, 030104 developmental biology, Pharmacogenetics, business, Oncology drugs, computer
Abstract

BackgroundOncology drugs are only effective in a small proportion of cancer patients. Our current ability to identify these responsive patients before treatment is still poor in most cases. Thus, there is a pressing need to discover response markers for marketed and research oncology drugs in order to improve patient survival, reduce healthcare costs and enhance success rates in clinical trials. Screening these drugs against a large panel of cancer cell lines has been employed to discover new genomic markers of in vitro drug response, which can now be further evaluated on more accurate tumour models. However, while the identification of discriminative markers among thousands of candidate drug-gene associations in the data is error-prone, an appraisal of the effectiveness of such detection task is currently lacking.ResultsHere we present a new non-parametric method to measuring the discriminative power of a drug-gene association. This is enabled by the identification of an auxiliary threshold posing this task as a binary classification problem. Unlike parametric statistical tests, the adopted non-parametric test has the advantage of not making strong assumptions about the data distorting the identification of genomic markers. Furthermore, we introduce a new benchmark to further validate these markers in vitro using more recent data not used to identify the markers. The application of this new methodology has led to the identification of 128 new genomic markers distributed across 61% of the analysed drugs, including 5 drugs without previously known markers, which were missed by the MANOVA test initially applied to analyse data from the Genomics of Drug Sensitivity in Cancer consortium.Abbreviation(WT)wild-type(GDSC)Genomics of Drug Sensitivity in Cancer(TP)true positive(TN)true negative(FP)false positive(FN)false negative(MCC)Matthews Correlation Co-efficient.

Published
2018

27. Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei

Author

Armelle Wauters, Frédérique Coppée, Céline Vanderplanck, Alexandra Belayew, Dalila Laoudj-Chenivesse, Kelly Vancutsem, Eugénie Ansseau, Céline Lancelot, Sébastien Charron, Alexandra Tassin, Université de Mons (UMons), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We acknowledge the funding from the Association Belge contre les MaladiesNeuro-Musculaires (https://www.telethon.be/), the Association Française contreles Myopathies (www.afm-telethon.fr), and the FSH Society (USA) (https://www.fshsociety.org).CV successively held a doctoral fellowship from the Fonds pour la Formation àla Recherche dans l’Industrie et dans l’Agriculture (FRIA Belgium) (www.fnrs.be)and the FSHD Global Foundation (Australia) (http://fshdglobal.org/). EA and ATwere post-doctoral associates of the Fonds National de la Recherche Scientifique(http://www.fnrs.be) (Belgium), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and BMC, BMC

Subjects
0301 basic medicine, Cytoplasm, lcsh:Diseases of the musculoskeletal system, Cellular differentiation, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Proliferation, Muscle Proteins, Muscle Development, Myoblasts, 0302 clinical medicine, Myocyte, Facioscapulohumeral muscular dystrophy, Orthopedics and Sports Medicine, RNA, Small Interfering, Cells, Cultured, beta Catenin, ComputingMilieux_MISCELLANEOUS, Cytoskeleton, Myogenesis, Cell Differentiation, Transfection, Muscular Dystrophy, Facioscapulohumeral, Cell biology, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Phenotype, Differentiation, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, DUX4, Troponin T, medicine, Humans, Gene Silencing, Muscle, Skeletal, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Nucleus, Homeodomain Proteins, Myonuclear clustering, Research, Skeletal muscle, Cell Biology, β-catenin, medicine.disease, Cell nucleus, 030104 developmental biology, lcsh:RC925-935, Disorganized myotubes, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Background Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initiates a gene deregulation cascade. FSHD primary myoblasts differentiate into either atrophic or disorganized myotubes. DUX4 expression induces atrophic myotubes and associated FSHD markers. Although DUX4 silencing normalizes the FSHD atrophic myotube phenotype, this is not the case for the disorganized phenotype. DUX4c overexpression increases the proliferation rate of human TE671 rhabdomyosarcoma cells and inhibits their differentiation, suggesting a normal role during muscle differentiation. Methods By gain- and loss-of-function experiments in primary human muscle cells, we studied the DUX4c impact on proliferation, differentiation, myotube morphology, and FSHD markers. Results In primary myoblasts, DUX4c overexpression increased the staining intensity of KI67 (a proliferation marker) in adjacent cells and delayed differentiation. In differentiating cells, DUX4c overexpression led to the expression of some FSHD markers including β-catenin and to the formation of disorganized myotubes presenting large clusters of nuclei and cytoskeletal defects. These were more severe when DUX4c was expressed before the cytoskeleton reorganized and myofibrils assembled. In addition, endogenous DUX4c was detected at a higher level in FSHD myotubes presenting abnormal clusters of nuclei and cytoskeletal disorganization. We found that the disorganized FSHD myotube phenotype could be rescued by silencing of DUX4c, not DUX4. Conclusion Excess DUX4c could disturb cytoskeletal organization and nuclear distribution in FSHD myotubes. We suggest that DUX4c up-regulation could contribute to DUX4 toxicity in the muscle fibers by favoring the clustering of myonuclei and therefore facilitating DUX4 diffusion among them. Defining DUX4c functions in the healthy skeletal muscle should help to design new targeted FSHD therapy by DUX4 or DUX4c inhibition without suppressing DUX4c normal function. Electronic supplementary material The online version of this article (10.1186/s13395-017-0148-4) contains supplementary material, which is available to authorized users.

Published
2018

28. Chronic exposure to tumor necrosis factor alpha induces retinal pigment epithelium cell dedifferentiation

Author

Touhami, Sara, Beguier, Fanny, Augustin, Sébastien, Charles-Messance, Hugo, Vignaud, Lucile, Nandrot, Emeline F., Reichman, Sacha, Forster, Valérie, Mathis, Thibaud, Sahel, José-Alain, Bodaghi, Bahram, Guillonneau, Xavier, Sennlaub, Florian, BMC, BMC, Equipe 14 - Inflammation dans la dégénérescence neuronale et le remodelage vasculaire (Inserm U968/CNRS UMR7210/UPMC UM80), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Ophtalmologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), This work was supported by grants from INSERM, ANR Geno 2009 (R09099DS), ANR MACLEAR (ANR-15-CE14-0015-01), LABEX LIFESENSES [ANR-10-LABX-65] supported by the ANR (Investissements d’Avenir programme [ANR-11-IDEX-0004-02]), and a generous donation by Doris and Michael Bunte., and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Lipopolysaccharides, Rhodopsin, [SDV]Life Sciences [q-bio], Neurodegenerative disease, lcsh:RC346-429, Monocytes, Cell Fusion, Phagocytosis, Neuroinflammation, Proto-Oncogene Proteins, Animals, Humans, RNA, Messenger, Retinal pigment epithelium, lcsh:Neurology. Diseases of the nervous system, Cell Proliferation, Otx Transcription Factors, Dose-Response Relationship, Drug, Tumor Necrosis Factor-alpha, Tumor necrosis factor alpha, Research, Age-related macular degeneration, Capillary Resistance, Cell Differentiation, Epithelial Cells, Actins, eye diseases, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Trans-Activators, Zonula Occludens-1 Protein, Transforming growth factor beta, sense organs
Abstract

International audience; BackgroundThe retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye. We have previously shown that acute stimulation of RPE cells by tumor necrosis factor alpha (TNFα) downregulates the expression of OTX2 (Orthodenticle homeobox 2) and dependent RPE genes. We here investigated the long-term effects of TNFα on RPE cell morphology and key functions in vitro.MethodsPrimary porcine RPE cells were exposed to TNFα (at 0.8, 4, or 20 ng/ml per day) for 10 days. RPE cell morphology, phagocytosis, barrier- and immunosuppressive-functions were assessed.ResultsChronic (10 days) exposure of primary RPE cells to TNFα increases RPE cell size and polynucleation, decreases visual cycle gene expression, impedes RPE tight-junction organization and transepithelial resistance, and decreases the immunosuppressive capacities of the RPE. TNFα-induced morphological- and transepithelial-resistance changes were prevented by concomitant Transforming Growth Factor β inhibition.ConclusionsOur results indicate that chronic TNFα-exposure is sufficient to alter RPE morphology and impede cardinal features that define the differentiated state of RPE cells with striking similarities to the alterations that are observed with age in neurodegenerative diseases such as age-related macular degeneration.

Published
2018

29. A 3-year follow-up study after treatment with simeprevir in combination with pegylated interferon-α and ribavirin for chronic hepatitis C virus infection

Author

Andrzej Horban, Peter Buggisch, Fabien Zoulim, Christophe Moreno, Bart Fevery, Samuel S. Lee, Eric Lawitz, Chris Corbett, W. Jessner, Umesh Shukla, Oliver Lenz, Thierry Verbinnen, BMC, BMC, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Université libre de Bruxelles (ULB), University of Calgary, Institute for Interdisciplinary Medicine Hamburg, Medical University of Warsaw - Poland, The University of Texas Health Science Center at Houston (UTHealth), Janssen Research & Development, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [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 ), Université Libre de Bruxelles [Bruxelles] ( ULB ), and University of Texas Health, San Antonio

Subjects
0301 basic medicine, Simeprevir, Male, [SDV]Life Sciences [q-bio], NS3 amino acid substitutions, Hepacivirus, Virologie générale, medicine.disease_cause, Direct-acting antivirals, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Pegylated interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Pathologie maladies infectieuses, media_common, Aged, 80 and over, education.field_of_study, Sustained virologic response, Hepatitis C virus, virus diseases, Middle Aged, Viral Load, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Treatment Outcome, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, medicine.drug, Adult, medicine.medical_specialty, Genotype, [SDV.IMM] Life Sciences [q-bio]/Immunology, Population, Biology, Antiviral Agents, Virus, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Virology, Internal medicine, Drug Resistance, Viral, Ribavirin, medicine, media_common.cataloged_instance, Humans, Protease inhibitor (pharmacology), lcsh:RC109-216, European union, education, Aged, [ SDV ] Life Sciences [q-bio], Research, Virologie médicale, Interferon-alpha, Hepatitis C, Chronic, digestive system diseases, 030104 developmental biology, chemistry, Mutation, Follow-Up Studies
Abstract

Background: Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union. Methods: This 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24 weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered. Results: Overall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8 months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9 weeks [41.3 months]). Conclusion: This 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients. Trial registration: NCT01349465; ClinicalTrials.gov., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

30. Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

Author

Ryan J. Weiss, Sébastien Blondeel, Mohamed Bennis, Constantin Yanicostas, Nadia Soussi-Yanicostas, Seyedeh Maryam Alavi Naini, Rahma Hassan-Abdi, Yitzhak Tor, Jeffrey D. Esko, Université de Paris, NeuroDiderot, Inserm U1141, F-75019 Paris, France, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Cadi Ayyad [Marrakech] (UCA), Department of Chemistry and Biochemistry, University of California [San Diego] (UC San Diego), University of California-University of California, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry and Biochemistry [La Jolla, CA, USA], Department of Cellular and Molecular Medicine (CMM), SMAN received a grant from Servier Research Institute. This work was supported by Institut National de la Santé et la Recherche Médicale (INSERM), the French National Research Agency (ANR-16-CE18–0010), and Fondation NRJ (Institut de France) to NSY and grants CA46462 and CA112278 from the National Institute of Health to JDE and YT., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC)-University of California (UC), yanicostas, constantin, 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)-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)-Centre National de la Recherche Scientifique (CNRS), BMC, BMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Aging, [SDV]Life Sciences [q-bio], Heparan sulfate, Neurodegenerative, lcsh:RC346-429, chemistry.chemical_compound, 0302 clinical medicine, Oxalyl surfen, 2.1 Biological and endogenous factors, Aetiology, Zebrafish, biology, medicine.diagnostic_test, Chemistry, Alzheimer's disease, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], MESH: Tauopathy, Zebrafish, Alzheimer’s disease, Tau protein, Tau hyperphosphorylation, Surfen, Oxalyl surfen, Heparan sulfate, Tauopathy, medicine.anatomical_structure, 5.1 Pharmaceuticals, Neurological, Surfen, Tau hyperphosphorylation, Development of treatments and therapeutic interventions, Alzheimer’s disease, Cognitive Neuroscience, Tau protein, Clinical Sciences, Short Report, 03 medical and health sciences, Cellular and Molecular Neuroscience, Western blot, In vivo, medicine, Acquired Cognitive Impairment, lcsh:Neurology. Diseases of the nervous system, Antagonist, Neurosciences, Correction, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), biology.organism_classification, medicine.disease, Brain Disorders, 030104 developmental biology, biology.protein, Dementia, Neurology (clinical), Neuron, 030217 neurology & neurosurgery
Abstract

Background Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies. Results In vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTauP301L; DsRed] embryos. Conclusion Our findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer’s disease.

Published
2018

31. Do pregnancies reduce iron overload in HFE hemochromatosis women? results from an observational prospective study

Author

Jean Baptiste Nousbaum, Gérald Le Gac, Marianne Uguen, Virginie Scotet, Marie Christine Merour, Brigitte Chanu, Claude Férec, C. L'Hostis, Céline Triponey, Philippe Saliou, BMC, BMC, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’Hygiène et de Santé Publique [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Etablissement Français du Sang Bretagne, EFS, Service d'Hépato-Gastroentérologie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], This study was supported by a grant from the Etablissement Français du Sang., EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest]

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Disease, Body Mass Index, 0302 clinical medicine, Phlebotomy, Genetic hemochromatosis, Risk Factors, Pregnancy, Epidemiology, Iron overload, Prospective cohort study, biology, Obstetrics, Confounding, Homozygote, Obstetrics and Gynecology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Regression Analysis, 030211 gastroenterology & hepatology, Female, France, Hemochromatosis, Menopause, Research Article, Adult, medicine.medical_specialty, Alcohol Drinking, Iron, lcsh:Gynecology and obstetrics, 03 medical and health sciences, Sex Factors, Hepcidin, medicine, Humans, Hemochromatosis Protein, lcsh:RG1-991, business.industry, Pregnancy Complications, Hematologic, medicine.disease, 030104 developmental biology, Ferritins, biology.protein, business
Abstract

International audience; BACKGROUND:HFE hemochromatosis is an inborn error of iron metabolism linked to a defect in the regulation of hepcidin synthesis. This autosomal recessive disease typically manifests later in women than men. Although it is commonly stated that pregnancy is, with menses, one of the factors that offsets iron accumulation in women, no epidemiological study has yet supported this hypothesis. The aim of our study was to evaluate the influence of pregnancy on expression of the predominant HFE p.[Cys282Tyr];[Cys282Tyr] genotype.METHODS:One hundred and forty p.Cys282Tyr homozygous women enrolled in a phlebotomy program between 2004 and 2011 at a blood centre in western Brittany (France) were included in the study. After checking whether the disease expression was delayed in women than in men in our study, the association between pregnancy and iron overload was assessed using multivariable regression analysis.RESULTS:Our study confirms that women with HFE hemochromatosis were diagnosed later than men cared for during the same period (52.6 vs. 47.4 y., P

Published
2018

32. The impact of regular school closure on seasonal influenza epidemics: A data-driven spatial transmission model for Belgium

Author

Pietro Coletti, Vittoria Colizza, Giancarlo De Luca, Niel Hens, Kim Van Kerckhove, Nathalie Bossuyt, Chiara Poletto, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hasselt University (UHasselt), Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] (WIV-ISP), Réseau International des Instituts Pasteur (RIIP), University of Antwerp (UA), ISI Foundation Torino, The present work was partially supported by the French ANR projectHarMS-flu (ANR-12-MONU-0018) to GDL and VC, the EC-Health projectPREDEMICS (Contract No. 278433) to VC, the European Research Council (ERC)under the European Union’s Horizon 2020 research and innovationprogramme (grant agreement 682540 - TransMID) to NH, PC, the University ofAntwerp scientific chair in Evidence-Based Vaccinology to NH, the AntwerpStudy centre for Infectious Diseases (ASCID) in 2009-2016 to NH, the IAPResearch Network P7/06 of the Belgian State (Belgian Science Policy) to KVK,NH, the PHC Tournesol Flanders program no.35686NE to GDL, KVK, CP, NH, VC., ANR-12-MONU-0018,HarMS-flu,Approches multi-échelles pour la modélisation de la propagation de la grippe pilotée par les données.(2012), European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), BMC, BMC, Modèles Numériques - Approches multi-échelles pour la modélisation de la propagation de la grippe pilotée par les données. - - HarMS-flu2012 - ANR-12-MONU-0018 - MN - VALID, and Preparedness, Prediction and Prevention of Emerging Zoonotic Viruses with Pandemic Potential using Multidisciplinary Approaches - PREDEMICS - - EC:FP7:HEALTH2011-11-01 - 2016-10-31 - 278433 - VALID

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], School closure, Distribution (economics), law.invention, Seasonal influenza, 0302 clinical medicine, Belgium, law, Spatial transmission, 030212 general & internal medicine, Child, Holidays, Travel, 0303 health sciences, Schools, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Transmission (mechanics), Geography, Metapopulation, Seasons, Research Article, Adult, Epidemic modeling, Influenza, lcsh:Infectious and parasitic diseases, Data-driven, 03 medical and health sciences, Mixing patterns, Influenza, Human, Humans, lcsh:RC109-216, Closure (psychology), Epidemics, 030304 developmental biology, business.industry, Travel behavior, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 13. Climate action, Demographic economics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, business, human activities
Abstract

Background: School closure is often considered as an option to mitigate influenza epidemics because of its potential to reduce transmission in children and then in the community. The policy is still however highly debated because of controversial evidence. Moreover, the specific mechanisms leading to mitigation are not clearly identified. Methods: We introduced a stochastic spatial age-specific metapopulation model to assess the role of holiday-associated behavioral changes and how they affect seasonal influenza dynamics. The model is applied to Belgium, parameterized with country-specific data on social mixing and travel, and calibrated to the 2008/ 2009 influenza season. It includes behavioral changes occurring during weekend vs. weekday, and holiday vs. school-term. Several experimental scenarios are explored to identify the relevant social and behavioral mechanisms. Results: Stochastic numerical simulations show that holidays considerably delay the peak of the season and mitigate its impact. Changes in mixing patterns are responsible for the observed effects, whereas changes in travel behavior do not alter the epidemic. Weekends are important in slowing down the season by periodically dampening transmission. Christmas holidays have the largest impact on the epidemic, however later school breaks may help in reducing the epidemic size, stressing the importance of considering the full calendar. An extension of the Christmas holiday of 1 week may further mitigate the epidemic. Conclusion: Changes in the way individuals establish contacts during holidays are the key ingredient explaining the mitigating effect of regular school closure. Our findings highlight the need to quantify these changes in different demographic and epidemic contexts in order to provide accurate and reliable evaluations of closure effectiveness. They also suggest strategic policies in the distribution of holiday periods to minimize the epidemic impact. The present work was partially supported by the French ANR project HarMS-flu (ANR-12-MONU-0018) to GDL and VC; the EC-Health project PREDEMICS (Contract No. 278433) to VC; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540 - TransMID) to NH, PC; the University of Antwerp scientific chair in Evidence-Based Vaccinology to NH; the Antwerp Study centre for Infectious Diseases (ASCID) in 2009-2016 to NH; the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) to KVK, NH; the PHC Tournesol Flanders program no. 35686NE to GDL, KVK, CP, NH, VC.

Published
2018

33. Electroencephalographic read-outs of the modulation of cortical network activity by deep brain stimulation

Author

Olivier David, Astrid Kibleur, BMC, BMC, Appel à projets générique - Neurophysiologie des réseaux corticaux modulés par la stimulation du noyau subthalamique dans les troubles obsessionnels compulsifs et la maladie de Parkinson - - PHYSIOBS2014 - ANR-14-CE13-0030 - Appel à projets générique - VALID, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), This work was funded by INSERM., and ANR-14-CE13-0030,PHYSIOBS,Neurophysiologie des réseaux corticaux modulés par la stimulation du noyau subthalamique dans les troubles obsessionnels compulsifs et la maladie de Parkinson(2014)

Subjects
0301 basic medicine, Signal processing, Deep brain stimulation, lcsh:Medical technology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Review, Electroencephalography, behavioral disciplines and activities, Cortical networks, 03 medical and health sciences, 0302 clinical medicine, Cortex (anatomy), Medicine, In patient, General Environmental Science, medicine.diagnostic_test, business.industry, Functional neuroanatomy, 3. Good health, nervous system diseases, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, surgical procedures, operative, lcsh:R855-855.5, nervous system, Cortical network, General Earth and Planetary Sciences, business, Neuroscience, therapeutics, 030217 neurology & neurosurgery
Abstract

International audience; AbstractDeep brain stimulation (DBS), a reversible and adjustable treatment for neurological and psychiatric refractory disorders, consists in delivering electrical currents to neuronal populations located in subcortical structures. The targets of DBS are spatially restricted, but connect to many parts of the brain, including the cortex, which might explain the observed clinical benefits in terms of symptomatology. The DBS mechanisms of action at a large scale are however poorly understood, which has motivated several groups to recently conduct many research programs to monitor cortical responses to DBS. Here we review the knowledge gathered from the use of electroencephalography (EEG) in patients treated by DBS. We first focus on the methodology to record and process EEG signals concurrently to DBS. In the second part of the review, we address the clinical and scientific benefits brought by EEG/DBS studies so far.

Published
2018

34. Nonlinear joint models for individual dynamic prediction of risk of death using Hamiltonian Monte Carlo: application to metastatic prostate cancer

Author

Desmée, Solène, Mentré, France, Veyrat-Follet, Christine, Sébastien, Bernard, Guedj, Jérémie, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Translational Informatics & Translational Medicine [Bridgewater, USA], Sanofi US, Clinical Trial Simulation [Chilly-Mazarin, France], Sanofi Aventis R&D [Chilly-Mazarin], The authors would like to thank the Drug Disposition Department, Sanofi, Paris, which supported Solène Desmée by a research grant during this work., Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, BMC

Subjects
Male, lcsh:R5-920, [SDV]Life Sciences [q-bio], Prostatic Neoplasms, Bayes Theorem, Prostate-Specific Antigen, Models, Biological, [SDV] Life Sciences [q-bio], Kinetics, Prostatic Neoplasms, Castration-Resistant, Nonlinear joint model, Nonlinear Dynamics, Risk Factors, Individual dynamic prediction, Calibration, Discrimination, Biomarkers, Tumor, Humans, Hamiltonian Monte Carlo, Neoplasm Metastasis, lcsh:Medicine (General), Monte Carlo Method, Algorithms, Research Article
Abstract

Background Joint models of longitudinal and time-to-event data are increasingly used to perform individual dynamic prediction of a risk of event. However the difficulty to perform inference in nonlinear models and to calculate the distribution of individual parameters has long limited this approach to linear mixed-effect models for the longitudinal part. Here we use a Bayesian algorithm and a nonlinear joint model to calculate individual dynamic predictions. We apply this approach to predict the risk of death in metastatic castration-resistant prostate cancer (mCRPC) patients with frequent Prostate-Specific Antigen (PSA) measurements. Methods A joint model is built using a large population of 400 mCRPC patients where PSA kinetics is described by a biexponential function and the hazard function is a PSA-dependent function. Using Hamiltonian Monte Carlo algorithm implemented in Stan software and the estimated population parameters in this population as priors, the a posteriori distribution of the hazard function is computed for a new patient knowing his PSA measurements until a given landmark time. Time-dependent area under the ROC curve (AUC) and Brier score are derived to assess discrimination and calibration of the model predictions, first on 200 simulated patients and then on 196 real patients that are not included to build the model. Results Satisfying coverage probabilities of Monte Carlo prediction intervals are obtained for longitudinal and hazard functions. Individual dynamic predictions provide good predictive performances for landmark times larger than 12 months and horizon time of up to 18 months for both simulated and real data. Conclusions As nonlinear joint models can characterize the kinetics of biomarkers and their link with a time-to-event, this approach could be useful to improve patient’s follow-up and the early detection of most at risk patients. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0382-9) contains supplementary material, which is available to authorized users.

Published
2017

35. Warning about drinking during pregnancy: lessons from the French experience

Author

Agnès Dumas, Stéphanie Toutain, Laurence Simmat-Durand, Christopher Hill, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-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 Sorbonne Paris Cité (USPC), This work was supported by the French Ministry of Health ('Ministère des Affaires sociales et de la Santé')., BMC, BMC, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Health Knowledge, Attitudes, Practice, Cross-sectional study, [SDV]Life Sciences [q-bio], Health Behavior, Breastfeeding, Alcohol drinking, Risque, 0302 clinical medicine, Pregnancy, Surveys and Questionnaires, Medicine, 030212 general & internal medicine, media_common, education.field_of_study, 030219 obstetrics & reproductive medicine, Obstetrics and Gynecology, food and beverages, Femmes enceintes, [SDV] Life Sciences [q-bio], Policy, Consommation d'alcool, Female, France, Risk assessment, Politique, Adult, Risk, medicine.medical_specialty, Prévention, media_common.quotation_subject, Population, Health Promotion, Breast feeding, lcsh:Gynecology and obstetrics, Risk Assessment, 03 medical and health sciences, Environmental health, Humans, Lactation, Allaitement, education, lcsh:RG1-991, business.industry, Public health, Research, Prevention, Pregnant women, Abstinence, Cross-Sectional Studies, Reproductive Medicine, Women's Health, Warning label, business
Abstract

Résumé en Français Objectif En France, depuis 2007, tous les contenants de boissons alcoolisées comportent un avertissement destiné aux femmes enceintes recommandant l’abstinence. On ignore si les femmes enceintes remarquent cet avertissement, qui est le plus souvent affiché sous la forme d’un petit pictogramme. L’objectif de cette étude était d'évaluer la connaissance de cet avertissement ainsi que la perception des risques sur la consommation d’alcool pendant la grossesse dans un échantillon de femmes enceintes ou venant d’accoucher. Méthodes Une enquête transversale a été menée par téléphone cinq ans après l’introduction de l’avertissement. Un total de 3603 femmes ont été interrogées alors qu’elles étaient enceintes ou en postpartum. Une méthode d’échantillonnage par quota a été utilisée pour que l’échantillon reflète la population. Des analyses multivariées examinaient les caractéristiques associées à la connaissance de l’avertissement et à la perception des risques. Résultats L’avertissement avait été remarqué par 66,1% des femmes et 77,3% des buveuses. Parmi celles qui avaient remarqué l’avertissement, 98,6% pensaient qu’il suggérait l’abstinence de consommation d’alcool. Au total, 40,8% des femmes pensaient que les alcools distillés (les alcools “forts”) étaient plus dangereux que le vin ou la bière, et 8,9% des femmes pensaient que la bière était recommandée pour l'allaitement. Conclusion Une part importante de femmes a remarqué l’avertissement mais la connaissance des risques est faible pour une part notable de femmes. Implications pour la pratique Les futures campagnes d’information devraient insister sur l’équivalence en alcool pur entre les différentes boissons alcoolisées, et devraient souligner les risques associés à la consommation d’alcool pendant l’allaitement.

Published
2017

36. Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

Author

Sabrina Falkowski, Jean-Baptiste Woillard, Deborah Postil, Denis Smith, Rosine Guimbaud, Claire Thalamas, Pierre Marquet, Nicolas Picard, Koukeb Rouguieg-Malki, Nicole Tubiana-Mathieu, Antoine Pariente, Eric Terrebonne, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre d'Investigation Clinique de Limoges (CIC1435), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépatologie et de gastroentérologie [CHU Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Unité de Pharmaco-épidémiologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Université de Bordeaux Ségalen [Bordeaux 2], Département d'Oncologie [CHU Bordeaux] (Cancérologie/Oncologie/Digestive), GH Sud Haut-Lévêque [CHU Hôpitaux de Bordeaux] (Centre médico chirurgical Magellan)-Hôpital Saint-André [CHU de Bordeaux], Département d'Oncologie Digestive [CHU Toulouse], CHU Toulouse [Toulouse], 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 Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], This work was funded by the Ligue Nationale contre le Cancer, the Regional Health Agency of Limousin and the Limoges University Hospital. The funders had no involvement in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript., BMC, BMC, Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan)-Hôpital Saint-André [CHU de Bordeaux], Département Oncologie médicale digestive [CHU Toulouse], Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and 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]

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Genotype, Biomarkers, Tumor, Genetics, medicine, Humans, Genetic Predisposition to Disease, Glucuronosyltransferase, Aged, OATP, Haplotype, Case-control study, Membrane Transport Proteins, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Colorectal cancer, Multidrug Resistance-Associated Protein 2, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Pharmacogenetics, Case-Control Studies, 030220 oncology & carcinogenesis, biology.protein, Efflux transporters, Population study, Female, Efflux, Colorectal Neoplasms, SLCO1B1, UGT, Follow-Up Studies, Research Article
Abstract

Background Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC. Methods Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6–9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and “environmental” risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with “environmental” risk factors. Results No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29–8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10–3.39], p = 0.0257) in the “never alcohol consumption subgroup” (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70–10.9], p 30 years (3.37[1.63–6.96], p = 0.0010). Conclusions Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup. Trial registration Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008–0144. Electronic supplementary material The online version of this article (10.1186/s12885-017-3728-0) contains supplementary material, which is available to authorized users.

Published
2017

37. Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort

Author

Dufouil , Carole, Dubois , Bruno, Vellas , Bruno, Pasquier , Florence, Blanc , Frédéric, Hugon , Hugo, Hanon , Olivier, Dartigues , Jean-François, Harston , Sandrine, Gabelle , Audrey, Ceccaldi , Mathieu, Beauchet , Olivier, Krolak-Salmon , Pierre, David , David, Rouaud , Olivier, Godefroy , Olivier, Belin , Catherine, Rouch , Isabelle, Auguste , Nicolas, Wallon , David, Benetos , Athanase, Pariente , Jeremie, Paccalin , Marc, Moreaud , Olivier, Hommet , Caroline, Sellal , François, Boutoleau-Bretonnière , Claire, Jalenques , Isabelle, Gentric , Armelle, Vandel , Pierre, Azouani , Chabha, Fillon , Ludovic, Fischer , Clara, Savarieau , Helen, Operto , Grégory, Bertin , Hugo, Chupin , Marie, Bouteloup , Vincent, Habert , Marie-Odile, Mangin , Jean-François, Chêne , Geneviève, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de physique de la matière condensée (LPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Groupe hospitalier Broca, CHU Bordeaux [Bordeaux], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), Hospices Civils de Lyon (HCL), Centre Mémoire de Ressources et de Recherche [Nice] (CMRR Nice), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Mines Nantes (Mines Nantes)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Système Nerveux Autonome - Epidémiologie, Physiologie, Ingénierie, Santé (SNA-EPIS), Université Jean Monnet [Saint-Étienne] (UJM)-Centre Hospitalier Universitaire de Saint-Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Rouen, Normandie Université (NU), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Psychologie et NeuroCognition (LPNC), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne (UCA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CATI Multicenter Neuroimaging Platform (CATI), 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), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuroimagerie Assistée par Ordinateur (LNAO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bordeaux (UB), Pôle de Santé publique [CHU Bordeaux], CHU de bordeaux, 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), Fédération des Centres Mémoire de Ressource et de Recherche du Sud de la France [CHU Toulouse] (F-CMRR-SF), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre Mémoire de Ressources et de Recherches [Bordeaux], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Mémoire de Ressources et de Recherche [Paris Nord], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologies (EA 4468), Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca, Centre de Mémoire de Ressources et de Recherche [Paris Broca], AP-HP - Hôpital Broca [Paris], Centre de Mémoire de Ressources et de Recherche [Hôpital Pellegrin, Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin [Bordeaux], Centre de Mémoire de Ressources et de Recherche [Hôpital Xavier Arnozan, Bordeaux], Hôpital Xavier Arnozan - CHU de Bordeaux, Centres Mémoire de Ressources et de Recherche [Hôpital Gui de Chauliac, Montpellier] (CMRR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac, Centre de Mémoire de Ressources et de Recherche [Hôpital La Timone, Marseille], Hôpital de la Timone [CHU - APHM] (TIMONE)-CHU Marseille, Centre Mémoire de Ressources et de Recherche [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Mémoire de Ressources et de Recherche [Lyon] (CMRR), Hospices Civils de Lyon (HCL)-Hôpital des Charpennes [CHU - HCL], Cognition Behaviour Technology (CobTek), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Centre Mémoire Ressources et Recherche [Dijon] (CMRR Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Mémoire de Ressources et de Recherche [CHU Amiens], Clinique de la Mémoire [Hôpitaux Universitaires Paris-Seine-Saint-Denis], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne Hôpital Nord], CHU de Saint-Étienne Hôpital Nord [Saint Etienne], Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne Hôpital de la Charité], CHU de Saint-Étienne Hôpital la Charite, Service de neurologie [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre Mémoire de Ressources et de Recherche [CHU de Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Mémoire [CHU de Toulouse], Centre Mémoire de Ressources et de Recherche [CHRU de Poitiers La Miletrie], CHRU de Poitiers La Miletrie [Poitiers], Centre Mémoire de Ressources et de Recherche [CHU Grenoble Alpes-Site NORD, La Tronche], CHU Grenoble Alpes - Site NORD [La Tronche], Centre Mémoire de Ressources et de Recherche [CHRU de Tours Hôpital Bretonneau], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau [Tours], Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche [Hôpitaux Civils de Colmar, Strasbourg], Hôpitaux Civils de Colmar, Centre Mémoire de Ressources et de Recherche [CHU de Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Mémoire de Ressources et de Recherche [CHU Clermont-Ferrand] (CMRR), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Mémoire de Ressources et de Recherche [CHRU de Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Centre pour l’Acquisition et le Traitement des Images [Saclay] (CATI), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut d'imagerie biomédicale (I²BM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Université Paris-Saclay, The MEMENTO cohort was sponsored by the Fondation Plan Alzheimer (Alzheimer Plan 2008–2012). This work was also supported by the following : CIC 1401-EC, Bordeaux University Hospital, Inserm and the University of Bordeaux., on behalf of the MEMENTO cohort Study Group, BMC, BMC, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Mémoire de Ressources et de Recherche [CHU de Saint-Etienne] (CMRR 42), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Mines Nantes (Mines Nantes)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut d'imagerie biomédicale (I²BM), 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 National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Toulouse - CHU Toulouse-Hôpital La Grave-Casselardit [Toulouse], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Gui de Chauliac-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice), Centre Mémoire de Ressources et de Recherche [CHU de Toulouse, Hôpital Purpan], Hôpital Purpan [Toulouse], Hôpital Bretonneau [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), INSERM Unit 708-Neuroepidemiology, Paris, France, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] ( IM2A ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Neurologie [Lille], Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Kalray, Service de gériatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR99-ISPED, Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Département de Médecine Interne et Gérontologie clinique, CHU Angers, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de génie des procédés - environnement - agroalimentaire ( GEPEA ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Nantes ( UN ) -IMT Atlantique Bretagne-Pays de la Loire ( IMT Atlantique ) -Université Bretagne Loire ( UBL ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ), Laboratoire de Neurosciences Fonctionnelles et Pathologies ( LNFP ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), AP-HP Hôpital Avicenne [Bobigny], Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Risque cardiovasculaire, rigidité-fibrose et hypercoagulabilité ( RCV ), Université Henri Poincaré - Nancy 1 ( UHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie cérébrale et handicaps neurologiques, Centre Mémoire de Ressources et de Recherche ( CM2R ), CHU de Poitiers-Hôpital Jean Bernard, Unité de Neuropsychologie, CHU Grenoble, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne ( NPsy-Sydo ), CHU Clermont-Ferrand-Université Clermont Auvergne ( UCA ), Service de Médecine Interne Gériatrique ( BREST - SMIG ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Acquisition et de Traitement des Images [Paris], Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, 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 ), 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 ), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux Ségalen [Bordeaux 2], Service de médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Neuroimagerie Assistée par Ordinateur ( LNAO ), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université de Bordeaux (UB), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Hôpital Bretonneau [Tours], Centre Mémoire de Ressources et de Recherche [CHU de Clermont-Ferrand], CHU Clermont-Ferrand, Centre Mémoire de Ressources et de Recherche [CHRU de Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Hôpital Saint-Jacques [CHRU de Besançon], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut d'imagerie biomédicale (I²BM), Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut d'imagerie biomédicale (I²BM), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA), Groupe hospitalier Pellegrin [Bordeaux] -CHU Bordeaux [Bordeaux], COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], 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 ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Fédération des Centres Mémoire de Ressource et de Recherche du Sud de la France [CHU Toulouse] ( F-CMRR-SF ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] ( CMRR ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro [Lille], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Université de Strasbourg ( UNISTRA ) -Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Sorbonne Paris Cité ( USPC ), Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologie ( EA 4468 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Groupe hospitalier Broca, Centre Hospitalier Universitaire de Bordeaux-Groupe hospitalier Pellegrin [Bordeaux], Centres Mémoire de Ressources et de Recherche [Hôpital Gui de Chauliac, Montpellier] ( CMRR ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Hôpital de la Timone [CHU - APHM] ( TIMONE ) -CHU Marseille, Centre Mémoire de Ressources et de Recherche [Lyon] ( CMRR ), Hospices Civils de Lyon ( HCL ) -Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon ( HCL ), Cognition Behaviour Technology ( CobTek ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice-Institut Claude Pompidou [Nice] ( ICP - Nice ), Centre Mémoire de Ressources et de Recherche [Nice] ( CMRR Nice ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice, Centre Mémoire Ressources et Recherche [Dijon] ( CMRR Dijon ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Amiens Picardie - Site Nord (Hôpital Nord) [Amiens], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre Hospitalier Régional Universitaire de Tours ( CHRU TOURS ) -Hôpital Bretonneau [Tours], Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean-Minjoz [CHRU de Besançon]-Hôpital Saint-Jacques [CHRU de Besançon], Centre pour l’Acquisition et le Traitement des Images [Saclay] ( CATI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -NeuroSpin-Institut d'imagerie biomédicale (I²BM), Sorbonne Universités, Département de Médecine Nucléaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Laboratoire d'Imagerie Biomédicale ( LIB ), and Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC )

Subjects
Male, [SDV]Life Sciences [q-bio], Neuroimaging, Neuropsychological Tests, Spinal Puncture, Pattern Recognition, Automated, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Diagnostic Self Evaluation, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cognitive aging, Fluorodeoxyglucose F18, Image Processing, Computer-Assisted, Humans, Cognitive Dysfunction, Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, Aged, [ SDV ] Life Sciences [q-bio], Cohort studies, Natural history studies (prognosis), Alzheimer''s disease, Research, Brain, Organ Size, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Research Design, Positron-Emission Tomography, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, France, Radiopharmaceuticals, Alzheimer’s disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background The natural history and disease mechanisms of Alzheimer’s disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. Methods In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR]

Published
2017

38. Fatal anaphylaxis registries data support changes in the who anaphylaxis mortality coding rules

Author

Pascal Demoly, Ségolène Aymé, Luciana Kase Tanno, Isabella Annesi-Maesano, F. Estelle R. Simons, Moises A. Calderon, Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Emergency Department [São Paulo, Brazil], Hospital Sírio-Libanês [São Paulo, Brazil], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Pediatrics & Child Health [Winnipeg, Canada], Section of Allergy & Clinical Immunology [Winnipeg, Canada], University of Manitoba [Winnipeg]-University of Manitoba [Winnipeg], Section of Allergy and Clinical Immunology [London, UK], Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, BMC

Subjects
0301 basic medicine, medicine.medical_specialty, Underlying cause of death, [SDV]Life Sciences [q-bio], Pharmacology toxicology, Review, World Health Organization, World health, 03 medical and health sciences, 0302 clinical medicine, International Classification of Diseases, Humans, Medicine, Genetics(clinical), Pharmacology (medical), Registries, Mortality, Intensive care medicine, Anaphylaxis, Genetics (clinical), Medicine(all), business.industry, Clinical Coding, Fatal anaphylaxis, General Medicine, medicine.disease, Classification, 3. Good health, [SDV] Life Sciences [q-bio], Hypersensitivity reaction, 030104 developmental biology, 030228 respiratory system, Icd codes, business, Coding (social sciences)
Abstract

International audience; AbstractAnaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction. The difficulty of coding anaphylaxis fatalities under the World Health Organization (WHO) International Classification of Diseases (ICD) system is recognized as an important reason for under-notification of anaphylaxis deaths. On current death certificates, a limited number of ICD codes are valid as underlying causes of death, and death certificates do not include the word anaphylaxis per se. In this review, we provide evidences supporting the need for changes in WHO mortality coding rules and call for addition of anaphylaxis as an underlying cause of death on international death certificates. This publication will be included in support of a formal request to the WHO as a formal request for this move taking the 11th ICD revision.

Published
2017

39. Prenatal and post-natal cost of small for gestational age infants: a national study

Author

Marzouk, Alicia, Filipovic-Pierucci, Antoine, Baud, Olivier, Tsatsaris, Vassilis, Ego, Anne, Charles, Marie-Aline, Goffinet, François, Evain-Brion, Danièle, Durand-Zaleski, Isabelle, PremUp Foundation, Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Clinique en Economie de la santé d'Ile de France (URC Eco), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de Gynécologie et Obstétrique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Equipe 6 : ORCHAD - Origines précoces de la santé du développement de l'enfant (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Hôpital Henri Mondor, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche clinique en économie de la santé d'Ile-de-France (URC Eco), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), PREMUP foundation, a non-profit organisation. AM, OB, VT, MAC, FG, and IDZ are members of the PREMUP foundation. DEB is the director of the PREMUP foundation., Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), AP-HP Hôpital universitaire Robert-Debré [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Unité de recherche clinique en économie de la santé d'Ile-de-France ( URC Eco ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie et Pharmacotoxicologie Placentaire Humaine ( U1139 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique ( CRESS - U1153 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables ( Inserm U1123 - ECEVE ), AP-HP Hôpital universitaire Robert-Debré [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), BMC, BMC, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Universités-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), and Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Length of Stay/economics, Adult, Male, Diseases/economics/therapy, [SDV]Life Sciences [q-bio], Mothers, Mothers/statistics & numerical data, Gestational Age, Infant, Premature, Diseases, Database, Sex Factors, Pregnancy, Birth Weight, Humans, Economic cost, Obstetric/economics, Premature, reproductive and urinary physiology, ComputingMilieux_MISCELLANEOUS, ddc:618, [ SDV ] Life Sciences [q-bio], Health Policy, Infant, Newborn, Infant, Small for gestational age, Length of Stay, Newborn, Delivery, Obstetric, female genital diseases and pregnancy complications, [SDV] Life Sciences [q-bio], Perinatal Care, Cross-Sectional Studies, Infant, Small for Gestational Age, Costs and Cost Analysis, Small for Gestational Age, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Perinatal Care/economics, France, Morbidity, Prematurity, Delivery, Infant, Premature, Research Article
Abstract

International audience; AbstractBackgroundSmall for gestational age (SGA) infants are at increased risk for preterm birth morbidities as well as a range of adverse perinatal outcomes that result in part from associated premature birth. We sought to evaluate the costs of SGA versus appropriate for gestational age (AGA) infants in France from pregnancy through the first year of life and separate the contributions of prematurity from the contribution of foetal growth on costs.MethodsThis is a cross-sectional population-based study using national hospital discharge data from French public and private hospitals. SGA infants were defined as newborns with a birth weight below the 10th percentile of French intrauterine growth curves adjusted for foetal sex. AGA infants were defined as newborns with a birth weight between the 25th and the 75th. All births were selected between January 1st, 2011 and December 31st, 2011. Costs were calculated from the hospital perspective for both mothers and children using their diagnostic related group and the French national cost study. Hospital outcomes were extracted from the database and compared by gestational age and mode of delivery.ResultsOf 777,720 total births in 2011, 84,688 SGA births (10.9%) and 395,760 AGA births (50.8%) were identified. After adjustment for gestational age, the cost for an SGA infant was €2,783 higher than for an AGA infant. The total maternal and infant hospital cost of SGA in France was estimated at 23% the total cost for deliveries. The high cost is explained by higher complication rates, more frequent hospital readmissions and longer lengths of stay.ConclusionsBeing small for gestational age is an independent contributor to 1-year hospital costs for both mothers and infants.

Published
2017

40. Neoboutonia melleri var velutina Prain: in vitro and in vivo hepatoprotective effects of the aqueous stem bark extract on acute hepatitis models

Author

Céline Rivière, Théophile Dimo, Thierry Hennebelle, Pierre Desreumaux, Anne Marie Endougou Effa, Emilie Gantier, Vincent Roumy, Pierre Kamtchouing, Laurent Dubuquoy, Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Physiologie Animale [Yaoundé, Cameroon], Université de Yaoundé I, Département de Biologie des Organismes Animaux [Douala, Cameroon], Université de Douala-Université de Douala [Cameroon], Groupe de Recherche Interdiscipinaire Innovation et Optimisation Thérapeutique - EA 4481 (GRIIOT), Université de Lille, Droit et Santé, Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Fédération Hospitalière de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de la Coopération et d’Action Culturelle de l’Ambassade de France au Cameroun (N° bourses/194/2010) and Inserm., Inserm, Université de Lille, CHU Lille, INRA, ISA, Univ. Artois, Univ. Littoral Côte d’Opale, Lille Inflammation Research International Center - U 995 [LIRIC], Institut Charles Viollette (ICV) - EA 7394 [ICV], BMC, BMC, Fédération Hospitalière de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Claude Huriez [Lille], and CHU Lille-CHU Lille

Subjects
Male, 0301 basic medicine, Antioxidant, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Protective Agents, Neoboutonia, Mice, 03 medical and health sciences, chemistry.chemical_compound, In vivo, Mesh:Cytokines/metabolism, Mesh:Plant Bark/chemistry, Mesh:Euphorbiaceae/chemistry, Mesh:Animals, Mesh:Plant Extracts/chemistry, Mesh:Male, Mesh:Plant Extracts/pharmacology, Mesh:Carbon Tetrachloride/toxicity, Mesh:Protective Agents/chemistry, Mesh:Chemical and Drug Induced Liver Injury/metabolism, Mesh:Liver/drug effects, Mesh:Mice, Mesh:Hep G2 Cells, Mesh:Protective Agents/pharmacology, Mesh:Cytokines/analysis, Mesh:Inbred C57BL, Mesh:Humans, medicine, Animals, Humans, Acute hepatitis, Medicinal plants, Carbon Tetrachloride, Hepatitis, Liver injury, biology, Traditional medicine, Plant Extracts, Euphorbiaceae, Hep G2 Cells, lcsh:Other systems of medicine, General Medicine, lcsh:RZ201-999, biology.organism_classification, medicine.disease, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, Liver, Complementary and alternative medicine, chemistry, Phytochemical, Neoboutonia melleri var. velutina Prain, Plant Bark, Carbon tetrachloride, Cytokines, Chemical and Drug Induced Liver Injury, Research Article, Preventive treatment
Abstract

Background Hepatitis is a liver inflammation caused by different agents and remains a public health problem worldwide. Medicinal plants are an important source of new molecules being considered for treatment of this disease. Our work aims at evaluating the hepatoprotective properties of Neoboutonia velutina, a Cameroonian medicinal plant. Methods The aqueous extract has been prepared using phytochemical methods. HepG2 cells were used to assess anti-inflammatory properties of the extract at different concentrations. Acute hepatitis models (Carbon tetrachloride and Concanavalin A) were performed in mice receiving or not receiving, different extract doses by gavage. Liver injury was assessed using histology, transaminases and pro-inflammatory markers. Extract antioxidant and radical scavenging capacities were evaluated. Results The extract led to a significant decrease in pro-inflammatory cytokine expression in vitro and to a remarkable protection of mice from carbon tetrachloride-induced liver injury, as shown by a significant decrease in dose-dependent transaminases level. Upon extract treatment, inflammatory markers were significantly decreased and liver injuries were limited as well. In the Concanavalin A model, the extract displayed weak effects. Conclusions Taking into account underlying mechanisms in both hepatitis models, we demonstrate the extract’s radical scavenging capacity. Neoboutonia velutina displays a potent hepatoprotective effect mediated through radical scavenging properties. Electronic supplementary material The online version of this article (10.1186/s12906-018-2091-2) contains supplementary material, which is available to authorized users.

Published
2017

41. Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia

Author

Dwivedi, Ankit, Reynes, Christelle, Kuehn, Axel, Roche, Daniel, Khim, Nimol, Hebrard, Maxime, Milanesi, Sylvain, Rivals, Eric, Frutos, Roger, Menard, Didier, Mamoun, Choukri Ben, Colinge, Jacques, Cornillot, Emmanuel, Institut de Biologie Computationnelle (IBC), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôtes-vecteurs-parasites-environnement dans les maladies tropicales négligées dues aux trypanosomatides (UMR INTERTRYP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université de Bordeaux (UB), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Yale School of Medicine [New Haven, Connecticut] (YSM), BMC, BMC, 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), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yale University School of Medicine, LPITI, Université Montpellier 2 - Sciences et Techniques (UM2), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), United States Naval Academy, Institut de Recherche en Infectiologie de Montpellier (IRIM), Institut Pasteur [Paris], Vaccination Antiparasitaire : Laboratoire de Biologie Cellulaire et Moléculaire (LBCM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut de Recherche pour le Développement (IRD)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Université de Montpellier (UM)-Université Montpellier 1 (UM1), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
k13, lcsh:Arctic medicine. Tropical medicine, MESH: Mutation, Genotype, lcsh:RC955-962, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Population fragmentation, L73 - Maladies des animaux, Polymorphism, Single Nucleotide, lcsh:Infectious and parasitic diseases, MESH: Genotype, Antimalarials, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Artemisinins, parasitic diseases, Humans, lcsh:RC109-216, Malaria, Falciparum, MESH: Protozoan Proteins, MESH: Plasmodium falciparum, MESH: Humans, Network based stratification, MESH: Cambodia, MESH: Malaria, Falciparum, MESH: Polymorphism, Single Nucleotide, Research, 000 - Autres thèmes, MESH: Antimalarials, Artemisinins, Malaria, Shifting balance theory, [SDV] Life Sciences [q-bio], Artemisinin resistance, Admixed subpopulations, Mutation, MESH: Drug Resistance, Redox metabolism, Cambodia
Abstract

Background Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008–2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs. Results Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population. Conclusions Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations. Electronic supplementary material The online version of this article (10.1186/s12936-017-2140-1) contains supplementary material, which is available to authorized users.

Published
2017

42. Management of rare diseases of the Head, Neck and Teeth: results of a French population-based prospective 8-year study

Author

Lisa Friedlander, Rémy Choquet, Eva Galliani, Myriam de Chalendar, Claude Messiaen, Amélie Ruel, Marie-Paule Vazquez, Ariane Berdal, Corinne Alberti, Muriel De La Dure Molla, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rares de la Face et de la Cavité Buccale (MAFACE), INSERM U 132, Hôpital Necker - Enfants Malades, Paris, France-Hôpital Rothschild [AP-HP], Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA Necker), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Service de chirurgie plastique et maxillofaciale [CHU Necker], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies (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), One funding/research grant was received to support this study from University Paris-Diderot (Action Structurante Dental faculty Garancière)., CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), BMC, BMC, Hôpital Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-INSERM U 132, Hôpital Necker - Enfants Malades, Paris, France, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables ( Inserm U1123 - ECEVE ), AP-HP Hôpital universitaire Robert-Debré [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Centre de référence des malformations rares de la face et de la cavité buccale [AP-HP Hôpital Rothschild], AP-HP Hôpital Rothschild, Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] ( MaMEA Necker ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Université Sorbonne Paris Cité ( USPC ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -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 ), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies ( Equipe Inserm U1163 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), and Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 )

Subjects
Male, Registry, [ SDV ] Life Sciences [q-bio], Epidemiology, Research, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, Poisons, Rare diseases, [SDV] Life Sciences [q-bio], Oral cleft, Risk Factors, Prevalence, Humans, Female, Orofacial diseases, France, Prospective Studies
Abstract

Background In the last ten years, national rare disease networks have been established in France, including national centres of expertise and regional ones, with storage of patient data in a bioinformatics tool. The aim was to contribute to the development and evaluation of health strategies to improve the management of patients with rare diseases. The objective of this study has been to provide the first national-level data concerning rare diseases of the head, neck and teeth and to assess the balance between demand and supply of care in France. Methods Centres of expertise for rare diseases record a minimum data set on their clinical cases, using a list of rare Head, Neck and Teeth diseases established in 2006. The present analysis focuses on 2008 to 2015 data based on the Orphanet nomenclature. Each rare disease RD “case” was defined by status “affected” and by the degree of diagnostic certainty, encoded as: confirmed, probable or non-classifiable. Analysed parameters, presented with their 95% confidence intervals using a Poisson model, were the following: time and age at diagnosis, proportions of crude and standardized RD prevalence by age, gender and geographical site. The criteria studied were the proportions of patients in Paris Region and the “included cases geography”, in which these proportions were projected onto the other French Regions, adjusting for local populations. Results In Paris Region, estimated prevalence of these diseases was 5.58 per 10,000 inhabitants (95% CI 4.3-7.1). At December 31st 2015, 11,342 patients were referenced in total in France, of whom 7294 were in Paris Region. More than 580 individual clinical entities (ORPHA code) were identified with their respective frequencies. Most abnormalities were diagnosed antenatally. Nearly 80% of patients recorded come to Paris hospitals to obtain either diagnosis, care or follow up. We observed that the rarer the disease, the more patients were referred to Paris hospitals. Conclusions A health network covering a range of aspects of the rare diseases problematic from diagnostics to research has been developed in France. Despite this, there is still a noticeable imbalance between health care supply and demand in this area. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0650-0) contains supplementary material, which is available to authorized users.

Published
2017

43. Investigating the epigenetic profile of the inflammatory gene IL-6 in late-life depression

Author

Katharina Neuhaus, Richard Saffery, Karen Ritchie, Marie-Laure Ancelin, Lauren Pilkington, Joanne Ryan, Department of Epidemiology and Preventive Medicine [Melbourne, VIC, Australia], Monash University [Clayton], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cancer & Disease Epigenetics [Parkville, VIC, Australia], University of Melbourne-Royal Children’s Hospital & Department of Paediatrics [Parkville, VIC, Australia]-Murdoch Children's Research Institute (MCRI), The ESPRIT project is financed by the regional government of Languedoc- Roussillon, the Agence Nationale de la Recherche (ANR) Project 07 LVIE 004, and an unconditional grant from Novartis. RS is funded by an NHMRC Senior Research Fellowship and the Victorian Government (Australia) Operational Infrastructure Support Scheme., ANR-07-LVIE-0004,ESPRIT-VIE,Interaction entre la vulnérabilité génétique, la dysrégulation biologique et le stress dans la dépression du sujet âgé(2007), BMC, BMC, Longévité et vieillissement - Interaction entre la vulnérabilité génétique, la dysrégulation biologique et le stress dans la dépression du sujet âgé - - ESPRIT-VIE2007 - ANR-07-LVIE-0004 - LVIE - VALID, University of Melbourne-Murdoch Children's Research Institute (MCRI)-Royal Children’s Hospital & Department of Paediatrics [Parkville, VIC, Australia], and Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Genotype, lcsh:RC435-571, [SDV]Life Sciences [q-bio], Late-life depression, Buccal, 03 medical and health sciences, 0302 clinical medicine, lcsh:Psychiatry, Internal medicine, medicine, Humans, Epigenetics, Depression (differential diagnoses), Aged, Mini-international neuropsychiatric interview, Inflammation, Depressive Disorder, Major, DNA methylation, Interleukin-6, Genetic Variation, Antidepressants, Methylation, Late life depression, medicine.disease, IL6, 3. Good health, 030227 psychiatry, Diagnostic and Statistical Manual of Mental Disorders, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Antidepressant, Major depressive disorder, Female, France, Psychology, 030217 neurology & neurosurgery, Follow-Up Studies, Research Article, Clinical psychology
Abstract

International audience; BackgroundIt is well established that there is a link between inflammation and depression, with several studies reporting increased circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL6), in depressed individuals. Peripheral epigenetic marks, including DNA methylation, hold promise as biomarkers for a range of complex conditions, with potential to inform diagnosis and tailor interventions. The aim of this study was to determine whether individuals with depression display differential methylation of the IL6 gene promoter compared to individuals without depression.MethodsThe ESPRIT study of later life neuropsychiatric disorders used a random sampling framework to select non-institutionalised participants aged ≥65 years and over living in the Montpellier region of France. Major depressive disorder (MDD) was assessed using the Mini International Neuropsychiatric Interview (MINI) according to DSM-IV criteria. High levels of depressive symptoms were defined as a score of ≥16 on the Centre for Epidemiologic Studies Depression Scale (CES-D). IL6 promoter DNA methylation was measured on a sub-sample of 380 participants who provided buccal samples.ResultsIndividuals with depression (current MDD or high depressive symptoms) had lower IL6 methylation levels at one of the four sites investigated, however the effect size was small (∆ 2.4%, SE 0.009, p = 0.006). Interestingly, antidepressant use was independently associated with higher IL-6 methylation at the same site (∆ 4.6%, SE 0.019, p = 0.015). In multivariate linear regression analyses adjusting for covariates, including sex and smoking status, these associations remained. There was no effect modification when considering IL6 genotype.ConclusionThis study presents evidence that IL6 methylation may be a marker of depression status in older individuals, however further work is now needed to replicate these findings and to assess the association with inflammatory status of individuals.

Published
2017

44. Moroccan strains of Leishmania major and Leishmania tropica differentially impact on nitric oxide production by macrophages

Author

Hasnaa Maksouri, Khadija Akarid, Pham My-Chan Dang, Vasco Rodrigues, Jérôme Estaquier, Myriam Riyad, Center for Doctoral Studies on Health Sciences - Immunopathology [UH2C - Casablanca, Morocco], Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat]-Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco], Immunopathology of Infectious And Systemic Diseases [UH2C - Casablanca, Morocco], Laboratory of Cellular and Molecular Pathology [UH2C - Casablanca, Morocco], Université Hassan II [Casablanca] (UH2MC)-Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco]-Université Hassan II [Casablanca] (UH2MC)-Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Glia-Glia and Glia-Neuron Interactions in Neurophysiopathology Group (FR 3636), Fédération de Recherche en Neurosciences (FR 3636), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Medicine [Québec, QC, Canada], Université Laval [Québec] (ULaval)-Centre Hospitalier Universitaire de Québec Research Center [Canada], Laboratory of Parasitology [UH2C, Casablanca, Morocco], Faculty of Medicine and Pharmacy [UH2C, Casablanca, Morocco]-Université Hassan II [Casablanca] (UH2MC), Molecular Genetics and Immunophysiopathology [UH2C, Casablanca, Morocco], Health and Environment Laboratory [UH2C, Casablanca, Morocco], Faculté des Sciences Aïn Chock [Casablanca] (FSAC), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC)-Faculté des Sciences Aïn Chock [Casablanca] (FSAC), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), This study was supported by the Partenariat Hubert Curien (PHC) program (Volubilis, MA/11/262). JE also thanks the Canada Research Chair program for its financial assistance., Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco]-Hassan II University of Casablanca [Morocco], Hassan II University of Casablanca - UH2C [Morocco]-Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco]-Hassan II University of Casablanca - UH2C [Morocco]-Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco], Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Glia-Glia and Glia-Neuron Interactions in Neurophysiopathology Group ( FR 3636 ), Fédération de Recherche en Neurosciences ( FR 3636 ), 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 ), Laval University [Québec]-Centre Hospitalier Universitaire de Québec Research Center [Canada], Faculty of Medicine and Pharmacy [UH2C, Casablanca, Morocco]-Hassan II University of Casablanca - UH2C [Casablanca, Morocco], Faculty of Sciences, University Hassan II Ain Chock, Casablanca, Morocco-Faculty of Sciences, University Hassan II Ain Chock, Casablanca, Morocco, BMC, BMC, Faculty of Medicine and Pharmacy [UH2C - Casablanca, Morocco]- Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat], 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), and Université Hassan II [Casablanca] (UH2MC)-Faculty of Medicine and Pharmacy [UH2C, Casablanca, Morocco]

Subjects
0301 basic medicine, Leishmania tropica, [SDV]Life Sciences [q-bio], Leishmaniasis, Cutaneous, Antigens, Protozoan, Cell Line, lcsh:Infectious and parasitic diseases, Microbiology, Mice, 03 medical and health sciences, Cutaneous leishmaniasis, Zoonoses, Soluble Leishmania antigens, parasitic diseases, medicine, Animals, Macrophage, lcsh:RC109-216, Leishmania major, Amastigote, Infectivity, Microscopy, [ SDV ] Life Sciences [q-bio], biology, Research, NO donors, Nitric oxide, biology.organism_classification, medicine.disease, Leishmania, macrophages, 3. Good health, [SDV] Life Sciences [q-bio], Morocco, 030104 developmental biology, Infectious Diseases, Immunology, Protozoa, Parasitology
Abstract

International audience; BackgroundCutaneous leishmaniasis (CL) is a vector-borne parasitic disease caused by protozoa of the genus Leishmania. In Morocco, CL is a public health problem mainly caused by Leishmania major and Leishmania tropica, which are responsible for zoonotic and anthroponotic CL, respectively. Macrophages are the primary cells infected by Leishmania parasites and their capacity to produce nitric oxide (NO) is of critical importance for parasite elimination. To our knowledge, the role of NO on autochthonous infections has never been investigated before. In this study, we evaluated in vitro the capacity of autochthonous primary dermotropic strains of L. major and L. tropica to modulate NO production by J774-macrophages and determine the sensitivity of both species to exogenous NO.MethodsThe infectivity of the J774 cell line was analyzed by optical microscopy. NO production by macrophages was measured by the Griess method. The sensitivity to NO by the two strains was assessed by the MTT assay using NO donors.ResultsOur results show that the percentage of infected macrophages and the average number of parasites per macrophage were similar for L. major and L. tropica strains. While L. tropica significantly inhibited NO production induced by LPS and IFN-γ stimulation in J774 macrophages, L. major did not affect it. However, soluble Leishmania antigens (SLAs) from both autochthonous primary strains significantly inhibited the production of NO by J774-macrophages in a dose-dependent manner. Finally, our results demonstrated that promastigotes and amastigotes from both strains are sensitive to SNAP NO donor in a dose-dependent manner, although L. tropica demonstrated an increased sensitivity.ConclusionsOur results suggest a differential ability of L. major and L. tropica strains to modulate the capacity of macrophages to produce NO. The increased ability of L. tropica to inhibit NO production by macrophages might come as a necessity due to its higher sensitivity to NO donor. Our results provide one explanation for the tendency of L. tropica to cause chronic lesions and may contribute to the different physiopathology of CL in Morocco.

Published
2017

45. Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension

Author

Zsuzsanna Szankai, Jutta Bergler-Klein, Dominika Lukovic, Andreas Spannbauer, Mariann Gyöngyösi, Andras Jakab, Denise Traxler, Rita Garamvölgyi, Sandor Batkai, Johannes Winkler, Frederic Jaisser, Faiez Zannad, Katrin Zlabinger, Thomas Thum, Noemi Pavo, Ljubica Mandic, Alfred Gugerell, Gerald Maurer, Georg Goliasch, Levente Tóth, BMC, BMC, Department of Cardiology [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Institute of Diagnostic Imaging and Radiation Oncology [Kaposvar, Hungary], University of Kaposvar [Hungary], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institute for Molecular and Translational Therapeutic Strategies - IMTTS [Hannover, Germany], Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Medical University of Vienna, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -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 ), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Zurich, and Gyöngyösi, Mariann

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Sus scrofa, lcsh:Medicine, Hemodynamics, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, Ejection fraction, medicine.diagnostic_test, Aortic isthmus stenosis, Translational large animal model, General Medicine, 3. Good health, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], Cardiac hypertrophy, medicine.anatomical_structure, Disease Progression, Cardiology, medicine.medical_specialty, Aortography, Systole, Heart Ventricles, Hypertension, Pulmonary, Magnetic Resonance Imaging, Cine, 610 Medicine & health, Cardiomegaly, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Afterload, 1300 General Biochemistry, Genetics and Molecular Biology, Internal medicine, medicine.artery, Pressure, medicine, Animals, Pressure overload, [ SDV ] Life Sciences [q-bio], business.industry, Myocardium, Research, lcsh:R, Aortic Valve Stenosis, medicine.disease, Fibrosis, Capillaries, Disease Models, Animal, 030104 developmental biology, 10036 Medical Clinic, Ventricle, Heart failure, PET-MRI imaging, Pulmonary artery, Gene expression, business, Biomarkers
Abstract

Background Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs. Methods For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure–volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction. Results At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure (44.6 ± 5.1 vs 25.9 ± 6.2 mmHg, HYPI vs control, p

Published
2017

46. Motivators and barriers of tamoxifen use as risk-reducing medication amongst women at increased breast cancer risk: a systematic literature review

Author

Gillian Mitchell, Bettina Meiser, W. K. T. Wong, Claire Julian-Reynier, Judy Kirk, Michelle Peate, BMC, BMC, Prince of Wales Clinical School [Sydney, Australia], Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], School of Social Sciences [Kensington, Australia], Department of Obstetrics and Oncology [Melbourne, Australia], University of Melbourne-Royal Women’s Hospital [Melbourne, Australia], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Familial Cancer Service [Westmead, Australia], Westmead Hospital [Sydney], The Westmead Institute for Medical Research, Sir Peter MacCallum Department of Oncology [Parkville, VIC, Australia], University of Melbourne, Familial Cancer Centre [Melbourne, VIC, Australia], Peter MacCallum Cancer Centre [East Melbourne, Australia], and This work was funded by a Strategic Partnership Grant from Cancer Council of New South Wales (ID SRP 13–02). Bettina Meiser is supported Senior Research Fellowship Level B (ID 1078523) from the National Health and Medical Research Council Australia. Michelle Peate is currently supported by a National Breast Cancer Foundation Early Career Fellowship (ECG-15-005).

Subjects
Risk-reducing medication, Oncology, medicine.medical_specialty, lcsh:QH426-470, [SDV]Life Sciences [q-bio], MEDLINE, Review, PsycINFO, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, skin and connective tissue diseases, Genetics (clinical), High risk, business.industry, Prevention, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Risk perception, Clinical trial, lcsh:Genetics, Tamoxifen, Systematic review, Selective estrogen receptor modulator, 030220 oncology & carcinogenesis, Family medicine, business, medicine.drug
Abstract

International audience; AbstractBackgroundSelective estrogen receptor modulators, such as tamoxifen, reduce breast cancer risk by up to 50% in women at increased risk for breast cancer. Despite tamoxifen’s well-established efficacy, many studies show that most women are not taking up tamoxifen. This systematic literature review aimed to identify the motivators and barriers to tamoxifen use ‘s amongst high-risk women.MethodsUsing MEDLINE, PsycINFO, and Embase plus reviewing reference lists of relevant articles published between 1995 and 2016, 31 studies (published in 35 articles) were identified, which addressed high-risk women’s decisions about risk-reducing medication to prevent breast cancer and were peer-reviewed primary clinical studies.ResultsA range of factors were identified as motivators of, and barriers to, tamoxifen uptake including: perceived risk, breast-cancer-related anxiety, health professional recommendation, perceived drug effectiveness, concerns about side-effects, knowledge and access to information about side-effects, beliefs about the role of risk-reducing medication, provision of a biomarker, preference for other forms of breast cancer risk reduction, previous treatment experience, concerns about randomization in clinical trial protocols and finally altruism.ConclusionsResults indicate that the decision for high-risk women regarding tamoxifen use or non-use as a risk-reducing medication is not straightforward. Support of women making this decision is essential and needs to encompass the full range of factors, both informational and psychological.

Published
2017

47. Evidence-based practice within nutrition

Author

Janus Christian Jakobsen, Martine Laville, Yves Boirie, Vittorio Bertele, Snezana Djurisic, Ana Rath, Christine Kubiak, Jacques Demotes-Mainard, Carlo La Vecchia, Cristina Ruano-Rodríguez, Christian Gluud, Annemie M. W. J. Schols, Silvio Garattini, Berenice Segrestin, Michael J Hiesmayr, Lluis Serra-Majem, Edmund Neugebauer, Maud Alligier, BMC, BMC, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CIBER Fisiopatología de la Obesidad y Nutrición [Madrid, Spain] ( (CIBEROBN)), Instituto de Salud Carlos III [Madrid] (ISC), Nutrition Research Group [Las Palmas, Spain] (Research Institute of Biomedical and Health Sciences), University of Las Palmas de Gran Canaria [Spain] (ULPGC), Division of Cardiac, Thoracic, Vascular Anaesthesia and Intensive Care [Vienna, Austria], Vienna General Hospital Währinger Gürtel, Department of Respiratory Medicine [Maastricht, The Netherlands], University Medical Centre Maastricht-NUTRIM School of Nutrition and Translational Research in Metabolism [Maastricht, The Netherlands], Department of Clinical Sciences and Community Health [Milan, Italy], Università degli Studi di Milano = University of Milan (UNIMI), Service de Nutrition Clinique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Brandenburg Medical School [Witten, Germany], Witten/Herdecke University, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], European Clinical Research Infrastructures Network [Paris] (ECRIN), Ecrin, Copenhagen Trial Unit -CTU [Copenhagen, Denmark] (Centre for Clinical Intervention Research), Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital-Copenhagen University Hospital, Department of Cardiology [Holbaek, Denmark], Holbæk Hospital [Denmark], The ECRIN-IA grant from the EU FP7 (GA 284395) provided support for meetings and for the conduct of this review. The Mario Negri Institute housed the ECRIN-IA meeting in February 2013., French-Clinical Research Infrastructure Network [Lyon] (FCRIN INI-CRCT - Coordination Nationale Réseau FORCE), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Instituto de Salud Carlos III (ISC), Università degli studi di Milano [Milano], Service de nutrition clinique [CHU Gabriel Montpied, Clermont-Ferrand], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Rigshospitalet [Copenhagen]-Copenhagen University Hospital, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Università degli Studi di Milano [Milano] (UNIMI), Copenhagen University Hospital-Rigshospitalet [Copenhagen], and Copenhagen University Hospital-Copenhagen University Hospital

Subjects
0301 basic medicine, Research design, Databases, Factual, [SDV]Life Sciences [q-bio], méthodologie de recherche, Medicine (miscellaneous), Review, Evidence-based clinical practice, 0302 clinical medicine, approche nutritionnelle, Medicine, EPIDEMIOLOGY, Nutritional Physiological Phenomena, Pharmacology (medical), Registries, 030212 general & internal medicine, Randomized Controlled Trials as Topic, 2. Zero hunger, RISK, lcsh:R5-920, Randomised clinical trials, CANCER, 3. Good health, [SDV] Life Sciences [q-bio], MEDITERRANEAN DIET, Treatment Outcome, Research Design, Evidence-based medicine, Assessment, Specific barriers, Nutrition, ECRIN, European Clinical Infrastructure Network, Alimentation et Nutrition, SURVIVAL, Nutrition Therapy, HEALTH, lcsh:Medicine (General), COUNTRIES, Blinding, Evidence-based practice, Endpoint Determination, Médecine humaine et pathologie, Context (language use), Clinical nutrition, 03 medical and health sciences, ADHERENCE, FOOD, Humans, Food and Nutrition, étude clinique, Medical education, 030109 nutrition & dietetics, business.industry, Clinical study design, Diet, Clinical trial, Nutrition Assessment, PROSPECTIVE COHORT, Human health and pathology, business
Abstract

Background Evidence-based clinical research poses special barriers in the field of nutrition. The present review summarises the main barriers to research in the field of nutrition that are not common to all randomised clinical trials or trials on rare diseases and highlights opportunities for improvements. Methods Systematic academic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Results Many nutrients occur in multiple forms that differ in biological activity, and several factors can alter their bioavailability which raises barriers to their assessment. These include specific difficulties with blinding procedures, with assessments of dietary intake, and with selecting appropriate outcomes as patient-centred outcomes may occur decennia into the future. The methodologies and regulations for drug trials are, however, applicable to nutrition trials. Conclusions Research on clinical nutrition should start by collecting clinical data systematically in databases and registries. Measurable patient-centred outcomes and appropriate study designs are needed. International cooperation and multistakeholder engagement are key for success. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2160-8) contains supplementary material, which is available to authorized users.

Published
2017

48. Atypical, non-standard functions of the microtubule associated Tau protein

Author

Maria Grazia Spillantini, David Blum, Eckhard Mandelkow, Efthimios M. C. Skoulakis, Susanne Wegmann, Carmen Laura Sayas, Ioannis Sotiropoulos, Eva-Maria Mandelkow, Jesús Avila, Mahmoud Bukar Maina, Marie-Christine Galas, Luc Buée, Amrit Mudher, Joana Silva, Nuno Sousa, Miguel Medina, Sotiropoulos, Ioannis [0000-0003-0115-0038], Apollo - University of Cambridge Repository, Life and Health Sciences Research Institute [Braga] (ICVS), University of Minho [Braga], ICVS/3B's [Braga, Portugal], PT Government Associate Laboratory, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Division of Neuroscience [Vari, Greece], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Alzheimer’s Disease Research Laboratory [Charlestown, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Life Sciences [Brighton, East Sussex, UK], University of Sussex, Centre for Biomedical Research of the Canary Islands - CIBICAN [Tenerife, Spain], Institute for Biomedical Technologies - ITB [Tenerife, Spain]-Universidad de La Laguna [Tenerife, Spain], Dendrite Differenciation Group [DZNE - Bonn], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Queen Sofia Foundation Alzheimer Center [Madrid, Spain] (CIEN Foundation), Faculty of Natural and Environmental Sciences [Southampton, UK] (Center for Biological Sciences), University of Southampton, 1st EuroTau meeting has been funded by French academic funds and charities/foundations such as Fondation Plan Alzheimer, LabEx DISTALZ, LiCEND Centre of Excellence, SFR DN2M - University of Lille., Universidade do Minho, Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'électromagnétisme et d'acoustique (LEMA - EPFL), Ecole Polytechnique Fédérale de Lausanne (EPFL), Universidad de La Laguna [Tenerife - SP] (ULL), CBM Severo Ochoa, Universidad Autonoma de Madrid (UAM), BMC, BMC, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Universidad de La Laguna [Tenerife - SP] (ULL)-Institute for Biomedical Technologies - ITB [Tenerife, Spain], Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Universidade do Minho = University of Minho [Braga], Universidad Autónoma de Madrid (UAM), and Blum, David

Subjects
0301 basic medicine, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Medicina Básica [Ciências Médicas], Excitotoxicity, Disease, Review, medicine.disease_cause, Tau, Alzheimer’s disease, lcsh:RC346-429, Synapse, Epilepsy, 0302 clinical medicine, Pathology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcellular localization, 3. Good health, [SDV] Life Sciences [q-bio], Tau isoform, Ciências Médicas::Medicina Básica, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer’s disease, metabolism [Alzheimer Disease], medicine.medical_specialty, Tau protein, tau Proteins, Nucleus, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Microtubule, Alzheimer Disease, Neuroplasticity, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:610, lcsh:Neurology. Diseases of the nervous system, Science & Technology, business.industry, Dendrites, medicine.disease, metabolism [tau Proteins], 030104 developmental biology, biology.protein, Neurology (clinical), Tau, business, Neuroscience, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Neuronal function
Abstract

Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau's role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system., 1st EuroTau meeting has been funded by French academic funds and charities/foundations such as Fondation Plan Alzheimer, LabEx DISTALZ, LiCEND Centre of Excellence, SFR DN2M - University of Lille, info:eu-repo/semantics/publishedVersion

Published
2017

49. Hospital quality measures: are process indicators associated with hospital standardized mortality ratios in French acute care hospitals?

Author

Catherine Grenier, Isabelle Evrard, Marie-Annick Le-Pogam, Marcus Ngantcha, Agathe Lamarche-Vadel, Grégoire Rey, Sophie Calmus, Centre d'épidémiologie sur les causes médicales de décès (CépiDc), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Social and Preventive Medicine [Lausanne, Switzerland], Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Haute Autorité de Santé [Saint-Denis La Plaine] (HAS), Interactions et dynamique des environnements de surface (IDES), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), The funders were public organisms that had no financial interest in the results of the study: the French National Authority for Health (HAS) and the National Institute of Health and Medical Research (INSERM). The study was financed by these two institutions to assess the potential association between Hospital Process Indicators and Hospital Standardized Mortality Ratios in order to improve the understandings of quality of care phenomenon especially in the French context. HAS provided hospital process indicators and selection criteria and funded the data analysis., BMC, BMC, and Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Hospital Standardized Mortality Ratio, Health informatics, Health administration, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Acute care, Environmental health, medicine, Humans, 030212 general & internal medicine, Poisson regression, Hospital Mortality, education, Quality Indicators, Health Care, Quality of Health Care, education.field_of_study, Hospital Process Indicators, business.industry, 030503 health policy & services, Health Policy, Nursing research, Medical record, Public health, Quality of care, medicine.disease, Hospitals, 3. Good health, Hospitalization, [SDV] Life Sciences [q-bio], France/epidemiology, Hospitals/standards, Hospitals/statistics & numerical data, Quality Indicators, Health Care/standards, SIMEX method, symbols, Medical emergency, France, 0305 other medical science, business, Research Article
Abstract

Background Results of associations between process and mortality indicators, both used for the external assessment of hospital care quality or public reporting, differ strongly across studies. However, most of those studies were conducted in North America or United Kingdom. Providing new evidence based on French data could fuel the international debate on quality of care indicators and help inform French policy-makers. The objective of our study was to explore whether optimal care delivery in French hospitals as assessed by their Hospital Process Indicators (HPIs) is associated with low Hospital Standardized Mortality Ratios (HSMRs). Methods The French National Authority for Health (HAS) routinely collects for each hospital located in France, a set of mandatory HPIs. Five HPIs were selected among the process indicators collected by the HAS in 2009. They were measured using random samples of 60 to 80 medical records from inpatients admitted between January 1st, 2009 and December 31, 2009 in respect with some selection criteria. HSMRs were estimated at 30, 60 and 90 days post-admission (dpa) using administrative health data extracted from the national health insurance information system (SNIIR-AM) which covers 77% of the French population. Associations between HPIs and HSMRs were assessed by Poisson regression models corrected for measurement errors with a simulation-extrapolation (SIMEX) method. Results Most associations studied were not statistically significant. Only two process indicators were found associated with HSMRs. Completeness and quality of anesthetic records was negatively associated with 30 dpa HSMR (0.72 [0.52–0.99]). Early detection of nutritional disorders was negatively associated with all HSMRs: 30 dpa HSMR (0.71 [0.54–0.95]), 60 dpa HSMR (0.51 [0.39–0.67]) and 90 dpa HSMR (0.52 [0.40–0.68]). Conclusion In absence of gold standard of quality of care measurement, the limited number of associations suggested to drive in-depth improvements in order to better determine associations between process and mortality indicators. A smart utilization of both process and outcomes indicators is mandatory to capture aspects of the hospital quality of care complexity. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-2534-3) contains supplementary material, which is available to authorized users.

Published
2017

50. Associations of cause-specific mortality with area level deprivation and travel time to health care in France from 1990 to 2007, a multilevel analysis

Author

Ghosn, Walid, Menvielle, Gwenn, Rican, Stéphane, Rey, Grégoire, Centre d'épidémiologie sur les causes médicales de décès (CépiDc), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Dynamiques Sociales et Recomposition des Espaces (LADYSS), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was financed by Cancéropôle Île-de-France (Grant Number: 2012–1-PL SHS-05-INSERM 11–1) and GIS-IReSp (Grant Number: A11226LS)., Université Paris Diderot - Paris 7 (UPD7)-Université Paris Nanterre (UPN)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, BMC, and PRIEUR, Cha

Subjects
Deprivation, [SHS.STAT]Humanities and Social Sciences/Methods and statistics, [SHS.GEO] Humanities and Social Sciences/Geography, lcsh:Public aspects of medicine, [SDV]Life Sciences [q-bio], lcsh:RA1-1270, [SHS.GEO]Humanities and Social Sciences/Geography, [SDV] Life Sciences [q-bio], Travel time to health care, [SHS.STAT] Humanities and Social Sciences/Methods and statistics, Geographical mortality disparities, Cause-specific mortality, Contextual association, Research Article
Abstract

Background It is now widely accepted that social and physical environment participate in shaping health. While mortality is used to guide public health policies and is considered as a synthetic measure of population health, few studies deals with the contextual features potentially associated with mortality in a representative sample of an entire country. This paper investigates the possible role of area deprivation (FDep99) and travel time to health care on French cause-specific mortality in a proper multilevel setting. Methods The study population was a 1% sample representative of the French population aged from 30 to 79 years in 1990 and followed up until 2007. A frailty Cox model was used to measure individual, contextual effects and spatial variances for several causes of death. The chosen contextual scale was the Zone d’Emploi of 1994 (348 units) which delimits the daily commute of people. The geographical accessibility to health care score was constructed with principal component analysis, using 40 variables of hospital specialties and health practitioners’ travel time. Results The outcomes highlight a positive and significant association between area deprivation and mortality for all causes (HR = 1.24), cancers, cerebrovascular diseases, ischemic heart diseases, and preventable and amenable diseases (HR from 1.14 to 1.29). These contextual associations exhibit no substantial differences by sex except for premature ischemic heart diseases mortality which was much greater in women. Unexpectedly, mortality decreased as the time to reach health care resources increased. Only geographical disparities in cerebrovascular and ischemic heart diseases mortality were explained by compositional and contextual effects. Discussion The findings suggest the presence of confounding factors in the association between mortality and travel time to health care, possibly owing to population density and health-selected migration. Although the spatial scale considered to define the context of residence was relatively large, the associations with area deprivation were strong in comparison to the existing literature and significant for almost all the causes of deaths investigated. Conclusion The broad spectrum of diseases associated with area deprivation and individual education support the idea of a need for a global health policy targeting both individual and territories to reduce social and socio-spatial inequalities. Electronic supplementary material The online version of this article (doi:10.1186/s12889-017-4562-7) contains supplementary material, which is available to authorized users.

Published
2017

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