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6,925 results on '"University Medical Center Göttingen"'

1. Ultrahypofractionated, Adaptive Radiation Therapy of Prostate Cancer (ultraHART)

Author: University Hospital Schleswig-Holstein, Klinikum Stuttgart, University Medical Center Göttingen, and Georg Wurschi, Principal Investigator
Published: 2024

2. Efficacy of MindAhead's Digital Behavioral Activation Therapy in Adults With MCI or Mild Dementia

Author: University Medical Center Göttingen
Published: 2024

3. Pancreatitis - Microbiome As Predictor of Severity (P-MAPS)

Author: Department of Medicine II, University Hospital Rostock, Medical Department II, Division of Gastroenterology, University Hospital of Leipzig, Department of Medicine II, University Hospital, LMU Munich, Department of Medicine I, University Hospital of Halle, Department of Medicine A, University Medicine Greifswald, Department of Medicine II, University Hospital rechts der Isar, Technical University Munich, Department of Medical Bioinformatics, University Medical Center Göttingen, Department if Medical Statistics, University Medical Center Göttingen, and Albrecht Neesse, Prof. Dr. Dr.
Published: 2024

4. CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome

Author: Marius Ringelstein, L. M. Yshii, Ilka Kleffner, Stephen W. Reddel, Brigitte Wildemann, Todd A. Hardy, Markus Schwaninger, Guillaume Martin-Blondel, Nicholas Schwab, Delphine Loussouarn, John Parratt, Marc Pawlitzki, Henrike Plate, Eduardo Beltrán, Catharina C. Gross, Anna R. Tröscher, Tanja Kuhlmann, Tilman Schneider-Hohendorf, Klaus Dornmair, Jan Dörr, Roland S. Liblau, Urvashi Bhatia, Hans Lassmann, Sven G. Meuth, Luisa Klotz, Sebastian Herich, Markus Kraemer, Jan Bauer, Céline Meyer, David-Axel Laplaud, Wolfgang Brück, Romana Höftberger, Michael Barnett, Michael E. Buckland, Andreas Schulte-Mecklenbeck, Heinz Wiendl, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medizinische Universität Wien = Medical University of Vienna, Institute for Experimental and Clinical Pharmacology and Toxicology [Lübeck, Germany], University of Lübeck [Germany], Institute of Neuropathology [Göttingen, Germany], University Medical Center Göttingen (UMG), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d’Anatomopathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Royal North Shore Hospital [Sydney, Australia], Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], The University of Sydney, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Heidelberg, Medical Faculty, University of Vienna [Vienna], Institute of Clinical Neuroimmunology [Munich, Germany], Ludwig-Maximilians University [Munich] (LMU), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Le Bihan, Sylvie, MECANISMES INTEGRES DE L'INFLAMMATION - Infiltration tissulaire des macrophages et inflammation : identification d'inhibiteurs de la migration cellulaire en trois dimensions. - - MigreFlame2010 - ANR-10-MIDI-0013 - MI2 - VALID, Blanc 2013 - Migration des lymp^hocytes T CD8 T dans le système nerveux central - - T cell Mig2013 - ANR-13-BSV3-0003 - Blanc 2013 - VALID, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Ruhr University Bochum (RUB), Universitätsklinikum Knappschaftskrankenhaus = University Hospital Knappschaftskrankenhaus [Bochum], Universität zu Lübeck = University of Lübeck [Lübeck], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Royal North Shore Hospital (RNSH), Royal Prince Alfred Hospital [Sydney, Australia], Ludwig-Maximilians-Universität München (LMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-10-MIDI-0013,MigreFlame,Infiltration tissulaire des macrophages et inflammation : identification d'inhibiteurs de la migration cellulaire en trois dimensions.(2010), ANR-13-BSV3-0003,T cell Mig,Migration des lymp^hocytes T CD8 T dans le système nerveux central(2013), Centre de Physiopathologie Toulouse Purpan (CPTP - U1043 INSERM - UMR5282 CNRS - UT3), University Medical Center Göttingen [Germany], Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, and Service des maladies infectieuses et tropicales[Toulouse]
Subjects: 0301 basic medicine, MESH: Integrin alpha4 / metabolism, [SDV]Life Sciences [q-bio], Neuroimmunology, General Physics and Astronomy, Autoimmunity, 0302 clinical medicine, Natalizumab, Cytotoxic T cell, MESH: Animals, lcsh:Science, MESH: Endothelium, Vascular / drug effects, Multidisciplinary, MESH: Central Nervous System / immunology, MESH: Endothelium, Vascular / pathology, MESH: Microvessels / pathology, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MESH: Cell Adhesion / drug effects, [SDV.IMM]Life Sciences [q-bio]/Immunology, Function and Dysfunction of the Nervous System, MESH: Central Nervous System / pathology, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, Science, Central nervous system, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, MESH: Microvessels / immunology, medicine, MESH: Cell Adhesion / immunology, Neuroinflammation, Susac Syndrome, MESH: Central Nervous System / blood suppl, MESH: Humans, business.industry, MESH: Adult, General Chemistry, MESH: Integrin alpha4 / antagonists & inhibitors, MESH: Male, Granzyme B, Susac syndrome, neuro-inflammation, endotheliopathy, 030104 developmental biology, Immunology, lcsh:Q, MESH: Endothelium, Vascular / immunology, MESH: Microvessels / drug effects, MESH: Disease Models, Animal, business, MESH: Female, 030217 neurology & neurosurgery, CD8
Abstract: International audience; Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
Published: 2019
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5. RNA editing alterations define manifestation of prion diseases

Author: Orr Shormoni, Inga Zerr, Katrin Thüne, Eirini Kanata, Juan Carlos Espinosa, Franc Llorens, Matthias Schmitz, Olivier Andreoletti, Athanasios Dimitriadis, Vincenzo Capece, Nikolaos Bekas, Stefan Bonn, Dimitra Dafou, Alba Marín-Moreno, Juan María Torres, Isidre Ferrer, Konstantinos Xanthopoulos, Theodoros Sklaviadis, Aristotle University of Thessaloniki, Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki-Aristotle University of Thessaloniki-School of Health Sciences, Aristotle University of Thessaloniki-Aristotle University of Thessaloniki, Institute of Health Carlos III, Network Center for Biomedical Research of Neurodegenerative Diseases, University Medical Center Göttingen (UMG), Department of Genetics, Development and Molecular Biology, School of Biology, Faculty of Sciences, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, Centro de Investigacion en Sanidad Animal (INIA-CISA), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), Institute Developmental Biochemistry, Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen (UMG)-University Medical Center Göttingen (UMG), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-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, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona (UB), This study was supported by the Research Funding program ARISTEIA II (Grant RNA edit 3739), cofinanced by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (to T.S.), the Alliance BioSecure Foundation project 'RNA editing in CJD' (T.S. and I.Z.), Federal Ministry of Education and Research grants within the German Network for Degenerative Dementia (to I.Z.), the Red Nacional de Priones AGL2015-71764-REDT-MINECO (to F.L., I.Z., J.M.T., and I.F.), the Spanish Ministry of Health-Instituto Carlos III/Fondo Social Europeo CP16/00041 (to F.L.), by the IKYDA Greek-German collaboration Project 57260006 (to F.L., I.Z., D.D., and T.S.), and and in part by Grant AGL2016-78054-R (AEI/FEDER, UE).
Subjects: RNA editing, genetics [Transcriptome], Disease, genetics [Gene Expression Regulation], Creutzfeldt-Jakob Syndrome, Transcriptome, Mice, [SPI]Engineering Sciences [physics], 0302 clinical medicine, Pathogen, 0303 health sciences, Multidisciplinary, Brain, genetics [Creutzfeldt-Jakob Syndrome], Biological Sciences, 3. Good health, medicine.anatomical_structure, PNAS Plus, Disease Progression, ER-stress, Neuropathogenesis, ddc:500, metabolism [Prion Diseases], Genotype, Prions, physiology [RNA Editing], RNA-sequencing, sporadic Creutzfeldt-Jakob disease, Context (language use), Biology, Prion Proteins, 03 medical and health sciences, Lysosome, genetics [Prion Diseases], medicine, Animals, Humans, 030304 developmental biology, Gene Expression Profiling, sporadic Creutzfeldt–Jakob disease, genetics [RNA Editing], prion diseases, Disease Models, Animal, Gene Expression Regulation, metabolism [Brain], Immunology, metabolism [Prions], Unfolded protein response, genetics [Prion Proteins], 030217 neurology & neurosurgery, methods [Gene Expression Profiling], Neuroscience
Abstract: Significance Prion diseases are fatal neurodegenerative disorders characterized by rapidly progressive dementia. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most prevalent. We report that, specific gene-expression alterations utilizing a reliable in vivo mouse model (tg340-PRNP129MM) with sCJD MM1 subtype, correlate with human disease manifestations in the brain cortex related to disease progression. RNA-editing functions mediated by the APOBEC and ADAR deaminases possibly affecting protein expression necessary for normal brain function, are altered in disease stages. Our data provide powerful evidence, derived from a humanized sCJD mouse model and human autopsy material, discerning the critical role of gene expression and RNA-editing signatures, introducing disease-associated targets that can be extrapolated in other neurodegenerative disorders with common clinical and molecular features., Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt–Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
Published: 2019
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6. A greener path for the EU common agricultural policy

Author: Stefan Schindler, Aletta Bonn, Jenny Schmidt, Sebastian Lakner, Robert Müller, Vasileios Bontzorlos, Dagmar Clough, Guy Pe'er, Gioele Passoni, Christian Schleyer, Yves Zinngrebe, Stefan Möckel, Bernd Hansjürgens, Peter Bezák, Francisco Moreira, Clélia Sirami, Angela Lomba, Dept Ecosystem Serv, Helmholtz Ctr Environm Res, Dept Econ, Helmholtz Ctr Environm Res, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), German Centre for Integrative Biodiversity Research, Dept Agr Econ & Rural Dev, University Medical Center Göttingen (UMG), Sch Agron, CIBIO InBIO, University of Lisbon, Dynamiques Forestières dans l'Espace Rural (DYNAFOR), Institut National de la Recherche Agronomique (INRA)-École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Div Conservat Biol Vegetat & Landscape Ecol, University of Vienna [Vienna], Bridge Builders UG, Social Science Research Center Berlin, Dept Forestry & Management Nat Environm, University of Thessaly, Ctr Environm & Climate Res, Lund University, Inst Landscape Ecol, Slovak Academy of Sciences (SAS), Inst Biodivers, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Fac Law & Econ, Martin Luther University Halle Wittenberg, Res Ctr Biodivers & Genet Resources CIBIO, Res Network Biodivers & Evolut Biol InBIO, Universidade do Porto, Dept Environm & Planning Law, Helmholtz Ctr Environm Res, Dept Econ, DTP Environm Res, University of Oxford [Oxford], Sect Int Agr Policy & Environm Governance, University of Kassel, Inst Geog, Universität Augsburg [Augsburg], Inst Ecol, Fac Sustainabil, Leuphana University of Lüneburg, Dept Environm Polit, Helmholtz Ctr Environm Res, CoKnow Consulting, Helmholtz Centre for Environmental Research (UFZ), University Medical Center Göttingen, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure Agronomique de Toulouse-Institut National Polytechnique (Toulouse) (Toulouse INP), University of Vienna, Slovak Academy of Sciences, Friedrich Schiller University of Jena, University of Porto, and University of Oxford
Subjects: 2. Zero hunger, Multidisciplinary, 010504 meteorology & atmospheric sciences, Ecology (disciplines), [SDV]Life Sciences [q-bio], Agriculture, 010501 environmental sciences, 15. Life on land, Environmental economics, Sustainable Development, 01 natural sciences, 7. Clean energy, 13. Climate action, 11. Sustainability, Path (graph theory), Business, European Union, Common Agricultural Policy, Biology, 0105 earth and related environmental sciences
Abstract: The Common Agricultural Policy (CAP) of the European Union (EU) is one of the world's largest agricultural policies and the EU's longest-prevailing one. Originally focused mostly on supporting production and farm income, the CAP has progressively integrated instruments to support the environment. Nonetheless, there is considerable agreement among EU citizens that the CAP still does not do enough to address ongoing environmental degradation and climate change (92% of nonfarmers, 64% of farmers) (1). In May and June 2018, the European Commission (EC) published the financial plan and legislative proposal for the CAP post-2020 (2), prompting numerous proposed amendments that the newly elected European Parliament (EP) will now have to consider. With an eye toward the next and final reform stages, including budget discussions and “trilogue” negotiations between the EC, the Council, and the EP to begin in autumn 2019, we examine whether the proposed post-2020 CAP can address key sustainability issues and meet societal demands for higher environmental performance.
Published: 2019
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7. Molecular and clinical diversity in primary central nervous system lymphoma

Author: Hernández-Verdin, I., Kirasic, E., Wienand, K., Mokhtari, K., Eimer, S., Loiseau, H., Rousseau, A., Paillassa, J., Ahle, G., Lerintiu, F., Uro-Coste, E., Oberic, L., Figarella-Branger, D., Chinot, O., Gauchotte, G., Taillandier, L., Marolleau, J.-P., Polivka, M., Adam, C., Ursu, R., Schmitt, A., Barillot, N., Nichelli, L., Lozano-Sánchez, F., Ibañez-Juliá, M.-J., Peyre, M., Mathon, B., Abada, Y., Charlotte, F., Davi, F., Stewart, C., de Reyniès, A., Choquet, S., Soussain, C., Houillier, C., Chapuy, B., Hoang-Xuan, K., Alentorn, A., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Göttingen (UMG), Freie Universität Berlin, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Bordeaux [Bordeaux], Imagerie moléculaire et thérapies innovantes en oncologie (IMOTION), Université de Bordeaux (UB), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Hôpitaux Civils de Colmar, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Institut Bergonié [Bordeaux], UNICANCER, Sorbonne Université (SU), Centre Hospitalier Saint Jean de Perpignan, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Curie - Saint Cloud (ICSC), DESSAIVRE, Louise, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [CHRU Nancy], and École pratique des hautes études (EPHE)
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Oncology, tumor heterogeneity, Hematology, multi-omics, microenvironment, PCNSL, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data.Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue.The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.
Published: 2023
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8. Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Author: Lalive, Patrice, Kreutzfeldt, Mario, Devergne, Odile, Metz, Imke, Bruck, Wolfgang, Merkler, Doron, Pot, Caroline, BMC, BMC, Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Neuropathology [Göttingen, Germany], University Medical Center Göttingen (UMG), Department of Clinical Neurosciences [Lausanne, Switzerland] (Division of Neurology and Neuroscience Research Center), Laboratories of Neuroimmunology [Lausanne, Switzerland], Lausanne University Hospital-Lausanne University Hospital, P.H.L. received support from the Swiss National Foundation (#310030-153164), D.M. receives support by the Swiss National Science Foundation (310030_173010), and C.P. holds stipendiary professorships of the Swiss National Science Foundation (No. PP00P3_157426). P.H.L., D.M. and C.P. received supports from the Swiss Multiple Sclerosis Society., University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Lausanne University Hospital [Switzerland]-Lausanne University Hospital [Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] ( Division of Neurology ), Department of Pathology and Immunology [Geneva, Switzerland] ( Clinical Pathology Division ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University Medical Center Göttingen [Germany], and Department of Clinical Neurosciences [Lausanne, Switzerland] ( Division of Neurology and Neuroscience Research Center )
Subjects: Adult, Central Nervous System, Male, Interleukin-27, Astrocytes/metabolism, Astrocytes/pathology, Central Nervous System/metabolism, Central Nervous System/pathology, Female, Glial Fibrillary Acidic Protein/metabolism, Humans, Interleukin-27/blood, Interleukin-27/cerebrospinal fluid, Interleukin-27/metabolism, Interleukins/metabolism, Middle Aged, Minor Histocompatibility Antigens/metabolism, Multiple Sclerosis/pathology, Oligoclonal Bands/metabolism, Severity of Illness Index, Statistics, Nonparametric, Young Adult, Cerebrospinal fluid, Cytokines, Immunohistochemistry, Multiple sclerosis, [SDV]Life Sciences [q-bio], ddc:616.07, lcsh:RC346-429, Minor Histocompatibility Antigens, Glial Fibrillary Acidic Protein, lcsh:Neurology. Diseases of the nervous system, [ SDV ] Life Sciences [q-bio], Interleukins, Research, Oligoclonal Bands, ddc:616.8, [SDV] Life Sciences [q-bio], Astrocytes
Abstract: Background Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients. Methods In this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions. Results We observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients. Conclusions Our results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation’s resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.
Published: 2017
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9. Dose-finding methods for Phase I clinical trials using pharmacokinetics in small populations

Author: Ursino, Moreno, Zohar, Sarah, Lentz, Frederike, Alberti, Corinne, Friede, Tim, Stallard, Nigel, Comets, Emmanuelle, 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 de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), 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), University Medical Center Göttingen (UMG), Statistics and Epidemiology Unit [Coventry, UK] (Division of Health Sciences), University of Warwick [Coventry]-Warwick Medical School, University of Warwick [Coventry], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), 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), Seventh Framework Programme. Grant Number: FP HEALTH 2013-602144, European Project: 602144,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,INSPIRE(2014), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris]-Université Paris Diderot - Paris 7 (UPD7), and University Medical Center Göttingen
Subjects: Population Density, RM, Dose‐finding, Clinical Trials, Phase I as Topic, Maximum Tolerated Dose, [SDV]Life Sciences [q-bio], Dose-finding, Dose‐toxicity relationship, Research Design, Dose-toxicity relationship, Phase I clinical trials, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, Computer Simulation, Pharmacokinetics, General, Research Paper
Abstract: International audience; The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose-finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker-defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose-finding and PK analyses to allow better estimation of the dose-toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose-finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose-toxicity curve while maintaining the performance in terms of MTD selection compared to dose-finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose-toxicity relationship, facilitating better dose recommendation for subsequent trials.
Published: 2017
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10. Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions

Author: Unkel, Steffen, Röver, Christian, Stallard, Nigel, Benda, Norbert, Posch, Martin, Zohar, Sarah, Friede, Tim, University Medical Center Göttingen, Warwick Medical School, University of Warwick [Coventry], Federal Institute for Drugs and Medical Devices (BfArM), Medizinische Universität Wien = 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 ), University Medical Center Göttingen (UMG), Federal Institute of Drugs and Medical Devices [Bonn], 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), HAL UPMC, Gestionnaire, and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: FOS: Computer and information sciences, Medicine(all), [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Paediatric multiple sclerosis, Quantitative Biology - Quantitative Methods, Statistics - Applications, Creutzfeldt-Jakob disease, Rare diseases, Clinical trials, Evidence synthesis, FOS: Biological sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Systematic review, Applications (stat.AP), Genetics(clinical), Pharmacology (medical), Quantitative Methods (q-bio.QM), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, RC
Abstract: BACKGROUND: Randomized controlled trials (RCTs) are the gold standard design of clinical research to assess interventions. However, RCTs cannot always be applied for practical or ethical reasons. To investigate the current practices in rare diseases, we review evaluations of therapeutic interventions in paediatric multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD). In particular, we shed light on the endpoints used, the study designs implemented and the statistical methodologies applied. METHODS: We conducted literature searches to identify relevant primary studies. Data on study design, objectives, endpoints, patient characteristics, randomization and masking, type of intervention, control, withdrawals and statistical methodology were extracted from the selected studies. The risk of bias and the quality of the studies were assessed. RESULTS: Twelve (seven) primary studies on paediatric MS (CJD) were included in the qualitative synthesis. No double-blind, randomized placebo-controlled trial for evaluating interventions in paediatric MS has been published yet. Evidence from one open-label RCT is available. The observational studies are before-after studies or controlled studies. Three of the seven selected studies on CJD are RCTs, of which two received the maximum mark on the Oxford Quality Scale. Four trials are controlled observational studies. CONCLUSIONS: Evidence from double-blind RCTs on the efficacy of treatments appears to be variable between rare diseases. With regard to paediatric conditions it remains to be seen what impact regulators will have through e.g., paediatric investigation plans. Overall, there is space for improvement by using innovative trial designs and data analysis techniques., Comment: 11 pages, 2 figures, 3 tables
Published: 2016
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11. Combined fibre atrophy and decreased muscle regeneration capacity driven by mitochondrial DNA alterations underlie the development of sarcopenia

Author: Sammy Kimoloi, Ayesha Sen, Stefan Guenther, Thomas Braun, Tobias Brügmann, Philipp Sasse, Rudolf J. Wiesner, David Pla‐Martín, Olivier R. Baris, Baris, Olivier, University of Cologne, Masinde Muliro University of Science and Technology [Kakamega, Kenya], Max Planck Institute for Heart and Lung Research (MPI-HLR), Max-Planck-Gesellschaft, University Medical Center Göttingen (UMG), University of Bonn, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Sarcopenia, [SDV]Life Sciences [q-bio], mtDNA deletions, DNA, Mitochondrial, Mitochondria, [SDV] Life Sciences [q-bio], Mice, Myofibres, Satellite cells, Physiology (medical), Muscle stem cells, Animals, Regeneration, Orthopedics and Sports Medicine, Muscle, Skeletal, Mutations
Abstract: International audience; BackgroundMitochondrial dysfunction caused by mitochondrial (mtDNA) deletions have been associated with skeletal muscle atrophy and myofibre loss. However, whether such defects occurring in myofibres cause sarcopenia is unclear. Also, the contribution of mtDNA alterations in muscle stem cells (MuSCs) to sarcopenia remains to be investigated.MethodsWe expressed a dominant-negative variant of the mitochondrial helicase, which induces mtDNA alterations, specifically in differentiated myofibres (K320Eskm mice) and MuSCs (K320Emsc mice), respectively, and investigated their impact on muscle structure and function by immunohistochemistry, analysis of mtDNA and respiratory chain content, muscle transcriptome and functional tests.ResultsK320Eskm mice at 24 months of age had higher levels of mtDNA deletions compared with controls in soleus (SOL, 0.07673% vs. 0.00015%, P = 0.0167), extensor digitorum longus (EDL, 0.0649 vs. 0.000925, P = 0.0015) and gastrocnemius (GAS, 0.09353 vs. 0.000425, P = 0.0004). K320Eskm mice revealed a progressive increase in the proportion of cytochrome c oxidase deficient (COX−) fibres in skeletal muscle cross sections, reaching a maximum of 3.03%, 4.36%, 13.58%, and 17.08% in EDL, SOL, tibialis anterior (TA) and GAS, respectively. However, mice did not show accelerated loss of muscle mass, muscle strength or physical performance. Histological analyses revealed ragged red fibres but also stimulated regeneration, indicating activation of MuSCs. RNAseq demonstrated enhanced expression of genes associated with protein synthesis, but also degradation, as well as muscle fibre differentiation and cell proliferation. In contrast, 7 days after destruction by cardiotoxin, regenerating TA of K320Emsc mice showed 30% of COX− fibres. Notably, regenerated muscle showed dystrophic changes, increased fibrosis (2.5% vs. 1.6%, P = 0.0003), increased abundance of fat cells (2.76% vs. 0.23%, P = 0.0144) and reduced muscle mass (regenerated TA: 40.0 mg vs. 60.2 mg, P = 0.0171). In contrast to muscles from K320Eskm mice, freshly isolated MuSCs from aged K320Emsc mice were completely devoid of mtDNA alterations. However, after passaging, mtDNA copy number as well as respiratory chain subunits and p62 levels gradually decreased.ConclusionsTaken together, accumulation of large-scale mtDNA alterations in myofibres alone is not sufficient to cause sarcopenia. Expression of K320E-Twinkle is tolerated in quiescent MuSCs, but progressively leads to mtDNA and respiratory chain depletion upon activation, in vivo and in vitro, possibly caused by an increased mitochondrial removal. Altogether, our results suggest that the accumulation of mtDNA alterations in myofibres activates regeneration during aging, which leads to sarcopenia if such alterations have expanded in MuSCs as well.
Published: 2022
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12. A straightforward meta‐analysis approach for oncology phase I dose‐finding studies

Author: Tim Friede, Moreno Ursino, Sarah Zohar, Christian Röver, University Medical Center Göttingen (UMG), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: FOS: Computer and information sciences, Statistics and Probability, Dose-Response Relationship, Drug, Maximum Tolerated Dose, Shrinkage estimation, Epidemiology, [SDV]Life Sciences [q-bio], Bayes Theorem, Medical Oncology, Bayesian statistics, [STAT]Statistics [stat], Methodology (stat.ME), Logistic Models, Research Design, Dose-escalation trial, Humans, Computer Simulation, Monte Carlo Method, Statistics - Methodology, Random-eﬀects meta-analysis
Abstract: Phase I early-phase clinical studies aim at investigating the safety and the underlying dose-toxicity relationship of a drug or combination. While little may still be known about the compound's properties, it is crucial to consider quantitative information available from any studies that may have been conducted previously on the same drug. A meta-analytic approach has the advantages of being able to properly account for between-study heterogeneity, and it may be readily extended to prediction or shrinkage applications. Here we propose a simple and robust two-stage approach for the estimation of maximum tolerated dose(s) (MTDs) utilizing penalized logistic regression and Bayesian random-effects meta-analysis methodology. Implementation is facilitated using standard R packages. The properties of the proposed methods are investigated in Monte-Carlo simulations. The investigations are motivated and illustrated by two examples from oncology., Comment: 30 pages, 11 figures, 8 tables
Published: 2022
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13. Interpretable automatic detection of incomplete hippocampal inversions using anatomical criteria

Author: Hemforth, Lisa, Cury, Claire, Frouin, Vincent, Desrivières, Sylvane, Grigis, Antoine, Garavan, Hugh, Brühl, Rüdiger, Martinot, Jean-Luc, Paillère Martinot, Marie-Laure, Artiges, Eric, Poustka, Luise, Hohmann, Sarah, Millenet, Sabina, Vaidya, Nilakshi, Walter, Henrik, Whelan, Robert, Schumann, Gunter, Couvy-Duchesne, Baptiste, Colliot, Olivier, 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 = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), Neuroimagerie: méthodes et applications (EMPENN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAL, IMAGE ET LANGAGE (IRISA-D6), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service NEUROSPIN (NEUROSPIN), 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), King‘s College London, University of Vermont [Burlington], Physikalisch-Technische Bundesanstalt [Berlin] (PTB), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), EPS Barthélemy Durand [Etampes], University Medical Center Göttingen (UMG), University Hospital Mannheim | Universitätsmedizin Mannheim, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Trinity College Dublin, Fudan University [Shanghai], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-12-SAMA-0004,ADODEP,Dépression à l'Adolescence: Structure cérébrale et myélinisation(2012), ANR-19-CE37-0017,GeBra,Approches translationelles, profilage transcriptomique, et imagerie cérébrale: vers des nouveaux biomarqueurs et réseaux biologiques dans la resilience au stress(2019), ANR-18-NEUR-0002,ADORe,TARGETING ADOLESCENT NEUROCOGNITIVE PROCESSES IN DEPRESSION TO PROMOTE INTERVENTION RESPONSE(2018), European Project: 351475,NHMRC::NHMRC Project Grants(2005), European Project: 695313,STRATIFY, European Project: 785907,H2020,HBP SGA2(2018), and European Project: 945539,H2020,H2020-SGA-FETFLAG-HBP-2019,HBP SGA3(2020)
Subjects: Deep Learning 3D, Machine Learning, Deep Learning, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Incomplete Hippocampal Inversion, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Hippocampus, MRI, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience; Incomplete Hippocampal Inversion (IHI) is an atypical anatomical pattern of the hippocampus that has been associated with several brain disorders (epilepsy, schizophrenia). IHI can be visually detected on coronal T1 weighted MRI images. IHI can be absent, partial or complete (no IHI, partial IHI, IHI). However, visual evaluation can be long and tedious, justifying the need for an automatic method. In this paper, we propose, to the best of our knowledge, the first automatic IHI detection method from T1-weighted MRI. The originality of our approach is that, instead of directly detecting IHI, we propose to predict several anatomical criteria, which each characterize a particular anatomical feature of IHI, and that can ultimately be combined for IHI detection. Such individual criteria have the advantage of providing interpretable anatomical information regarding the morphological aspect of a given hippocampus. We relied on a large population of 2,008 participants from the IMAGEN study. The approach is general and can be used with different machine learning models. In this paper, we explored two different backbone models for the prediction: a linear method (ridge regression) and a deep convolutional neural network. We demonstrated that the interpretable, anatomical based prediction was at least as good as when predicting directly the presence of IHI, while providing interpretable information to the clinician or neuroscientist. This approach may be applied to other diagnostic tasks which can be characterized radiologically by several anatomical features.
Published: 2023

14. Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure

Author: Markousis-Mavrogenis, George, Minich, Waldemar B, Al-Mubarak, Ali A, Anker, Stefan D, Cleland, John G F, Dickstein, Kenneth, Lang, Chim C, Leong L, Ng, Samani, Nilesh J, Zannad, Faiez, Metra, Marco, Seemann, Petra, Hoeg, Antonia, Lopez, Patricio, van Veldhuisen, Dirk J, de Boer, Rudolf A, Voors, Adriaan A, van der Meer, Peter, Schomburg, Lutz, Bomer, Nils, University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], ImmunometriX GmbH i.L., Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University Medical Center Göttingen (UMG), University of Glascow, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, University of Bergen (UiB), Stavanger University Hospital, University of Dundee, Department of Cardiovascular Sciences [Leicester], University of Leicester, NIHR Leicester Cardiovascular Biomedical Research Unit, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), 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)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), and European Project
Subjects: immune system, Physiology, Physiology (medical), [SDV]Life Sciences [q-bio], autoimmunity, M2, beta 1, beta 2, beta 3, Cardiology and Cardiovascular Medicine, beta 1 beta 2 beta 3 M2 immune system autoimmunity
Abstract: AimsThe importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.Methods and resultsSerum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04–1.81), P = 0.024] and HF rehospitalization [1.57 (1.13–2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05–2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function.ConclusionsAAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.
Published: 2023
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15. Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

Author: Nele Wagener, Malte Buchholz, Philippe Bertolino, Chang X. Zhang, Pietro Di Fazio, Philipps Universität Marburg = Philipps University of Marburg, University Medical Center Göttingen (UMG), 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), and Manship, Brigitte
Subjects: Cell death, Pharmacology, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, Caspase 8, Cancer Research, endocrine system diseases, Caspase 3, [SDV]Life Sciences [q-bio], Biochemistry (medical), Clinical Biochemistry, Pharmaceutical Science, Apoptosis, Cell Biology, Fibroblasts, [SDV] Life Sciences [q-bio], Pancreatic Neoplasms, Mice, MEN1, Pancreatic neuroendocrine neoplasia, Caspases, Proto-Oncogene Proteins, Animals, Humans, Spheroids
Abstract: MEN1 mutation causes pancreatic neuroendocrine neoplasia and benign malignancies of the parathyroid, the adrenal cortex and pituitary gland. The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of MEN1, performed by using a specific siRNA, caused a significant down-regulation of CDKN1A and TP53 transcripts. The treatment with 1 µM of staurosporine caused also a significant down-regulation of MEN1 and was able to restore the basal expression of TP53 only in QGP1 cells. Transient or permanent MEN1 inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and MEN1−/− MEFs treated with staurosporine. Caspase 3/7 activity was suppressed after administration of staurosporine in MEN1 knocked down HPSC2.2 and MEN1−/− MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after MEN1 knockdown and in MEN1−/− MEFs. The treatment with staurosporine caused a reduction of the size of MEN1+/+ MEFs spheroids. Instead, MEN1−/− MEFs spheroids did not show any significant reduction of their size. In conclusion, MEN1 controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional MEN1 and interfering with the apoptotic mechanism could represent a future strategy for the treatment of MEN1-related malignancies.
Published: 2021
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16. Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation- (4Is) related cardiovascular diseases: a joint collaboration of the EACVI and the EANM: summary

Author: Alessia Gimelli, Christoph Rischpler, Panagiotis Georgoulias, Hein J. Verberne, Gilbert Habib, Andor W. J. M. Glaudemans, Jan Bucerius, Marc R. Dweck, Fabien Hyafil, Paola Anna Erba, Riemer H. J. A. Slart, Mark Lubberink, Olivier Gheysens, Antti Saraste, Tanja Kero, Oliver Gaemperli, Slart, R, Glaudemans, A, Gheysens, O, Lubberink, M, Kero, T, Dweck, M, Habib, G, Gaemperli, O, Saraste, A, Gimelli, A, Georgoulias, P, Verberne, H, Bucerius, J, Rischpler, C, Hyafil, F, Erba, P, University Medical Center Groningen [Groningen] (UMCG), Cliniques Universitaires Saint-Luc [Bruxelles], Uppsala University, University of Edinburgh, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hirslanden Medical Center, Department of Radiology, Turku PET Center, Turku University Hospital, University of Turku, Fondazione Toscana Gabriele Monasterio, Univ Hosp Larissa, Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], University Medical Center Göttingen (UMG), University of Duisburg-Essen, CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, University of Pisa - Università di Pisa, Univ Groningen, COMBE, Isabelle, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Translational Immunology Groningen (TRIGR), Cardiovascular Centre (CVC), UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre du cancer, and UCL - (SLuc) Service de médecine nucléaire
Subjects: medicine.medical_specialty, Standardization, [SDV]Life Sciences [q-bio], Medizin, Joined procedurals, Computed tomography, 030204 cardiovascular system & hematology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Eacvi/Eanm Recommendation, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Medical imaging, medicine, Humans, AcademicSubjects/MED00200, Radiology, Nuclear Medicine and imaging, Cardiac PET/CT • Joined procedurals • 4Is • cardiovascular diseases, 4I, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, General Medicine, Reference Standards, Cardiovascular disease, 3. Good health, [SDV] Life Sciences [q-bio], Clinical trial, 4Is, Cardiovascular diseases, Joined procedural, Cardiovascular Diseases, Cardiac PET, Positron emission tomography, Positron-Emission Tomography, Radiology, Radiopharmaceuticals, Ct imaging, Cardiac PET/CT, Cardiology and Cardiovascular Medicine, business
Abstract: With this summarized document we share the standard for positron emission tomography (PET)/(diagnostic)computed tomography (CT) imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is) as recently published in the European Journal of Nuclear Medicine and Molecular Imaging. This standard should be applied in clinical practice and integrated in clinical (multicentre) trials for optimal standardization of the procedurals and interpretations. A major focus is put on procedures using [18F]-2-fluoro-2-deoxyglucose ([18F]FDG), but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this summarized document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicentre trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Diagnosis and management of 4Is related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/magnetic resonance, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.
Published: 2021
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17. Usp22 is an intracellular regulator of systemic emergency hematopoiesis

Author: Nikolaus Dietlein, Xi Wang, Jonas Metz, Olivier Disson, Fuwei Shang, Celine Beyersdörffer, Esther Rodríguez Correa, Daniel B. Lipka, Yvonne Begus-Nahrmann, Robyn Laura Kosinsky, Steven A. Johnsen, Marc Lecuit, Thomas Höfer, Hans-Reimer Rodewald, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Heidelberg [Heidelberg] = Heidelberg University, Nanjing Medical University, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), University Medical Center Göttingen (UMG), Mayo Clinic [Rochester], Robert Bosch Centre for Tumor Diseases [Stuttgart, Germany] (RBCT), Centre National de Référence Listeria - National Reference Center Listeria (CNR), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), N.D. was supported by a Helmholtz Graduate School for Cancer Research fellowship, D.B.L. was supported by Deutsche Krebshilfe Grant 70112574, M.L. and O.D. were supported by Institut Pasteur and Inserm core funding, H.-R.R. and T.H. were supported by Sonderforschungsbereich (SFB) 873-B11, and and H.-R.R. was supported by the European Research Council Advanced Grant 742883, the Helmholtz I & I Initiative program, and the Leibniz program of the Deutsche Forschungsgemeinschaft.
Subjects: [SDV]Life Sciences [q-bio], Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, General Medicine
Abstract: Emergency hematopoiesis is a concerted response aimed toward enhanced protection from infection, involving multiple cell types and developmental stages across the immune system. Despite its importance, the underlying molecular regulation remains poorly understood. The deubiquitinase USP22 regulates the levels of monoubiquitinated histone H2B (H2Bub1), which is associated with activation of interferon responses upon viral infection. Here, we show that in the absence of infection or inflammation, mice lacking Usp22 in all hematopoietic cells display profound systemic emergency hematopoiesis, evident by increased hematopoietic stem cell proliferation, myeloid bias, and extramedullary hematopoiesis. Functionally, loss of Usp22 results in elevated phagocytosis by neutrophilic granulocytes and enhanced innate protection against Listeria monocytogenes infection. At the molecular level, we found this state of emergency hematopoiesis associated with transcriptional signatures of myeloid priming, enhanced mitochondrial respiration, and innate and adaptive immunity and inflammation. Augmented expression of many inflammatory genes was linked to elevated locus-specific H2Bub1 levels. Collectively, these results demonstrate the existence of a tunable epigenetic state that promotes systemic emergency hematopoiesis in a cell-autonomous manner to enhance innate protection, identifying potential paths toward immune enhancement.
Published: 2022
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18. Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

Author: Max M, Owens, Matthew D, Albaugh, Nicholas, Allgaier, Dekang, Yuan, Gabriel, Robert, Renata B, Cupertino, Philip A, Spechler, Anthony, Juliano, Sage, Hahn, Tobias, Banaschewski, Arun L W, Bokde, Sylvane, Desrivières, Herta, Flor, Antoine, Grigis, Penny, Gowland, Andreas, Heinz, Rüdiger, Brühl, Jean-Luc, Martinot, Marie-Laure Paillère, Martinot, Eric, Artiges, Frauke, Nees, Dimitri Papadopoulos, Orfanos, Herve, Lemaitre, Tomáš, Paus, Luise, Poustka, Sabina, Millenet, Juliane H, Fröhner, Michael N, Smolka, Henrik, Walter, Robert, Whelan, Scott, Mackey, Gunter, Schumann, Hugh, Garavan, Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Neuroimagerie: méthodes et applications (EMPENN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAL, IMAGE ET LANGAGE (IRISA-D6), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Université de Rennes (UR), Laureate Institute for Brain Research [Tulsa] (LIBR), University Hospital Mannheim | Universitätsmedizin Mannheim, Heidelberg University, Trinity College Dublin, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Service NEUROSPIN (NEUROSPIN), 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), University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Freie Universität Berlin, Physikalisch-Technische Bundesanstalt [Berlin] (PTB), Physikalisch-Technische Bundesanstalt [Braunschweig] (PTB), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Trajectoires Développementales en Psychiatrie [Paris], Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-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), EPS Barthélemy Durand [Etampes], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], University of Toronto, University Medical Center Göttingen (UMG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Fudan University [Shanghai], IMAGEN Consortium: Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Herve Lemaitre, Tomáš Paus, Luise Poustka, Sarah Hohmann, Sabina Millenet, Juliane H Fröhner, Michael N Smolka, Henrik Walter, Robert Whelan, Gunter Schumann., Medical Faculty [Mannheim], Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and robert, gabriel
Subjects: Adolescent, Substance-Related Disorders, [SDV]Life Sciences [q-bio], Bayes Theorem, Cerebral Cortical Thinning, [STAT] Statistics [stat], [SDV] Life Sciences [q-bio], [STAT]Statistics [stat], Cellular and Molecular Neuroscience, Psychiatry and Mental health, Hallucinogens, Humans, Biological Psychiatry, Cannabis
Abstract: While there is substantial evidence that cannabis use is associated with differences in human brain development, most of this evidence is correlational in nature. Bayesian causal network (BCN) modeling attempts to identify probable causal relationships in correlational data using conditional probabilities to estimate directional associations between a set of interrelated variables. In this study, we employed BCN modeling in 637 adolescents from the IMAGEN study who were cannabis naïve at age 14 to provide evidence that the accelerated prefrontal cortical thinning found previously in adolescent cannabis users by Albaugh et al. [1] is a result of cannabis use causally affecting neurodevelopment. BCNs incorporated data on cannabis use, prefrontal cortical thickness, and other factors related to both brain development and cannabis use, including demographics, psychopathology, childhood adversity, and other substance use. All BCN algorithms strongly suggested a directional relationship from adolescent cannabis use to accelerated cortical thinning. While BCN modeling alone does not prove a causal relationship, these results are consistent with a body of animal and human research suggesting that adolescent cannabis use adversely affects brain development.
Published: 2022
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19. A Large-Scale ENIGMA Multisite Replication Study of Brain Age in Depression

Author: Laura K.M. Han, Richard Dinga, Ramona Leenings, Tim Hahn, James H. Cole, Lyubomir I. Aftanas, Alyssa R. Amod, Bianca Besteher, Romain Colle, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Konstantin V. Danilenko, Paola Fuentes-Claramonte, Ali Saffet Gonul, Ian H. Gotlib, Roberto Goya-Maldonado, Nynke A. Groenewold, Paul Hamilton, Naho Ichikawa, Jonathan C. Ipser, Eri Itai, Sheri-Michelle Koopowitz, Meng Li, Go Okada, Yasumasa Okamoto, Olga S. Churikova, Evgeny A. Osipov, Brenda W.J.H. Penninx, Edith Pomarol-Clotet, Elena Rodríguez-Cano, Matthew D. Sacchet, Hotaka Shinzato, Kang Sim, Dan J. Stein, Aslihan Uyar-Demir, Dick J. Veltman, Lianne Schmaal, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, University of Melbourne, Tilburg University [Tilburg], Netspar, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University College of London [London] (UCL), Scientific-Research Institute of Neurosciences and Medicine [Novosibirsk], University of Cape Town, Jena University Hospital [Jena], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), 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 = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Bioscience, University of Queensland [Brisbane], Fundació per a la Investigació i la Docència Maria Angustias Giménez [Barcelone] (FIDMAG), FIDMAG Germanes Hospitalaries, Ege University [Izmir], Stanford University, University Medical Center Göttingen (UMG), Linköping University (LIU), Hiroshima University, Novosibirsk State University (NSU), Vrije Universiteit Amsterdam [Amsterdam] (VU), Harvard Medical School [Boston] (HMS), and National University of Singapore (NUS)
Subjects: Biological aging, ENIGMA consortium, Depression, [SCCO.NEUR]Cognitive science/Neuroscience, Replication study, General Engineering, General Earth and Planetary Sciences, Brain age, General Environmental Science
Abstract: BackgroundSeveral studies have evaluated whether depressed persons have older appearing brains than their nondepressed peers. However, the estimated neuroimaging-derived “brain age gap” has varied from study to study, likely driven by differences in training and testing sample (size), age range, and used modality/features. To validate our previously developed ENIGMA brain age model and the identified brain age gap, we aim to replicate the presence and effect size estimate previously found in the largest study in depression to date (N=2,126 controls & N=2,675 cases; +1.08 years [SE 0.22], Cohen’s d=0.14, 95% CI: 0.08-0.20), in independent cohorts that were not part of the original study.MethodsA previously trained brain age model (www.photon-ai.com/enigma_brainage) based on 77 FreeSurfer brain regions of interest was used to obtain unbiased brain age predictions in 751 controls and 766 persons with depression (18-75 years) from 13 new cohorts collected from 20 different scanners.ResultsOur ENIGMA MDD brain age model generalized reasonably well to controls from the new cohorts (predicted age vs. age: r = 0.73, R2=0.47, MAE=7.50 years), although the performance varied from cohort to cohort. In these new cohorts, on average, depressed persons showed a significantly higher brain age gap of +1 year (SE 0.35) (Cohen’s d□=□□.15, 95% CI: 0.05–0.25) compared with controls, highly similar to our previous finding.ConclusionsThis study further validates our previously developed ENIGMA brain age algorithm. Importantly, we replicated the brain age gap in depression with a comparable effect size. Thus, two large-scale independent mega-analyses across in total 32 cohorts and >3,400 patients and >2,800 controls worldwide show reliable but subtle effects of brain aging in adult depression.
Published: 2022
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20. A Provenance-aware Memory Object Model for C

Author: Jens Gustedt, Peter Sewell, Kayvan Memarian, Victor Gomes, Martin Uecker, Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-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))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), University Medical Center Göttingen (UMG), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-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)-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, 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)-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), and 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)
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL], GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract: Draft Technical Specification, proposed to the national bodies for standardization; International audience
Published: 2022

21. Predicting depression onset in young people based on clinical, cognitive, environmental, and neurobiological data

Author: Yara J. Toenders, Akhil Kottaram, Richard Dinga, Christopher G. Davey, Tobias Banaschewski, Arun L.W. Bokde, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Herve Lemaitre, Tomáš Paus, Luise Poustka, Sarah Hohmann, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Argyris Stringaris, Betteke van Noort, Jani Penttilä, Yvonne Grimmer, Corinna Insensee, Andreas Becker, Gunter Schumann, Lianne Schmaal, Developmental Neuroscience in Society, University of Melbourne, Radboud University [Nijmegen], Heidelberg University, Trinity College Dublin, King‘s College London, Universität Mannheim, Service NEUROSPIN (NEUROSPIN), 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), University of Vermont [Burlington], University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Physikalisch-Technische Bundesanstalt [Braunschweig] (PTB), Trajectoires Développementales en Psychiatrie [Paris], Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Institut National de la Santé et de la Recherche Médicale (INSERM), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Kiel University, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Toronto, University Medical Center Göttingen (UMG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), National Institute of Mental Health (NIMH), Leibniz Institute for Neurobiology [Magdeburg] (LIN), Fudan University [Shanghai], This work was supported by the MQ Brighter Futures Award (MQBFC/2 [to LS]), the National Institute of Mental Health of the National Institutes of Health (Award Number R01MH117601 [to LS]), a National Health and Medical Research Council (NHMRC) Career Development Fellowship (1140764 [to LS]), the Dame Kate Campbell Fellowship from the Faculty of Medicine, Dentistry and Health Sciences at The University of Melbourne, and an NHMRC Career Development Award (141738 [to CGD]).This work received support from the following sources: the European Union–funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the Horizon 2020–funded ERC Advanced Grant 'STRATIFY' (Brain network based stratification of reinforcement-related disorders) (695313), Human Brain Project (HBP SGA 2, 785907, and HBP SGA 3, 945539), the Medical Research Council Grant 'c-VEDA' (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institutes of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministerium für Bildung und Forschung (BMBF Grant Nos. 01GS08152, 01EV0711, Forschungsnetz AERIAL 01EE1406A, 01EE1406B, Forschungsnetz IMAC-Mind 01GL1745B), the Deutsche Forschungsgemeinschaft (DFG Grant Nos. SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1), the Medical Research Foundation and Medical Research Council (Grant Nos. MR/R00465X/1 and MR/S020306/1), and the NIH-funded ENIGMA (Grant Nos. 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from the ANR (ANR-12-SAMA-0004, AAPG2019 – GeBra), the Eranet Neuron (AF12-NEUR0008-01 – WM2NA, and ANR-18-NEUR00002-01 – ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau, the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence, RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence., Project IMAGEN, Human Brain Project, ANR-12-SAMA-0004,ADODEP,Dépression à l'Adolescence: Structure cérébrale et myélinisation(2012), and ANR-18-NEUR-0002,ADORe,TARGETING ADOLESCENT NEUROCOGNITIVE PROCESSES IN DEPRESSION TO PROMOTE INTERVENTION RESPONSE(2018)
Subjects: Longitudinal study, Adolescent, Cognitive Neuroscience, MESH: Cognition, Major depressive disorder, Logistic regression, Adolescents, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Cognition, MESH: Risk Factors, Risk Factors, Machine learning, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Longitudinal Studies, Big Five personality traits, MESH: Longitudinal Studies, Biological Psychiatry, Depression (differential diagnoses), MESH: Adolescent, Depressive Disorder, Major, MESH: Humans, Receiver operating characteristic, business.industry, Depression, 05 social sciences, MESH: Depression / psychology, medicine.disease, Neuroticism, Penalized logistic regression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), MESH: Depressive Disorder, Major* / diagnosis, business, Prediction, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Clinical psychology
Abstract: BackgroundAdolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level. MethodsA subsample of a multisite longitudinal study in adolescents, the IMAGEN study, was used to predict future (subthreshold) major depressive disorder onset in healthy adolescents. Based on 2-year and 5-year follow-up data, participants were grouped into the following: 1) those developing a diagnosis of major depressive disorder or subthreshold major depressive disorder and 2) healthy control subjects. Baseline measurements of 145 variables from different modalities (clinical, cognitive, environmental, and structural magnetic resonance imaging) at age 14 years were used as input to penalized logistic regression (with different levels of penalization) to predict depression onset in a training dataset (n = 407). The features contributing the highest to the prediction were validated in an independent hold-out sample (three independent IMAGEN sites; n = 137). ResultsThe area under the receiver operating characteristic curve for predicting depression onset ranged between 0.70 and 0.72 in the training dataset. Baseline severity of depressive symptoms, female sex, neuroticism, stressful life events, and surface area of the supramarginal gyrus contributed most to the predictive model and predicted onset of depression, with an area under the receiver operating characteristic curve between 0.68 and 0.72 in the independent validation sample. ConclusionsThis study showed that depression onset in adolescents can be predicted based on a combination multimodal data of clinical characteristics, life events, personality traits, and brain structure variables.
Published: 2022
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22. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure

Author: Stefano Savonitto, D Soon, V Tseluyko, J Heymeriks, L Petrescu, Fabio T. M. Costa, P Garcia Pacho, G Chapidze, Michael Motro, M Diez, A Prado, Piotr Ponikowski, Sanjib Kumar Sharma, DL Serban, A. Salvioni, S del Prado, Giuseppe Boriani, Stephan von Haehling, HG Cestari, PR Nierop, LC Iosipescu, Hans Kragten, Má Hominal, Bridget-Anne Kirwan, Andre Keren, D Horvat, J Thierer, D Sim, Rabih R. Azar, Peter van der Meer, G Stanciulescu, F Cosmi, Sy Loh, Jarosław Drożdż, David Sim, K Paposhvili, M Berli, Alain Cohen-Solal, Stefan D. Anker, Arnaout, ML Parody, GO Zapata, T Ben-Gal, J Schaap, Bas L.J.H. Kietselaer, O Raed, G Kiwan, Marco Metra, Shaul Atar, Udo Michael Göhring, Edoardo Gronda, A Ružić, C Beltrano, Dpw Beelen, Davor Milicic, R Ray, JM Weinstein, FI Ga Bosa Ojeda, Y-K Wong, Dalton Bertolim Précoma, Javed Butler, JR Gonzalez Juanatey, V Chumburidze, Gerasimos Filippatos, V Witzling, Y Malynovsky, I Kraiz, A Samodol, J Trevelyan, L Nigro Maia, M Stanislavchuk, Gilmar Reis, I Khintibidze, D Zdrenghea, Beata Wożakowska-Kapłon, BD Molina, C Abdallah, Ham van Kesteren, Tim Friede, Marcin Gruchała, Majdi Halabi, Ewa A. Jankowska, P Van Bergen, Constantin Militaru, O Koval, DA Darabantiu, A Kormann, J Szachniewicz, Maria Dorobantu, M van de Wetering, R Nijmeijer, H Hamdan, Stefano Ghio, Henry J. Dargie, G Azize, Nicolas Danchin, S Chaaban, S Gerward, P Pimentel Filho, M Uguccioni, K Abdelbaki, N Vita, J.F.K. Saraiva, D Almeida, Michael Shochat, M Ohlsson, R Van de Wal, V Zolotaikina, W Kinany, A Tycińska, A Hershson, T Shaburishvili, Vincent Fabien, FR dos Santos, Alfredo Bardají, Rgej Groutars, M Flugelman, J Bono, M Udovicic, M Artuković, K Šutalo, J Drozdz, TJ Yeo, F Ferre Pacora, Z Lominadze, M Emans, S Pettit, HA Luquez, P Terrosu, Marcus Ohlsson, M Gąsior, S Tušek, Enrico Passamonti, Nyy Al-Windy, P Midi, DA Pascual Figal, P van der Meer, V Zvi, Wilco Tanis, Felipe Martinez, RR Borelli, Diana A. Gorog, O Parhomenko, Klaus H Jensen, M Meijs, J Nessler, M Piepoli, DM Toader, Jose C. Nicolau, A Glenny, José Luis Zamorano, L Tilling, T McDonagh, K Pesek, H Fernandez, Davor Miličić, Domingo A. Pascual-Figal, Theresa McDonagh, G Khabeishvili, Josep Comin-Colet, Israel Gotsman, S Rassi, M Dorobantu, E Straburzyńska-Migaj, L Fattore, L Rudenko, D Crisu, S.S. Kabbani, M Gomez Bueno, Basil S. Lewis, S Goland, Y Arbel, M Bronisz, I Vakaliuk, A Fucili, A Mortara, R Zukermann, N Emukhvari, B Hassouna, K Mizia-Stec, F Turrini, R Szelemej, A Rodica Dan, L Lobo Marquez, Hadi Skouri, A Kabir, Frank Ruschitzka, R García Durán, R Gil, Michael Shechter, P Westendorp, Piergiuseppe Agostoni, A Fernandez, Oscar Pereira Dutra, P Ameri, Wolfram Doehner, JG Smith, Irakli Khintibidze, Luciano Moreira Baracioli, J Šikić, Stuart Pocock, Olivier C. Manintveld, MC Tomescu, M Di Biase, Luiz Carlos Bodanese, E Mirek-Bryniarska, Alexander Parkhomenko, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Cardiology, leboeuf, Christophe, Wrocław Medical University, London School of Hygiene and Tropical Medicine (LSHTM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], King's College Hospital (KCH), Universitatea din Bucuresti (UB), University of Lódź, Vifor Pharma Ltd [Glattbrugg, Switzerland], National and Kapodistrian University of Athens (NKUA), Hadassah Hebrew University Medical Center [Jerusalem], Tbilisi State University, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Prague University of Economics and Business, Università degli Studi di Brescia = University of Brescia (UniBs), University of Zagreb, Universidade de São Paulo = University of São Paulo (USP), Skane University Hospital [Malmo], Lund University [Lund], National Scientific Center 'M.D. Strazhesko Institute of Cardiology' [Kyiv, Ukraine] (NSC/MDSIC), Universidad de Murcia, University hospital of Zurich [Zurich], National Heart Centre Singapore (NHCS), Saint Joseph Medical Center [Beirut], University Medical Center Groningen [Groningen] (UMCG), Clinical Cardiovascular Research Institute [Haifa, Israel] (2CRI), Bellvitge University Hospital [Barcelona, Spain], University Medical Center Göttingen (UMG), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Charité Campus Virchow-Klinikum (CVK), University of Glasgow, Tel Aviv University (TAU), University of Southern Mississippi (USM), Socar Research S.A. [Nyon, Switzerland] (SR), and AFFIRM-AHF investigators: G Azize, A Fernandez, G O Zapata, P Garcia Pacho, A Glenny, F Ferre Pacora, M L Parody, J Bono, C Beltrano, A Hershson, N Vita, H A Luquez, H G Cestari, H Fernandez, A Prado, M Berli, R García Durán, J Thierer, M Diez, L Lobo Marquez, R R Borelli, M Á Hominal, M Metra, P Ameri, P Agostoni, A Salvioni, L Fattore, E Gronda, S Ghio, F Turrini, M Uguccioni, M Di Biase, M Piepoli, S Savonitto, A Mortara, P Terrosu, A Fucili, G Boriani, P Midi, E Passamonti, F Cosmi, P van der Meer, P Van Bergen, M van de Wetering, Nyy Al-Windy, W Tanis, M Meijs, Rgej Groutars, Hks The, B Kietselaer, Ham van Kesteren, Dpw Beelen, J Heymeriks, R Van de Wal, J Schaap, M Emans, P Westendorp, P R Nierop, R Nijmeijer, O C Manintveld, M Dorobantu, D A Darabantiu, D Zdrenghea, D M Toader, L Petrescu, C Militaru, D Crisu, M C Tomescu, G Stanciulescu, A Rodica Dan, L C Iosipescu, D L Serban, J Drozdz, J Szachniewicz, M Bronisz, A Tycińska, B Wozakowska-Kaplon, E Mirek-Bryniarska, M Gruchała, J Nessler, E Straburzyńska-Migaj, K Mizia-Stec, R Szelemej, R Gil, M Gąsior, I Gotsman, M Halabi, M Shochat, M Shechter, V Witzling, R Zukermann, Y Arbel, M Flugelman, T Ben-Gal, V Zvi, W Kinany, J M Weinstein, S Atar, S Goland, D Milicic, D Horvat, S Tušek, M Udovicic, K Šutalo, A Samodol, K Pesek, M Artuković, A Ružić, J Šikić, T McDonagh, J Trevelyan, Y-K Wong, D Gorog, R Ray, S Pettit, S Sharma, A Kabir, H Hamdan, L Tilling, L Baracioli, L Nigro Maia, O Dutra, G Reis, P Pimentel Filho, J F Saraiva, A Kormann, F R Dos Santos, L Bodanese, D Almeida, D Precoma, S Rassi, F Costa, S Kabbani, K Abdelbaki, C Abdallah, M S Arnaout, R Azar, S Chaaban, O Raed, G Kiwan, B Hassouna, A Bardaji, J Zamorano, S Del Prado, J R Gonzalez Juanatey, F I Ga Bosa Ojeda, M Gomez Bueno, B D Molina, D A Pascual Figal, D Sim, T J Yeo, S Y Loh, D Soon, M Ohlsson, J G Smith, S Gerward, I Khintibidze, Z Lominadze, G Chapidze, N Emukhvari, G Khabeishvili, V Chumburidze, K Paposhvili, T Shaburishvili, G Khabeishvili, O Parhomenko, I Kraiz, O Koval, V Zolotaikina, Y Malynovsky, I Vakaliuk, L Rudenko, V Tseluyko, M Stanislavchuk.
Subjects: Male, medicine.medical_specialty, Anemia, 030204 cardiovascular system & hematology, Rate ratio, Placebo, Ferric Compounds, Ventricular Function, Left, law.invention, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Double-Blind Method, Randomized controlled trial, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Maltose, Adverse effect, TOLVAPTAN, Aged, Aged, 80 and over, Heart Failure, RISK, Ejection fraction, Anemia, Iron-Deficiency, business.industry, MORTALITY, Hazard ratio, DEATH, General Medicine, Middle Aged, medicine.disease, Patient Discharge, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Hospitalization, Treatment Outcome, Heart failure, Administration, Intravenous, Female, HOSPITALIZATIONS, business
Abstract: Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin
Published: 2020
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23. Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction

Author: Wilfried Mullens, Kenneth Dickstein, Faiez Zannad, Leong L. Ng, Kevin Damman, Marco Metra, John G.F. Cleland, Nilesh J. Samani, Gerasimos Filippatos, Chim C. Lang, Pieter Martens, Stefan D. Anker, Piotr Ponikowski, Hans L. Hillege, Dirk J. van Veldhuisen, Jozine M. ter Maaten, Adriaan A. Voors, BOZEC, Erwan, University Medical Center Groningen [Groningen] (UMCG), Ziekenhuis Oost-Limburg (ZOL), University of Bergen (UiB), Stavanger University Hospital, Wrocław Medical University, Ninewells Hospital and Medical School [Dundee], University of Dundee, University of Leicester, Glenfield Hospital, Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Centre for Cardiovascular Research (DZHK) partner site Berlin, University Medical Center Göttingen (UMG), National and Kapodistrian University of Athens (NKUA), University of Cyprus [Nicosia] (UCY), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), 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)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University of Brescia, Wroclaw Medical University [Wrocław, Pologne], University of Cyprus [Nicosia], Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), and Groningen Kidney Center (GKC)
Subjects: Male, 030204 cardiovascular system & hematology, THERAPY, Renin-Angiotensin System, 0302 clinical medicine, Mineralocorticoid receptor, Sodium Potassium Chloride Symporter Inhibitors, 030212 general & internal medicine, Prospective Studies, Registries, ESC GUIDELINES, Mineralocorticoid Receptor Antagonists, Ejection fraction, biology, Furosemide, General Medicine, ACEi/ARB, Loop diuretic, ARB, EUROPEAN-SOCIETY, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Treatment Outcome, HOSPITALIZATION, Cardiology, Female, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, medicine.drug_class, PATHOPHYSIOLOGY, Heart failure, DIAGNOSIS, Loop diuretics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Guideline recommended treatment, medicine, Humans, cardiovascular diseases, Aged, ACEi, Original Paper, Dose-Response Relationship, Drug, business.industry, MORTALITY, Angiotensin-converting enzyme, Stroke Volume, medicine.disease, Loop (topology), Propensity score matching, biology.protein, business, Follow-Up Studies
Abstract: Background Loop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system. Methods Loop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score. Results Baseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021]. Conclusions Higher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk. Graphic abstract This figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0
Published: 2020
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24. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Author: Edward A. Fon, Armaghan Alam, Richard Y.J. Wu, Cornelis Blauwendraat, Jennifer A. Ruskey, Luigi Ferini-Strambi, Paul Cannon, Mathias Toft, Mariarosaria Valente, Alex Desautels, Andrew B. Singleton, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, C. Trenkwalder, Kari Anne Bjørnarå, Abril Beatriz, Christelle Charley Monaca, Jacques Montplaisir, Nicolas Dupré, Mineke Viaene, Peter Young, Birgit Högl, Giuseppe Plazzi, Monica Puligheddu, W. H. Oertel, Marco Toffoli, Bradley F. Boeve, Owen A. Ross, Friederike Sixel-Döring, Lasse Pihlstrøm, Michele T.M. Hu, Isabelle Arnulf, Sandra B. Laurent, Karl Heilbron, Michela Figorilli, Anna Heidbreder, Lynne Krohn, Guy A. Rouleau, Karel Sonka, Ziv Gan-Or, Mike A. Nalls, Jean-François Gagnon, David Kemlink, Evi Holzknecht, Femke Dijkstra, Ambra Stefani, Gian Luigi Gigli, Brit Mollenhauer, Ronald B. Postuma, Krohn L., Wu R.Y.J., Heilbron K., Ruskey J.A., Laurent S.B., Blauwendraat C., Alam A., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Toft M., Bjornara K.A., Stefani A., Holzknecht E., Monaca C.C., Abril B., Plazzi G., Antelmi E., Ferini-Strambi L., Young P., Heidbreder A., Cochen De Cock V., Mollenhauer B., Sixel-Doring F., Trenkwalder C., Sonka K., Kemlink D., Figorilli M., Puligheddu M., Dijkstra F., Viaene M., Oertel W., Toffoli M., Gigli G.L., Valente M., Gagnon J.-F., Nalls M.A., Singleton A.B., Desautels A., Montplaisir J.Y., Cannon P., Ross O.A., Boeve B.F., Dupre N., Fon E.A., Postuma R.B., Pihlstrom L., Rouleau G.A., Gan-Or Z., Krohn, L., R. Y. J., Wu, Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Nalls, M. A., Singleton, A. B., Desautels, A., Montplaisir, J. Y., Cannon, P., Ross, O. A., Boeve, B. F., Dupre, N., Fon, E. A., Postuma, R. B., Pihlstrom, L., Rouleau, G. A., Gan-Or, Z., McGill University Health Center [Montreal] (MUHC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Imperial College London, 23andMe Inc., National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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 Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Innsbruck Medical University [Austria] (IMU), Oslo University Hospital [Oslo], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Alma Mater Studiorum University of Bologna (UNIBO), University of Bologna, Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Paracelsus-Elena-Klinik, Kassel, Germany., University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Universita degli Studi di Cagliari [Cagliari], Algemeen Ziekenhuis Sint-Dimpna, Philipps University of Marburg, Università degli Studi di Udine - University of Udine [Italie], University College of London [London] (UCL), Department of Mathematics and Computer Science [Udine], Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Data Tecnica International, Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Mayo Clinic [Jacksonville], Mayo Clinic [Rochester], Laval University Medical center, and Université Laval [Québec] (ULaval)
Subjects: Male, 0301 basic medicine, Oncology, Linkage disequilibrium, Synucleinopathies, REM sleep behavior disorder, MESH: Logistic Models, REM Sleep Behavior Disorder, 0302 clinical medicine, synucleinopathy, SNCA, Odds Ratio, RBD-specific risk variants, MESH: Aged, MESH: Middle Aged, Rapid eye movement sleep behavior disorder (RBD), MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, Middle Aged, MESH: Case-Control Studies, 3. Good health, Neurology, MESH: Synucleinopathies, alpha-Synuclein, Female, Adult, Lewy Body Disease, medicine.medical_specialty, Prodromal Symptoms, Single-nucleotide polymorphism, Locus (genetics), Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, MESH: alpha-Synuclein, medicine, Humans, Genetic Predisposition to Disease, MESH: Prodromal Symptoms, Allele frequency, MESH: Lewy Body Disease, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Adult, Odds ratio, medicine.disease, MESH: Odds Ratio, MESH: Male, synucleinopathies, Logistic Models, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Synuclein, Neurology (clinical), business, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery
Abstract: Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.
Published: 2020
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25. The motif EXEXXXL in the cytosolic tail of the secretory human proprotein convertase PC7 regulates its trafficking and cleavage activity

Author: Robert Day, Alexandra Evagelidis, Loreleï Durand, Emilia Sikorska, Vahid Dianati, Peter Schu, Johann Guillemot, Stéphanie Duval, Nabil G. Seidah, Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), Affiliated to the University of Montreal, Montreal, Quebec, Canada, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de médecine et des sciences de la santé [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS), University of Gdańsk (UG), and University Medical Center Göttingen (UMG)
Subjects: 0301 basic medicine, Proteases, 030102 biochemistry & molecular biology, Endosome, Chemistry, [SDV]Life Sciences [q-bio], Signal transducing adaptor protein, Cell Biology, 16. Peace & justice, Proprotein convertase, Biochemistry, Transmembrane protein, Cell biology, Serine, 03 medical and health sciences, 030104 developmental biology, Secretory protein, Proprotein Convertases, Molecular Biology
Abstract: Many secretory proteins are activated by cleavage at specific sites. The proprotein convertases (PCs) form a family of nine secretory subtilisin-like serine proteases, seven of which cleave at specific basic residues within the trans-Golgi network, granules, or at the cell surface/endosomes. The seventh member, PC7, is a type-I transmembrane (TM) protein with a 97-residue–long cytosolic tail (CT). PC7 sheds human transferrin receptor 1 (hTfR1) into soluble shTfR1 in endosomes. To better understand the physiological roles of PC7, here we focused on the relationship between the CT-regulated trafficking of PC7 and its ability to shed hTfR1. Deletion of the TMCT resulted in soluble PC7 and loss of its hTfR1 shedding activity. Extensive CT deletions and mutagenesis analyses helped us zoom in on three residues in the CT, namely Glu-719, Glu-721, and Leu-725, that are part of a novel motif, EXEXXXL725, critical for PC7 activity on hTfR1. NMR studies of two 14-mer peptides mimicking this region of the CT and its Ala variants revealed that the three exposed residues are on the same side of the molecule. This led to the identification of adaptor protein 2 (AP-2) as a protein that recognizes the EXEXXXL725 motif, thus representing a potentially new regulator of PC7 trafficking and cleavage activity. Immunocytochemistry of the subcellular localization of PC7 and its Ala variants of Leu-725 and Glu-719 and Glu-721 revealed that Leu-725 enhances PC7 localization to early endosomes and that, together with Glu-719 and Glu-721, it increases the endosomal activity of PC7 on hTfR1.
Published: 2020
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26. Alterations of the axon initial segment in multiple sclerosis grey matter

Author: Aysegul Dilsizoglu Senol, Giulia Pinto, Maxime Beau, Vincent Guillemot, Jeffrey L Dupree, Christine Stadelmann, Jonas Ranft, Catherine Lubetzki, Marc Davenne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Virginia Commonwealth University (VCU), Hunter Holmes McGuire Hospital [Richmond, VA, USA], University Medical Center Göttingen (UMG), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This work was funded by INSERM (Institut national de la santé et de la recherche médicale) Paris Brain Institute—Institut du Cerveau et de la Moelle (ICM), fondation pour l’Aide à la Recherche sur la Sclérose En Plaques (ARSEP) grant (to M.D.), Prix Bouvet-Labruyer̀e—Fondation de France (to M.D.), as well as a Multiple Sclerosis International Federation (MSIF) McDonald fellowship and ARSEP travel grant fellowship (to A.D.S.).
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, cerebellum, Neurology, [SDV]Life Sciences [q-bio], neocortex, grey matter lesion, multiple sclerosis, axon initial segment, Biological Psychiatry
Abstract: Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analysed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e. axon initial segment length and position. We found that the axon initial segment length was increased only in pyramidal neurons of inactive demyelinated lesions, compared with normal appearing grey matter tissue. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show, for the first time, changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.
Published: 2022
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27. Properly define blocks as part of the grammar

Author: Gustedt, Jens, Uecker, Martin, Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-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))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Göttingen (UMG), ISO JCT1/SC22/WG14, and Gustedt, Jens
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL], [INFO.INFO-PL] Computer Science [cs]/Programming Languages [cs.PL]
Abstract: Blocks are a fundamental concept in C for the definition of visibility scopes of identifiers and for the lifetime of objects. Currently, there is no closed definition what a block is and the different definitions that compose the term have to be collected in different places that spread over several clauses. In particular, the fact that dependent statements of iteration or selection statements form blocks of their own is easily overlooked and leads to misunderstandings for example concerning the lifetime of compound literals. We propose to change that situation by introducing terms primary block and secondary block in the syntax and by referring to the other definitions of blocks, namely functions definitions and lambda expressions (if added to C23), in a summary definition.
Published: 2022

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

Author: Janina Noster, Martin B. Koeppel, Marie Desnos-Olivier, Maria Aigner, Oliver Bader, Karl Dichtl, Stephan Göttig, Andrea Haas, Oliver Kurzai, Arthur B. Pranada, Yvonne Stelzer, Grit Walther, Axel Hamprecht, Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), Ludwig-Maximilians-Universität München (LMU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Medical Center Göttingen (UMG), Goethe-Universität Frankfurt am Main, Julius-Maximilians-Universität Würzburg (JMU), Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute), MVZ Dr. Eberhard & Partner Dortmund, German Centre for Infection Research (DZIF), Universität zu Köln = University of Cologne, and Work in the NRZMyk is supported by the Robert-Koch-Institute from funds provided by the German Ministry of Health (grant no. 1369-240). This study was supported by internal funding.
Subjects: Pharmacology, Saprochaete capitata, Infectious Diseases, Magnusiomyces clavatus, [SDV]Life Sciences [q-bio], Saprochaete clavata, Pharmacology (medical), bloodstream infection, MIC, Magnusiomyces capitatus, Geotrichum
Abstract: International audience; Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. Our objectives were to determine the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. In seven institutions, a total of 34 Magnusiomyces BSI were identified. Identification was done by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/L), followed by posaconazole (MIC50, 0.125/0.25 mg/L). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, low essential agreement between gradient test and microdilution was recorded for all antifungals (0 to 70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.
Published: 2022
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29. Modeling native and seeded Synuclein aggregation and related cellular dysfunctions in dopaminergic neurons derived by a new set of isogenic iPSC lines with SNCA multiplications

Author: Angelo Iannielli, Mirko Luoni, Serena Gea Giannelli, Rosangela Ferese, Gabriele Ordazzo, Matteo Fossati, Andrea Raimondi, Felipe Opazo, Olga Corti, Jochen H. M. Prehn, Stefano Gambardella, Ronald Melki, Vania Broccoli, San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Istituto di Neuroscienze - Institute of Neuroscience [Milan, Italy] (CNR), Università degli Studi di Milano = University of Milan (UNIMI)-Consiglio Nazionale delle Ricerche [Milano] (CNR), Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Humanitas Research Hospital, University Medical Center Göttingen (UMG), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Royal College of Surgeons in Ireland (RCSI), Università degli Studi di Urbino 'Carlo Bo', CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), 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), and European Project: 821522,PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2)
Subjects: Cancer Research, Cellular and Molecular Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dopaminergic Neurons, Immunology, Induced Pluripotent Stem Cells, alpha-Synuclein, Humans, Calcium, Parkinson Disease, Cell Biology
Abstract: Triplication of the SNCA gene, encoding the protein alpha-Synuclein (αSyn), is a rare cause of aggressive and early-onset parkinsonism. Herein, we generated iPSCs from two siblings with a recently described compact SNCA gene triplication and suffering from severe motor impairments, psychiatric symptoms, and cognitive deterioration. Using CRISPR/Cas9 gene editing, each SNCA copy was inactivated by targeted indel mutations generating a panel of isogenic iPSCs with a decremental number from 4 down to none of functional SNCA gene alleles. We differentiated these iPSC lines in midbrain dopaminergic (DA) neuronal cultures to characterize αSyn aggregation in native and seeded conditions and evaluate its associated cellular dysfunctions. Utilizing a new nanobody-based biosensor combined with super-resolved imaging, we were able to visualize and measure αSyn aggregates in early DA neurons in unstimulated conditions. Calcium dysregulation and mitochondrial alterations were the first pathological signs detectable in early differentiated DA neuronal cultures. Accelerated αSyn aggregation was induced by exposing neurons to structurally well-characterized synthetic αSyn fibrils. 4xSNCA DA neurons showed the highest vulnerability, which was associated with high levels of oxidized DA and amplified by TAX1BP1 gene disruption. Seeded DA neurons developed large αSyn deposits whose morphology and internal constituents resembled Lewy bodies commonly observed in Parkinson’s disease (PD) patient brain tissues. These findings provide strong evidence that this isogenic panel of iPSCs with SNCA multiplications offers a remarkable cellular platform to investigate mechanisms of PD and validate candidate inhibitors of native and seeded αSyn aggregation.
Published: 2022
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30. Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: Machine learning approach

Author: Cearns, Micah, Amare, Azmeraw, Schubert, Klaus Oliver, Thalamuthu, Anbupalam, Frank, Joseph, Streit, Fabian, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna, Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr, Dalkner, Nina, Dayer, Alexandre, Degenhardt, Franziska, Zompo, Maria Del, Depaulo, J Raymond, Étain, Bruno, Falkai, Peter, Forstner, Andreas, Frisen, Louise, Frye, Mark, Fullerton, Janice, Gard, Sébastien, Garnham, Julie, Goes, Fernando, Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Hou, Liping, Hsu, Yi-Hsiang, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael, Mcelroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis, Monteleone, Palmiero, Nievergelt, Caroline, Nöthen, Markus, Novák, Tomas, O'Donovan, Claire, Ozaki, Norio, Millischer, Vincent, Papiol, Sergi, Pfennig, Andrea, Pisanu, Claudia, Potash, James, Reif, Andreas, Reininghaus, Eva, Rouleau, Guy, Rybakowski, Janusz, Schalling, Martin, Schofield, Peter, Schweizer, Barbara, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul, Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire, Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tekola-Ayele, Fasil, Tortorella, Alfonso, Turecki, Gustavo, Veeh, Julia, Vieta, Eduard, Witt, Stephanie, Roberts, Gloria, Zandi, Peter, Alda, Martin, Bauer, Michael, Mcmahon, Francis, Mitchell, Philip, Schulze, Thomas, Rietschel, Marcella, Clark, Scott, Baune, Bernhard, Cearns, Micah, Amare, Azmeraw T, Schubert, Klaus Oliver, Thalamuthu, Anbupalam, Frank, Joseph, Streit, Fabian, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Dayer, Alexandre, Degenhardt, Franziska, Zompo, Maria Del, Depaulo, J Raymond, Étain, Bruno, Falkai, Peter, Forstner, Andreas J, Frisen, Louise, Frye, Mark A, Fullerton, Janice M, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Heilbronner, Ur, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Hou, Liping, Hsu, Yi-Hsiang, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Novák, Toma, O'Donovan, Claire, Ozaki, Norio, Millischer, Vincent, Papiol, Sergi, Pfennig, Andrea, Pisanu, Claudia, Potash, James B, Reif, Andrea, Reininghaus, Eva, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Schofield, Peter R, Schweizer, Barbara W, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M, Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Tekola-Ayele, Fasil, Tortorella, Alfonso, Turecki, Gustavo, Veeh, Julia, Vieta, Eduard, Witt, Stephanie H, Roberts, Gloria, Zandi, Peter P, Alda, Martin, Bauer, Michael, Mcmahon, Francis J, Mitchell, Philip B, Schulze, Thomas G, Rietschel, Marcella, Clark, Scott R, Baune, Bernhard T, Etain, Bruno, University of South Australia [Adelaide], South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, University Medical Center Heidelberg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], National Institute of Mental Health (NIMH), National Institutes of Health [Bethesda] (NIH), Dokkyo Medical University, Università degli Studi di Cagliari = University of Cagliari (UniCa), University of Barcelona, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Karolinska Institute, Karolinska University Hospital [Stockholm], University of California [San Diego] (UC San Diego), University of California (UC), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Medical University of Graz, Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, McGill University Health Center [Montreal] (MUHC), National Taiwan University [Taiwan] (NTU), University of Bonn, University Hospital Basel [Basel], Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Poznan University of Medical Sciences [Poland] (PUMS), Johns Hopkins University (JHU), Ludwig Maximilian University [Munich] (LMU), University of Basel (Unibas), Karolinska Institutet [Stockholm], University of New South Wales [Sydney] (UNSW), Centre hospitalier Charles Perrens [Bordeaux], Dalhousie University [Halifax], 'Prof. Dr. Alexandru Obregia' Clinical Hospital of Psychiatry [Bucharest, Romania], Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], Osaka University [Osaka], Georg-August-University = Georg-August-Universität Göttingen, University Medical Center Göttingen (UMG), Institute of Psychiatric Phenomics and Genomics (IPPG), Ludwig-Maximilians-Universität München (LMU), Harvard School of Public Health, Harvard Medical School [Boston] (HMS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Psychothérapique de Nancy [Laxou] (CPN), Juntendo University, Frankfurt University Hospital, Landesklinikum Neunkirchen (LK Neunkirchen), Hokkaido University [Sapporo, Japan], Sahlgrenska Academy at University of Gothenburg [Göteborg], VA San Diego Healthcare System [San Diego, CA, USA] (VASDHS), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, University of Cincinnati (UC), IMIM-Hospital del Mar, Generalitat de Catalunya, Instituto de Salud Carlos III [Madrid] (ISC), Università degli Studi di Salerno = University of Salerno (UNISA), National Institute of Mental Health [Klecany, Czech Republic] (NIMH), Nagoya University, Medizinische Universität Wien = Medical University of Vienna, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Montreal Neurological Institute and Hospital, Neuroscience Research Australia (NeuRA), Sigmund Freud University (SFU), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Università degli Studi di Perugia = University of Perugia (UNIPG), Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg], Johns Hopkins Bloomberg School of Public Health [Baltimore], University Medical Center, University of Adelaide, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University of Melbourne, and The Florey Institute of Neuroscience and Mental Health
Subjects: Psychiatry and Mental health, depressive disorder, bipolar affective disorder, outcome studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Mood stabiliser, Mood stabilisers, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, genetics, genetic, depressive disorders, bipolar affective disorders
Abstract: BackgroundResponse to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.AimsTo use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.MethodThis study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.ResultsThe best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.ConclusionsUsing PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Published: 2022
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31. Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial

Author: Meinel, Thomas R., Kaesmacher, Johannes, Darcourt, Jean, Bourcier, Romain, Guillon, Benoit, Papagiannaki, Chrysanthi, Costentin, Guillaume, Sibolt, Gerli, Räty, Silja, Gory, Benjamin, Richard, Sébastien, Liman, Jan, Buetikofer, Lukas, Ernst, Marielle, Boulanger, Marion, Barbier, Charlotte, Mechtouff, Laura, Zhang, Liqun, Marnat, Gaultier, Sibon, Igor, Nikoubashman, Omid, Reich, Arno, Consoli, Arturo, Strbian, Daniel, Weisenburger, David, Requena, Manuel, Garcia-Tornel, Alvaro, Saleme, Suzana, Moulin, Solène, Pagano, Paolo, Saliou, Guillaume, Carrera, Emmanuel, Janot, Kevin, Boix, Marti, Eker, Omer Faruk, Pop, Raoul, Della Schiava, Lucie, Luft, Andreas, Piotin, Michel, Gentric, Jean Christophe, Pikula, Aleksandra, Pfeilschifter, Waltraud, Arnold, Marcel, Siddiqui, Adnan, Froehler, Michael T., Cognard, Christophe, Furlan, Anthony J., Chapot, René, Wiesmann, Martin, Machi, Paolo, Diener, Hans-Christoph, Kulcsar, Zsolt, Bonati, Leo, Bassetti, Claudio, Escalard, Simon, Liebeskind, David, Mordasini, Pasquale, Saver, Jeffrey L., Fischer, Urs, Gralla, Jan, SWIFT-DIRECT investigators, Deppeler, Sandro, Mendes Pereira, Vitor, Albucher, Jean François, University of Bern, Bern University Hospital [Berne] (Inselspital), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsinki University Hospital [Finland] (HUS), Département de Neuroradiologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service Neuroradiologie Diagnostique et Thérapeutique [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Toronto, Toronto Western Hospital, Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Rouen], Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Klinikum Nürnberg Nord, University Medical Center Göttingen (UMG), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Départment de Neuroradiologie [CHU Caen], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), St George’s University Hospitals, Département de Neuro-Radiologie [Bordeaux] (DNR - Bordeaux), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Service Neuroradiologie diagnostique et interventionnelle [Hôpital Foch], Hôpital Foch [Suresnes], Vall d'Hebron University Hospital [Barcelona], CHU Limoges, Service de neurologie [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Lausanne = University of Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Neurology [Genève], Hôpitaux Universitaires de Genève (HUG), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Département de Neuroradiologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University hospital of Zurich [Zurich], cereneo Vitznau - center for Neurology & Rehabilitation [Vitznau, Switzerland] (CV - CNR), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Service de Neuroradiologie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Frankfurt University Hospital, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], Alfried Krupp Krankenhaus [Essen], Institute of Medical Informatics, Biometrics and Epidemiology [ Essen, Germany] (IMIBE), University Hospital Basel [Basel], Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), SWIFT-DIRECT investigators, and CarMeN, laboratoire
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Surgery, 610 Medicine & health, Neurology (clinical), General Medicine, Thrombolysis, Thrombectomy
Abstract: Journal of neuroInterventional surgery (2022). doi:10.1136/jnis-2022-019207, Published by BMJ Journals, London
Published: 2022
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32. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial

Author: Urs Fischer, Johannes Kaesmacher, Daniel Strbian, Omer Eker, Christoph Cognard, Patricia S Plattner, Lukas Bütikofer, Pasquale Mordasini, Sandro Deppeler, Vitor M Pereira, Jean François Albucher, Jean Darcourt, Romain Bourcier, Guillon Benoit, Chrysanthi Papagiannaki, Ozlem Ozkul-Wermester, Gerli Sibolt, Marjaana Tiainen, Benjamin Gory, Sébastien Richard, Jan Liman, Marielle Sophie Ernst, Marion Boulanger, Charlotte Barbier, Laura Mechtouff, Liqun Zhang, Gaultier Marnat, Igor Sibon, Omid Nikoubashman, Arno Reich, Arturo Consoli, Bertrand Lapergue, Marc Ribo, Alejandro Tomasello, Suzana Saleme, Francisco Macian, Solène Moulin, Paolo Pagano, Guillaume Saliou, Emmanuel Carrera, Kevin Janot, María Hernández-Pérez, Raoul Pop, Lucie Della Schiava, Andreas R Luft, Michel Piotin, Jean Christophe Gentric, Aleksandra Pikula, Waltraud Pfeilschifter, Marcel Arnold, Adnan H Siddiqui, Michael T Froehler, Anthony J Furlan, René Chapot, Martin Wiesmann, Paolo Machi, Hans-Christoph Diener, Zsolt Kulcsar, Leo H Bonati, Claudio L Bassetti, Mikael Mazighi, David S Liebeskind, Jeffrey L Saver, Jan Gralla, Angelika Alonso, Caroline Arquizan, Xavier Barreau, Rémy Beaujeux, Daniel Behme, Tobias Boeckh-Behrens, Christian Boehme, Martí Boix, Grégoire Boulouis, Nicolas Bricout, Nicolas Broc, Carlo W. Cereda, Emmanuel Chabert, Tae-Hee Cho, Alessandro Cianfoni, Vincent Costalat, Christian Denier, Frederico Di Maria, Richard du Mesnil de Rochemont, Patricia Fearon, Anna Ferrier, Sebastian Fischer, Maxime Gauberti, Marie Gaudron, Laetitia Gimenez, Christoph Globas, Michael Görtler, Mayank Goyal, Ruediger Hilker-Roggendorf, Michael D. Hill, Vi Tuan Hua, Lisa Humbertjean, Olav Jansen, Simon Jung, Georg Kägi, Michael E. Kelly, Ilka Kleffner, Michael Knoflach, Krassen Nedeltchev, Lars Udo Krause, Kimmo Lappalainen, Margaux Lefebvre, Joe Leyon, Liang Liao, Jean-Sebastien Liegey, Christian Loehr, Patrik Michel, Stefania Nannoni, Patrick Nicholson, Lorena Nico, Michael Obadia, Julien Ognard, Ayokunle Ogungbemi, Jean-Marc Olivot, Simon Escalard, Marco Pasi, Lissa Peeling, Jane Perez, Martina Petersen, Eike Piechowiak, Roberto Raposo, Silja Räty, Sarah C. Reitz, Sebastià Remollo, Luca Remonda, Ian Rennie, Manuel Requena, Alexander Riabikin, Roberto Riva, Aymeric Rouchaud, Andrea Rosi, Marta Rubiera, Laurent Spelle, Marlena Schnieder, Joanna D. Schaafsma, Tilman Schubert, Jörg B. Schulz, Mohammed Siddiqui, Sébastien Soize, Michael Sonnberger, Emmanuel Touze, Aude Triquenot, Guillaume Turc, Lucy Vieira, Wagih Ben Hassen, Judith N. Wagner, Katrin Wasser, Johannes Weber, Holger Wenz, David Weisenburger-Lile, Fritz Wodarg, Valérie Wolff, Silke Wunderlich, University of Bern, Bern University Hospital [Berne] (Inselspital), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Service de neuroradiologie [Lyon], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Toulouse [Toulouse], Département de Neuro-Radiologie [Bordeaux] (DNR - Bordeaux), CHU Bordeaux [Bordeaux], University of Toronto, Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Rouen], Helsinki University Hospital [Finland] (HUS), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de neurologie [CHRU Nancy], University Medical Center Göttingen (UMG), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interférométrie, In situ et Instrumentation pour la Microscopie Electronique (CEMES-I3EM), Centre d'élaboration de matériaux et d'études structurales (CEMES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Hôpital Foch [Suresnes], Institut de Ciencies del Cosmos (ICCUB), Universitat de Barcelona (UB), Observatoire océanologique de Banyuls (OOB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Environnement, Bioénergie, Microalgues et Plantes (EBMP), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hôpitaux Universitaires de Genève (HUG), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Département de Neuroradiologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Lille, University hospital of Zurich [Zurich], Fondation Ophtalmologique Adolphe de Rothschild [Paris], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toronto Western Hospital, Frankfurt University Hospital, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], Alfried Krupp Krankenhaus [Essen], Geneva University Hospitals and Geneva University, Institute of Medical Informatics, Biometrics and Epidemiology [ Essen, Germany] (IMIBE), University Hospital Basel [Basel], University of Basel (Unibas), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), FHU NeuroVasc [Site Sainte-Anne, Paris] (GHU-PPN), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of California (UC), SWIFT DIRECT Collaborators: Angelika Alonso, Caroline Arquizan, Xavier Barreau, Rémy Beaujeux, Daniel Behme, Tobias Boeckh-Behrens, Christian Boehme, Martí Boix, Grégoire Boulouis, Nicolas Bricout, Nicolas Broc, Carlo W Cereda, Emmanuel Chabert, Tae-Hee Cho, Alessandro Cianfoni, Vincent Costalat, Christian Denier, Frederico Di Maria, Richard du Mesnil de Rochemont, Patricia Fearon, Anna Ferrier, Sebastian Fischer, Maxime Gauberti, Marie Gaudron, Laetitia Gimenez, Christoph Globas, Michael Görtler, Mayank Goyal, Ruediger Hilker-Roggendorf, Michael D Hill, Vi Tuan Hua, Lisa Humbertjean, Olav Jansen, Simon Jung, Georg Kägi, Michael E Kelly, Ilka Kleffner, Michael Knoflach, Krassen Nedeltchev, Lars Udo Krause, Kimmo Lappalainen, Margaux Lefebvre, Joe Leyon, Liang Liao, Jean-Sebastien Liegey, Christian Loehr, Patrik Michel, Stefania Nannoni, Patrick Nicholson, Lorena Nico, Michael Obadia, Julien Ognard, Ayokunle Ogungbemi, Jean-Marc Olivot, Simon Escalard, Marco Pasi, Lissa Peeling, Jane Perez, Martina Petersen, Eike Piechowiak, Roberto Raposo, Silja Räty, Sarah C Reitz, Sebastià Remollo, Luca Remonda, Ian Rennie, Manuel Requena, Alexander Riabikin, Roberto Riva, Aymeric Rouchaud, Andrea Rosi, Marta Rubiera, Laurent Spelle, Marlena Schnieder, Joanna D Schaafsma, Tilman Schubert, Jörg B Schulz, Mohammed Siddiqui, Sébastien Soize, Michael Sonnberger, Emmanuel Touze, Aude Triquenot, Guillaume Turc, Lucy Vieira, Wagih Ben Hassen, Judith N Wagner, Katrin Wasser, Johannes Weber, Holger Wenz, David Weisenburger-Lile, Fritz Wodarg, Valérie Wolff, Silke Wunderlich., Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), St George’s University Hospitals, Vall d'Hebron University Hospital [Barcelona], and CarMeN, laboratoire
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], General Medicine, 610 Medicine & health
Abstract: Background Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. Methods In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0.9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. Findings Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7 .3%, 95% CI -16.6 to 2.1, lower limit of one-sided 95% CI -15.1%, crossing the non-inferiority margin of - 12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy ( risk difference -1.0%, 95% CI -4.8 to 2 .7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [ 91%] of 201 vs 199 [96%] of 207, risk difference -5.1%, 95% CI -10.2 to 0. 0, p=0.047). Interpretation Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
Published: 2022
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33. Patiromer for the management of hyperkalaemia in patients receiving renin-angiotensin-aldosterone system inhibitors for heart failure: design and rationale of the DIAMOND trial

Author: Carol Moreno Quinn, Javed Butler, Ileana L. Piña, Peter Szecsödy, Bertram Pitt, Fausto J. Pinto, Lars H. Lund, Udo-Michael Göhring, Gerasimos Filippatos, Stefan D. Anker, Fabio Dorigotti, Peter van der Meer, Tim Friede, Matthew R. Weir, Marco Metra, Andrew J.S. Coats, Patrick Rossignol, Tariq Jamal Siddiqi, Mikhail Kosiborod, Repositório da Universidade de Lisboa, BOZEC, Erwan, University of Mississippi Medical Center (UMMC), Charité Campus Virchow-Klinikum (CVK), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Department of Internal Medicine, Dow University of Health Sciences, University of Warwick [Coventry], Vifor Pharma Ltd [Glattbrugg, Switzerland], National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), Attikon University Hospital, University Medical Center Göttingen (UMG), University of Missouri [Kansas City] (UMKC), University of Missouri System, Saint Luke's Mid America Heart Institute, Karolinska Institutet [Stockholm], Università degli Studi di Brescia = University of Brescia (UniBs), Civic Hospital of Brescia, Central Michigan University (CMU), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Hospital de Santa Maria [Lisboa], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), 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)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], University of Maryland School of Medicine, University of Maryland System, University of Michigan [Ann Arbor], University of Michigan System, This study was sponsored and funded by Vifor Pharma, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Università degli Studi di Brescia [Brescia], Universidade de Lisboa (ULISBOA), and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Subjects: Trial design, medicine.medical_specialty, Randomization, Polymers, Heart failure, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, Placebo, GUIDELINES, Mineralocorticoid receptor antagonists, Renin-Angiotensin System, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Hyperkalaemia, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Adherence, Patiromer, Potassium, Renin-angiotensin-aldosterone system inhibitors, Humans, Stroke Volume, Heart Failure, Hyperkalemia, Renal Insufficiency, Chronic, Renin–angiotensin system, medicine, Clinical endpoint, QD, Renal Insufficiency, 030212 general & internal medicine, Chronic, Adverse effect, Ejection fraction, business.industry, medicine.disease, QP, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, chemistry, Cardiology, Cardiology and Cardiovascular Medicine, business, RC
Abstract: © 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Aims: In patients with current or a history of hyperkalaemia, treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) is often compromised. Patiromer, a novel potassium (K+ ) binder, may improve serum K+ levels and adherence to RAASi. Methods: The DIAMOND trial will enroll ∼820 patients with heart failure with reduced ejection fraction (HFrEF; ejection fraction ≤40%). Patients meeting the screening criteria will enter a single-blinded run-in phase where they will be started or continued on a mineralocorticoid receptor antagonist (MRA) titrated to 50 mg/day and other RAASi therapy to ≥50% target dose, and patiromer. Patiromer will be titrated up to a maximum three packs/day (8.4 g/pack) to achieve optimal doses of RAASi without hyperkalaemia. The run-in phase will last up to 12 weeks, following which patients will undergo double-blind randomization in a 1:1 ratio to receive either continued patiromer or placebo (patiromer withdrawal). The primary endpoint is the mean difference in serum K+ from randomization between patiromer and placebo arms. Secondary endpoints will include hyperkalaemia events with K+ value >5.5 mEq/L, durable enablement of MRA at target dose, investigator-reported adverse events of hyperkalaemia, hyperkalaemia-related clinical endpoints and an overall RAASi use score (using a 0-8-point scale) comprising all-cause death, occurrence of cardiovascular hospitalization or usage of comprehensive heart failure medication. Conclusion: The DIAMOND trial is designed to determine if patiromer can favourably impact K+ control in patients with HFrEF with hyperkalaemia or a history of hyperkalaemia leading to RAASi therapy compromise, and in turn improve RAASi use.
Published: 2021
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34. Wide Function Pointer Types for Pairing Code and Data

Author: Martin Uecker, Jens Gustedt, University Medical Center Göttingen (UMG), Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-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))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), ISO JCT1/SC22/WG14, 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)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), and 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)
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL]
Published: 2021

35. Lactate is a major energy substrate for cortical neurons and enhances their firing activity

Author: Dongdong Li, Anastassios Karagiannis, Benjamin Le Gac, Jean Rossier, Bruno Cauli, Richard Egger, Alexandre Lacroix, Susumu Seino, Jochen F. Staiger, Juliette Piquet, Hélène Geoffroy, Jochen Roeper, Hiromi Imamura, Jérémie Naudé, Fabrice Plaisier, Régine Hepp, Thierry Gallopin, Bertrand Lambolez, Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Goethe-University Frankfurt am Main, University Medical Center Göttingen (UMG), Kyoto University [Kyoto], Kobe University, Cauli, Bruno, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), 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), and Kyoto University
Subjects: 0303 health sciences, endocrine system, Neocortex, Chemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Substrate (chemistry), Oxidative phosphorylation, Cortical neurons, Cell biology, 03 medical and health sciences, Crosstalk (biology), 0302 clinical medicine, medicine.anatomical_structure, nervous system, Cerebral cortex, medicine, Premovement neuronal activity, Glycolysis, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SummaryGlucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with Kir6.2 and SUR1 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function.HighlightsMost cortical neurons subtypes express pancreatic beta-cell like KATP channels.Lactate enhances spiking activity via its uptake and closure of KATP channels.Cortical neurons take up and oxidize lactate.Cortical neurons produce ATP mainly by oxidative phosphorylation.
Published: 2021

36. Disambiguate the storage class of some compound literals

Author: Gustedt, Jens, Uecker, Martin, Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-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))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Göttingen (UMG), ISO JCT1/SC22/WG14, and Gustedt, Jens
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL], [INFO.INFO-PL] Computer Science [cs]/Programming Languages [cs.PL]
Abstract: We noticed that there is a need for clarification about the storage class of compound literals that are evaluated in the type expressions of function parameters. It turned out that clang has them as static storage duration while gcc has them as automatic. We asked WG14 to clarify this situation and consensus (13-0-8) has been reached that it should be specified asautomatic. This paper implements that change.
Published: 2021

37. Properly define blocks as part of the grammar

Author: Jens Gustedt, Martin Uecker, Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), 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)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), 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), University Medical Center Göttingen (UMG), ISO JCT1/SC22/WG14, 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 (FMNGE), 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)-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), 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), 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), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE)
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL]
Abstract: Blocks are a fundamental concept in C for the definition of visibility scopes of identifiers and for the lifetime of objects. Currently, there is no closed definition what a block is and the different definitions that compose the term have to be collected in different places that spread over several clauses. In particular, the fact that dependent statements of iteration or selection statements form blocks of their own is easily overlooked and leads to misunderstandings for example concerning the lifetime of compound literals. We propose to change that situation by introducing terms primary block and secondary block in the syntax and by referring to the other definitions of blocks, namely functions definitions and lambda expressions (if added to C23), in a summary definition.
Published: 2021

38. Disambiguate the storage class of some compound literals: change request for C23

Author: Jens Gustedt, Martin Uecker, Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-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))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Göttingen (UMG), ISO JCT1/SC22/WG14, 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)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), and 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)
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL]
Abstract: We noticed that there is a need for clarification about the storage class of compound literals that are evaluated in the type expressions of function parameters. It turned out that clang has them as static storage duration while gcc has them as automatic. We asked WG14 to clarify this situation and consensus (13-0-8) has been reached that it should be specified asautomatic. This paper implements that change.
Published: 2021

39. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: The results of the AFFIRM-AHF study

Author: Marco Metra, Marcus Andreas Ohlsson, Basil S. Lewis, Wolfram Doehner, Peter van der Meer, Irakli Khintibidze, Hans Kragten, Bridget-Anne Kirwan, Jose C. Nicolau, Vincent Fabien, Tim Friede, Nicolas Danchin, Ewa A. Jankowska, Gerasimos Filippatos, Alain Cohen-Solal, Fabio Dorigotti, Hadi Skouri, Davor Miličić, Andre Keren, Alexander Parkhomenko, Jarosław Drożdż, David Sim, Stuart J. Pocock, Michael Motro, Javed Butler, Domingo A. Pascual-Figal, Theresa McDonagh, Henry J. Dargie, Josep Comín-Colet, Maria Dorobantu, Mikhail Kosiborod, Frank Ruschitzka, Stephan von Haehling, Piotr Ponikowski, Stefan D. Anker, Felipe Martinez, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), leboeuf, Christophe, Wrocław Medical University, Socar Research S.A. [Nyon, Switzerland] (SR), London School of Hygiene and Tropical Medicine (LSHTM), Saint Luke's Mid America Heart Institute, University of Missouri [Kansas City] (UMKC), University of Missouri System, University of Mississippi Medical Center (UMMC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], King‘s College London, Universitatea din Bucuresti (UB), Medical University of Łódź (MUL), National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), Assuta Hospital in Ramat HaHayal [Tel Aviv-Yafo, Israel] (AHRH), Tbilisi State University, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Prague University of Economics and Business, Università degli Studi di Brescia = University of Brescia (UniBs), Civic Hospital of Brescia, University of Zagreb, Skane University Hospital [Malmo], Lund University [Lund], National Scientific Center 'M.D. Strazhesko Institute of Cardiology' [Kyiv, Ukraine] (NSC/MDSIC), Universidad de Murcia, University hospital of Zurich [Zurich], National Heart Centre Singapore (NHCS), American University of Beirut Faculty of Medicine and Medical Center (AUB), University Medical Center Groningen [Groningen] (UMCG), Rappaport faculty of Medicine, Technion - Israel Institute of Technology [Haifa], L’Hospitalet de Llobregat [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), University Medical Center Göttingen (UMG), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, 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), University of Glasgow, Tel Aviv University (TAU), Kfar Saba and Sackler School of Medicine, Vifor Pharma Ltd [Glattbrugg, Switzerland], and University College of London [London] (UCL)
Subjects: medicine.medical_specialty, Randomization, Heart diseases, Iron, Health-related quality of life, Population, Heart failure, 030204 cardiovascular system & hematology, Placebo, law.invention, Malalties del cor, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Quality of life, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, law, Clinical Research, Internal medicine, medicine, Humans, Clinical Trials, AcademicSubjects/MED00200, 030212 general & internal medicine, education, education.field_of_study, Ejection fraction, Dèficit de ferro, Anemia, Iron-Deficiency, business.industry, Iron deficiency, Acute heart failure, medicine.disease, Confidence interval, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Dietary Supplements, Intravenous ferric carboxymaltose therapy, Iron deficiency diseases, Randomized clinical trial, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. Methods and results The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5–5.3, P = 0.018) for OSS and 2.8 (0.3–5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3–5.6, P = 0.028) for OSS and 2.9 (0.2–5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. Conclusion In iron-deficient patients with HF and left ventricular ejection fraction, Graphical Abstract
Published: 2021
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40. Indeterminate Values and Trap Representations

Author: Martin Uecker, Jens Gustedt, University Medical Center Göttingen (UMG), Compilation pour les Architectures MUlti-coeurS (CAMUS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), 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)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), 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), ISO TC1/SC22/WG14, 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), 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)-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), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE)
Subjects: [INFO.INFO-PL]Computer Science [cs]/Programming Languages [cs.PL], [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC]
Published: 2021

41. Patient-centered management of actinic keratosis. Results of a multi-center clinical consensus analyzing non-melanoma skin cancer patient profiles and field-treatment strategies

Author: Kai Martin Thoms, Wolfgang G. Philipp-Dormston, Maxime Battistella, Lise Boussemart, Paolo Broganelli, Alessandro Di Stefani, Universität Witten Herdecke, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università cattolica del Sacro Cuore [Milano] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, City of Health and Science University Hospital [Turin, Italy], University Medical Center Göttingen (UMG), LEO Pharma A/S, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], and Jonchère, Laurent
Subjects: medicine.medical_specialty, Consensus, Cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma, [SDV]Life Sciences [q-bio], Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Patient-Centered Care, Health care, medicine, Humans, Intensive care medicine, 030203 arthritis & rheumatology, business.industry, Actinic keratosis, medicine.disease, 3. Good health, Keratosis, Actinic, [SDV] Life Sciences [q-bio], Treatment strategy, Skin cancer, business, Psychosocial, management, Dermatologists, Non melanoma, Patient centered
Abstract: International audience; Actinic keratosis (AK) is a chronic skin condition that can be a precursor to cutaneous squamous cell carcinoma. AK can recur and patients are likely to undergo multiple treatments. It is important that AK lesions are managed appropriately, and that patients are involved in treatment decisions. Materials and methods The Supporting Professional Expertise in AK (SPEAK) program aims to facilitate this patient-centered care by identifying patient needs and aiding healthcare practitioners (HCPs) in selecting optimal treatment and communication strategies for different types of patients. Twenty-two dermato-oncologists with established expertise in the treatment of AK collaborated to describe commonly encountered psychosocial patient profiles, and to develop respective communication and treatment strategies. Results and conclusion Six patient profiles were defined based on different psychosocial characteristics and were used to develop appropriate management approaches. We provide a systematic way of identifying these patient profiles in clinical practice and we outline communication strategies tailored to the primary needs of each type of patient. In addition, we provide recommendations for potential field-treatments that may be best suited for each profile. The recommendations provided here may help improve the communication and relationship between patients and HCPs, resulting in higher treatment adherence and improved patient outcomes.
Published: 2019
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42. Tumor vessel co-option probed by single-cell analysis

Author: Steven Van Laere, Mieke Dewerchin, Lena-Christin Conradi, Peter Carmeliet, Anna Rita Cantelmo, Federico Taverna, Massimiliano Mazzone, Yonglun Luo, Stefan Vinckier, Stefaan J. Soenen, Nuphar Veiga, Tobias K. Karakach, Peter B. Vermeulen, Lucas Treps, Joanna Kalucka, Sébastien J. Dumas, Luc Dirix, Elda Meta, Shawez Khan, Vincent Geldhof, Guy Eelen, Laure-Anne Teuwen, Luc Schoonjans, Nadine V. Conchinha, Katerina Rohlenova, Lisa M. Becker, Anne Cuypers, Melissa García-Caballero, Laura P.M.H. de Rooij, Jacob Amersfoort, [Teuwen,LA, De Roji,PMH, Cuypers,A, Rohlenova,A, Dumas,SH, García-Caballero,M, Meta,E, Amersfoort,J, Taverna,F, Becker,LM, Veiga,N, Cantelmo,AR, Geldhof,V, Conchinha,NV, Kalucka,J, Treps,L, Conradi,LC, Khan,S, Karakach,TK, Vinckier,S, Schoonjans,L, Eelen,G, Dewerchin,M, Carmeliet,P] Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. [Teuwen,LA, Van Laere,S, Dirix,L, Vermeulen,P] Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. [Teuwen,LA, Vermeulen,P] Center for Oncological Research, University of Antwerp, Antwerp, Belgium. [Soenen,S] NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. [Schoonjans,L, Carmeliet,P] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. [Mazzone,M] Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. [Luo,Y] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Luo,Y] Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao, P.R. China. [Luo,Y] BGI-Shenzhen, Shenzhen, China. [Luo,Y] China National GeneBank, BGI-Shenzhen, Shenzhen, P.R. China. [Carmeliet,P] Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Rohlenova,K] Institute of Biotechnology of the Czech Academy of Sciences, Praha – za´ pad, Central Bohemia, Czechia. [García-Caballero,M] Department of Molecular Biology and Biochemistry, Faculty of Sciences, and IBIMA (Biomedical Research Institute of Málaga), University of Málaga, Andalucía Tech, Málaga, Spain. [Cantelmo,AR] Laboratory of Cell Physiology, Lille University, Villeneuve d’Ascq, France. [Kalucka,J] Aarhus Institute of Advanced Studies (AIAS), Department of Biomedicine, Aarhus University, Aarhus, Denmark. [Conradi,LC] Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany. [Khan,S] National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. [Karakach,TK] Bioinformatics Core Laboratory, Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada. [Karakach,TK] Rady Faculty of Health Sciences, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba Canada., L.-A.T., L.D., S.V.L., and P.V. are supported by Fonds Oncologie Augustinus-Koning Boudewijnstichting and GZA Ziekenhuizen, A.C., K.R., N.V.C., L.P.M.H.d.R., and L.T. by the Fonds Wetenschappelijk Onderzoek (FWO), S.J.D. by a Marie Curie-IEF fellowship, V.G. by Strategisch Basisonderzoek FWO (SB-FWO), Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF-1337-00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR), and and P.C. by Methusalem funding (Flemish government), Fund for Scientific Research-Flanders (FWO-Vlaanderen), Foundation Against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), European Research Council (ERC Proof of Concept grant ERC-713758 and Advanced ERC Research grant EU-ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (NNF19OC0055802).
Subjects: Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], 0301 basic medicine, Lung Neoplasms, Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Kidney Neoplasms [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Cytological Techniques::Single-Cell Analysis [Medical Subject Headings], Vascular permeability, Metastasis, Transcriptome, anti-angiogenic therapy, Mice, 0302 clinical medicine, Single-cell analysis, Neoplasms, Organisms::Eukaryota::Animals [Medical Subject Headings], Anatomy::Cells::Epithelial Cells::Endothelial Cells [Medical Subject Headings], Macrophage, Myeloid Cells, Biology (General), Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred BALB C [Medical Subject Headings], Inbred BALB C, Mice, Inbred BALB C, Tumor, cancer cells, endothelial cells, macrophages, metastasis, pericytes, resistance, single-cell RNA sequencing, tumor angiogenesis, tumor vessel co-option, Animals, Cell Line, Tumor, Endothelial Cells, Female, Kidney Neoplasms, Macrophages, Pericytes, Single-Cell Analysis, Diseases::Neoplasms [Medical Subject Headings], 3. Good health, Metástasis de la neoplasia, Pericitos, Anatomy::Cells::Pericytes [Medical Subject Headings], Cell type, QH301-705.5, Anatomy::Cells::Myeloid Cells [Medical Subject Headings], Biology, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, medicine, Macrófagos, Inductores de la angiogénesis, Células endoteliales, Cancer, medicine.disease, 030104 developmental biology, Cancer cell, Cancer research, Human medicine, 030217 neurology & neurosurgery
Abstract: Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent. ispartof: CELL REPORTS vol:35 issue:11 ispartof: location:United States status: published
Published: 2021
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43. Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts

Author: Laurent Elkrief, Sean Spinney, Daniel E. Vosberg, Tobias Banaschewski, Arun L. W. Bokde, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Sarah Hohmann, Sabina Millenet, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Zdenka Pausova, Tomáš Paus, Guillaume Huguet, Patricia Conrod, the IMAGEN consortium, Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Universität Heidelberg [Heidelberg], Trinity College Dublin, King‘s College London, Heidelberg University, University of Mannheim, University of Vermont [Burlington], University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Freie Universität Berlin, Berlin Institute of Health (BIH), Physikalisch-Technische Bundesanstalt [Berlin] (PTB), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service NEUROSPIN (NEUROSPIN), 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), University Medical Center Göttingen (UMG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Humboldt-Universität zu Berlin, The Hospital for sick children [Toronto] (SickKids), University of Toronto, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Mannheim, Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Humboldt University Of Berlin, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [SDV]Life Sciences [q-bio], RC435-571, Alcohol use disorder, alcohol use disorder, Logistic regression, 03 medical and health sciences, 0302 clinical medicine, Gene interaction, MGLL, Medicine, DAGL, endocannabinoid system, Original Research, 030304 developmental biology, Psychiatry, 0303 health sciences, CNR1, Alcohol Use Disorders Identification Test, Multifactor dimensionality reduction, business.industry, Odds ratio, medicine.disease, cannabinoid receptor 1, Psychiatry and Mental health, Exact test, Cohort, business, 030217 neurology & neurosurgery, Demography
Abstract: Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14–18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; ORCNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.
Published: 2021
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44. Thrombectomy for Primary Distal Posterior Cerebral Artery Occlusion Stroke

Author: Meyer, Lukas, Stracke, Christian Paul, Jungi, Noël, Wallocha, Marta, Broocks, Gabriel, Sporns, Peter, Maegerlein, Christian, Dorn, Franziska, Zimmermann, Hanna, Naziri, Weis, Abdullayev, Nuran, Kabbasch, Christoph, Behme, Daniel, Jamous, Ala, Maus, Volker, Fischer, Sebastian, Möhlenbruch, Markus, Weyland, Charlotte Sabine, Langner, Sönke, Meila, Dan, Miszczuk, Milena, Siebert, Eberhard, Lowens, Stephan, Krause, Lars Udo, Yeo, Leonard, Tan, Benjamin Yong-Qiang, Anil, Gopinathan, Gory, Benjamin, Galván, Jorge, Arteaga, Miguel Schüller, Navia, Pedro, Raz, Eytan, Shapiro, Maksim, Arnberg, Fabian, Zelenák, Kamil, Martinez-Galdamez, Mario, Fischer, Urs, Kastrup, Andreas, Roth, Christian, Papanagiotou, Panagiotis, Kemmling, André, Gralla, Jan, Psychogios, Marios-Nikos, Andersson, Tommy, Chapot, Rene, Fiehler, Jens, Kaesmacher, Johannes, Hanning, Uta, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Bern University Hospital [Berne] (Inselspital), Alfried Krupp Krankenhaus [Essen], University Hospital Basel [Basel], Klinikums rechts der Isar, University-Hospital Munich-Großhadern [München], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Universitätsklinikum Köln (Uniklinik Köln), University Medical Center Göttingen (UMG), Universitätsklinikum Knappschaftskrankenhaus [Bochum], Heidelberg University Hospital [Heidelberg], University Medical Center Rostock, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], National University Health System [Singapore] (NUHS), Yong Loo Lin School of Medicine [Singapore], Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Hospital Clinico Universitario de Valladolid [Castilla y León, Spain] (HCUV), Hospital Universitario La Paz, New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Karolinska University Hospital [Stockholm], Jessenius Medical Faculty [Commenius University, Slovaquie] (JFMED), Commenius University in Bratislava - Univerzita Komenského, Klinikum Bremen-Mitte, National and Kapodistrian University of Athens (NKUA), and Karolinska Institutet [Stockholm]
Subjects: [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2021
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45. Control of Microbial Opsin Expression in Stem Cell Derived Cones for Improved Outcomes in Cell Therapy

Author: Marcela Garita-Hernandez, Antoine Chaffiol, Laure Guibbal, Fiona Routet, Hanen Khabou, Luisa Riancho, Lyes Toualbi, Serge Picaud, José-Alain Sahel, Olivier Goureau, Jens Duebel, Deniz Dalkara, 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), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center Göttingen (UMG), Gestionnaire, Hal Sorbonne Université, and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Transgene, [SDV]Life Sciences [q-bio], Population, Cell, Biology, lcsh:RC321-571, Cell therapy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, cones, medicine, Induced pluripotent stem cell, education, optogenetics, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, education.field_of_study, promoter, human induced pluripotent stem cell, Cell sorting, Cell biology, Transplantation, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Cellular Neuroscience, human retinal organoid, vision restoration, Stem cell, cell therapy, 030217 neurology & neurosurgery
Abstract: International audience; Human-induced pluripotent stem cell (hiPSC) derived organoids have become increasingly used systems allowing 3D-modeling of human organ development, and disease. They are also a reliable source of cells for transplantation in cell therapy and an excellent model to validate gene therapies. To make full use of these systems, a toolkit of genetic modification techniques is necessary to control their activity in line with the downstream application. We have previously described adeno-associated viruse (AAV) vectors for efficient targeting of cells within human retinal organoids. Here, we describe biological restriction and enhanced gene expression in cone cells of such organoids thanks to the use of a 1.7-kb L-opsin promoter. We illustrate the usefulness of implementing such a promoter to enhance the expression of the red-shifted opsin Jaws in fusion with a fluorescent reporter gene, enabling cell sorting to enrich the desired cell population. Increased Jaws expression after transplantation improved light responses promising better therapeutic outcomes in a cell therapy setting. Our results point to the importance of promoter activity in restricting, improving, and controlling the kinetics of transgene expression during the maturation of hiPSC retinal derivatives. Differentiation requires mechanisms to initiate specific transcriptional changes and to reinforce those changes when mature cell states are reached. By employing a cell-type-specific promoter we put transgene expression under the new transcriptional program of mature cells.
Published: 2021
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46. A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients

Author: Xuegong Wang, Per Ljungman, Carlos Solano, Christopher Lademacher, Gerald Wulf, Michael Boeckh, Christine Fredericks, Dominik Selleslag, Dong-Gun Lee, Rodrigo Martino, Amelia Langston, Larry R. Smith, John R. Wingard, Shinichiro Okamoto, Arancha Bermúdez, Aaron C Logan, James Young, Mohamed A. Kharfan-Dabaja, Johan Maertens, Kazuhiko Kakihana, Beth Cywin, Patrice Chevallier, Bernardo, Elizabeth, Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Hospital Universitario Marqués de Valdecilla [Santander], University of California [San Francisco] (UC San Francisco), University of California (UC), University of South Florida [Tampa] (USF), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hospital de la Santa Creu i Sant Pau, University Medical Center Göttingen (UMG), AZ Sint-Jan, Tokyo Metropolitan University [Tokyo] (TMU), Emory University [Atlanta, GA], Catholic University of Korea, Universitat de València (UV), Keio University School of Medicine [Tokyo, Japan], Vical Inc. [San Diego, CA, USA], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), University of Washington [Seattle], University of Florida [Gainesville] (UF), Astellas Pharma Global Development, Inc. [Northbrook, IL, USA], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), and Astellas Pharma Global Development, Inc .
Subjects: medicine.medical_specialty, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, GANCICLOVIR, Placebo, 01 natural sciences, PROPHYLAXIS, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, Medicine, General & Internal, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, General & Internal Medicine, medicine, CYTOMEGALOVIRUS DISEASE, 030212 general & internal medicine, 0101 mathematics, Adverse effect, lcsh:R5-920, Science & Technology, business.industry, Incidence (epidemiology), 010102 general mathematics, General Medicine, Odds ratio, Confidence interval, 3. Good health, business, Complication, lcsh:Medicine (General), Life Sciences & Biomedicine, Research Paper
Abstract: BACKGROUND: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients. METHODS: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting). FINDINGS: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (n = 246) or placebo (n = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (n = 87) with ASP0113 and 30•2% (n = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85; p = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (p = 0.027). INTERPRETATION: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups. FUNDING: Astellas Pharma Global Development, Inc . ispartof: ECLINICALMEDICINE vol:33 ispartof: location:England status: published
Published: 2021
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47. Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study

Author: Bernhard W. Müller, Daniele Altomare, Marco Salvatore, Renaud Lopes, Paolo Maria Rossini, Jens Wiltfang, Moira Marizzoni, Martina Montalti, Stéphanie Bombois, Giovanni B. Frisoni, Clarissa Ferrari, Karl Titus Hoffmann, Camillo Marra, Massimo Caulo, Francesca B. Pizzini, David Bartrés-Faz, Ute Fiedler, Antonio Ferretti, Mira Didic, Manos Constantinidis, Andrea Soricelli, Federica Ribaldi, Joost P.A. Kuijer, Carlo Cavaliere, Antonios Drevelegas, Flavio Nobili, Piero Floridi, Luca Roccatagliata, Julien Sein, Régis Bordet, Franco Alessandrini, Pierre Payoux, Roberto Tarducci, Jorge Jovicich, Olivier Blin, Agnese Picco, Jean-Philippe Ranjeva, Frederik Barkhof, Beatriz Bosch, Magda Tsolaki, Pieter Jelle Visser, Lucilla Parnetti, Tilman Hensch, Jill C. Richardson, Núria Bargalló, Anna Mega, Helene Gros-Dagnac, Marco Aiello, Peter Schönknecht, Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], Laboratory of Neuroimaging of aging, Memory clinic and LANVIE, Geneva University Hospital and Geneva University, Center for Mind/Brain Sciences (CIMEC), University of Trento [Trento], Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili [Genova] (DINOGMI), Universita degli studi di Genova, Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), University of Verona (UNIVR), IRCCS SDN Napoli, Department of Clinic Sciences and Bioimaging, University G. d'Annunzio Chieti-Pescara, Interbalkan Medical Center of Thessaloniki, Dept. of Child and Adolescent Psychiatry and Psychology, Institut Clinic of Neurosciences IDIBAPS (Institut d'Investigacions Biomèdiques August Pi Sunyer), Hospital Clínic Universitari of Barcelona, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Universität Duisburg-Essen [Essen], Department of Neuroscience, Catholic University, Roma, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Toulouse Neuro Imaging Center (ToNIC), 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)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), University Medical Center Göttingen (UMG), Department of Neuroradiology, University Hospital Leipzig, Section of Neurology, Centre for Memory Disturbances, University of Perugia, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Neurology Department, Hospital Clinic, IDIBAPS, Facultad de Medicina, Barcelona, Dept. Neuroscience & Neurorehabilitation, IRCCS-San Raffaele-Pisana, Rome, University of Leipzig Medical Center, Neuroradiology Unit, Perugia General Hospital, Perugia, Alzheimer Center Amsterdam, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Medical Physics Unit, Perugia General Hospital, Perugia, Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, LVR-Clinic for Psychiatry and Psychotherapy, Institutes and Clinics of the University Duisburg-Essen, Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Università degli Studi di Brescia = University of Brescia (UniBs), Università degli studi di Genova = University of Genoa (UniGe), Università degli studi di Verona = University of Verona (UNIVR), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Leipzig University, Università degli Studi di Perugia = University of Perugia (UNIPG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, and Amsterdam Neuroscience - Neurodegeneration
Subjects: Adult, Male, Aging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Image Processing, Medizin, Biomedical Engineering, Biophysics, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Automation, 0302 clinical medicine, Computer-Assisted, Sørensen–Dice coefficient, Image Processing, Computer-Assisted, White matter hyperintensities, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Segmentation, Lesion segmentation toolbox, ComputingMilieux_MISCELLANEOUS, Accuracy, Reproducibility, Lesion segmentation, business.industry, Lesion growth, Automated segmentation algorithms, Multi site, Reproducibility of Results, Gold standard (test), White Matter, Magnetic Resonance Imaging, Hyperintensity, Settore MED/26 - NEUROLOGIA, Cross-Sectional Studies, Algorithms, Female, Nuclear medicine, business, 030217 neurology & neurosurgery
Abstract: Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was −0.22[IQR = 0.50] for LGA-SPM8, −0.12[0.57] for LGA-SPM12, −0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies.
Published: 2021
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48. The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Author: Jan Wenzel, Julian U. G. Wagner, Cyril Robil, Peter König, Rolf Hilgenfeld, Beate Lembrich, Christine Stadelmann, Jonas Franz, Denisa Bojkova, Helge Müller-Fielitz, Valentin Sencio, Yun Jiang, François Trottein, Dimitry Ofengeim, Susanne Pfefferle, Kristin Müller, Markus Glatzel, Roberto Villaseñor, Matija Zelic, Markus Krohn, Fabian Ott, Hauke Busch, Frauke Spiecker, Anke Fähnrich, Ludovic Collin, Caio Coelho, Vincent Prevot, Jakob Körbelin, Josephine Lampe, Mariana Shumliakivska, Umit Ozorhan, Stefanie Dimmeler, Klaus Püschel, Jindrich Cinatl, Hermann C. Altmeppen, Rubén Nogueiras, Olaf Jöhren, Florent Sauve, Vanessa Neve, Raphael Schuster, Sonja Binder, Linlin Zhang, Manolis Pasparakis, Markus Schwaninger, Nina Feller, Marietta Zille, TROTTEIN, François, Universität zu Lübeck = University of Lübeck [Lübeck], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Institute of Cardiovascular Regeneration [Frankfurt, Germany] (Centre for Molecular Medicine), Goethe-University Frankfurt am Main, Frankfurt University Hospital, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Excellence Laboratory LabEx DISTALZ, University Medical Center Göttingen (UMG), Georg-August-University = Georg-August-Universität Göttingen, Max Planck Institute for Experimental Medicine [Göttingen, Germany], German Center for Lung Research, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], University of Cologne, Sanofi US, Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela (IDIS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), and 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)
Subjects: Basement membrane, Pathology, medicine.medical_specialty, Protease, biology, business.industry, General Neuroscience, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Neuropathology, Human brain, biology.organism_classification, [SDV] Life Sciences [q-bio], Mediator, medicine.anatomical_structure, Vero cell, Medicine, business, Protein kinase A, Mesocricetus
Abstract: Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
Published: 2021
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49. TB and COVID-19 co-infection: rationale and aims of a global study

Author: Casco, N., Jorge, A. L., Palmero, D., Alffenaar, J. -W., Fox, G., Ezz, W., Cho, J. -G., Skrahina, A., Solodovnikova, V., Bachez, P., Arbex, M. A., Galvao, T., Rabahi, M., Pereira, G. R., Sales, R., Silva, D. R., Saffie, M. M., Miranda, R. C., Cancino, V., Carbonell, M., Cisterna, C., Concha, C., Cruz, A., Salinas, N. E., Revillot, M. E., Farias, J., Fernandez, I., Flores, X., Gallegos, P., Garavagno, A., Guajardo, C., Bahamondes, M. H., Merino, L. M., Munoz, E., Munoz, C., Navarro, I., Navarro, J., Ortega, C., Palma, S., Pardenas, A. M., Pereira, G., Castillo, P. P., Pinto, M., Pizarro, R., Rivas, F., Rodriguez, P., Sanchez, C., Serrano, A., Soto, A., Taiba, C., Venegas, M., Vergara, M. S., Vilca, E., Villalon, C., Yucra, E., Li, Y., Guelvez, B., Plaza, R., Tello, K., Andrejak, C., Blanc, F. -X., Dourmane, S., Froissart, A., Izadifar, A., Riviere, F., Schlemmer, F., Gupta, N., Ish, P., Mishra, G., Sharma, S., Singla, R., Udwadia, Z. F., Manika, K., Diallo, B. D., Hassane-Harouna, S., Artiles, N., Mejia, L. A., Alladio, F., Calcagno, A., Centis, R., Codecasa, L. R., D'Ambrosio, L., Formenti, B., Gaviraghi, A., Giacomet, V., Goletti, D., Gualano, G., Matteelli, A., Migliori, G. B., Motta, I., Palmieri, F., Prestileo, T., Riccardi, N., Saderi, L., Saporiti, M., Sotgiu, G., Stochino, C., Tadolini, M., Torre, A., Visca, D., Villa, S., Kuksa, L., Danila, E., Diktanas, S., Miliauskas, S., Ridaura, R. L., Lopez, F. L. L., Torrico, M. M., Rendon, A., Akkerman, O. W., Piubello, A., Souleymane, M. B., Aizpurua, E., Gonzales, R., Jurado, J., Loban, A., Aguirre, S., De Egea, V., Irala, S., Medina, A., Sequera, G., Sosa, N., Vazquez, F., Manga, S., Villanueva, R., Araujo, D., Duarte, R., Marques, T. S., Grecu, V. I., Socaci, A., Barkanova, O., Bogorodskaya, M., Borisov, S., Mariandyshev, A., Kaluzhenina, A., Stosic, M., Beh, D., Ng, D., Ong, C. W. M., Solovic, I., Dheda, D., Gina, P., Caminero, J. A., Cardoso-Landivar, J., De Souza Galvao, M. L., Dominguez-Castellano, A., Garcia-Garcia, J. -M., Pinargote, I. M., Fernandez, S. Q., Sanchez-Montalva, A., Huguet, E. T., Murguiondo, M. Z., Bruchfeld, J., Bart, P. -A., Mazza-Stalder, J., Tiberi, S., Arrieta, F., Heysell, S., Logsdon, J., Young, L., Department of Physics [Glasgow], University of Strathclyde [Glasgow], Instituto de Fisica Corpuscular (IFIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universitat de València (UV), Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Added Value Solutions (AVS), Universidade de Santiago de Compostela [Spain] (USC ), Departamento de Ingeniería Térmica y de Fluidos, Avda. Universidad 30, University Medical Center Göttingen (UMG), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, 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), Réanimation Médicale [CHU Henri Mondor - APHP] (DHU A-TVB), CHU Henri Mondor-Université Paris-Est Créteil, Faculté de Médecine [Créteil] (UPEC-Médecine), Inter-University Centre for Astronomy and Astrophysics [Pune] (IUCAA), Alma Mater Studiorum University of Bologna (UNIBO), Laboratoire des EcoSystèmes et des Sociétés en Montagne (UR LESSEM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Milano = University of Milan (UNIMI), Vilnius University [Vilnius], Instituto de Ciencias Nucleares [Mexico], Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Instituto Mexicano del Petróleo (IMP), University of Cadiz, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Bart's and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Southwest Research Institute [Boulder] (SwRI), BIOLOGICAL AND AGRICULTURAL ENGINEERING NORTH CAROLINA STATE UNIVERSITY RALEIGH USA, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Microbes in Health and Disease (MHD), Université Paris-Est Créteil, Faculté de Médecine [Créteil] (UPEC-Médecine)-CHU Henri Mondor, Università degli Studi di Milano [Milano] (UNIMI), and Universidad Nacional Autónoma de México (UNAM)
Subjects: Pulmonary and Respiratory Medicine, Research design, medicine.medical_specialty, Tuberculosis, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], MEDLINE, Global Health, medicine, Global health, Humans, Multicenter Studies as Topic, Prospective Studies, Intensive care medicine, Prospective cohort study, Tuberculosis, Pulmonary, ComputingMilieux_MISCELLANEOUS, business.industry, Coinfection, COVID-19, Pulmonary, medicine.disease, Infectious Diseases, Research Design, business, Co infection
Abstract: International audience
Published: 2021
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50. Combining brain perturbation and neuroimaging in non-human primates

Author: Adam Messinger, Sean Froudist-Walsh, Doris Y. Tsao, Wim Vanduffel, Jean-François Aubry, Richard J. Krauzlis, Melanie Wilke, Angela C. Roberts, Béchir Jarraya, Hiroyuki Oya, Igor Kagan, Andrew S. Fox, Michael Ortiz-Rios, Charles E. Schroeder, P. Christiaan Klink, Anna S. Mitchell, Lynn Uhrig, Elisa E. Konofagou, Vincent P. Ferrera, Michael C. Schmid, Christopher I. Petkov, Jerome Sallet, Matthew F. S. Rushworth, Anna W. Roe, Jordy Tasserie, HAL UVSQ, Équipe, Equipements d'excellence - Thérapie et Neurostimulation cérébrale de très haute précision par Ultrasons Transcraniens - - ULTRABRAIN2010 - ANR-10-EQPX-0015 - EQPX - VALID, Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Physique pour la médecine (PhysMed Paris), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], University of California [Davis] (UC Davis), University of California (UC), New York University [New York] (NYU), NYU System (NYU), Service NEUROSPIN (NEUROSPIN), 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 de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], National Eye Institute [Bethesda, MD, États-Unis] (NEI), National Institutes of Health [Bethesda] (NIH), National Institute of Mental Health (NIMH), University of Oxford, Leibniz Institute for Primate Research, German Primate Centre, Institute for Cell and Molecular Biosciences, The Medical School Newcastle University, University of Northumbria at Newcastle [United Kingdom], University of Iowa [Iowa City], University of Cambridge [UK] (CAM), Zhejiang Gongshang University [Hangzhou] (ZJSU), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Fribourg, Howard Hughes Medical Institute (HHMI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], University Medical Center Göttingen (UMG), German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), Newcastle University [Newcastle], 2015AA020515, IDEX/IMP/2020/14 MECHIDENT 724198 945539 G0B8617N, G0C1920N, G0E0520N, VS02219N ZIA EY000511 637638 National Science Foundation, NSF: 2020C03004, 31627802, 81430010 National Institutes of Health, NIH: MH112142 Howard Hughes Medical Institute, HHMI National Institute of Mental Health, NIMH: ZIA MH002918 California National Primate Research Center, CNPRC: P51-OD011107 Wellcome Trust, WT: WT 110157/Z/15/Z European Research Council, ERC Deutsche Forschungsgemeinschaft, DFG: GA1475-B4, KA 3726/2-1, WI 4046/1-1, WT092606AIA Agence Nationale de la Recherche, ANR: ANR-10-EQPX-15, R01-DC04290 KU Leuven: C14/17/109 Fondation Bettencourt Schueller National Key Research and Development Program of China, NKRDPC: 2018YFA0701400, This work was supported by NIH -MH112142 (V.F. and E.K.), California National Primate Research Center Base Grant ( P51-OD011107 ) (A.F.), Fondation Bettencourt Schueller, France and Human Brain Project (B.J., L.U., J.T.), the Intramural Research Program of the NIMH (ZIA MH002918) (A.M.), Wellcome Trust ( WT 110157/Z/15/Z ) (A.S.M.), European Research Council (ERC StG, OptoVision, 637638 ) (M.C.S and M.O.R.), National Key R&D Program of China 2018YFA0701400 (A.W.R.), Chinese NSF ( 81430010 and 31627802 ) (A.W.R.), Zhejiang province 2020C03004 (A.W.R.), Chinese National R&D Program Grant 2015AA020515 (A.W.R.), IDEXLYON 'IMPULSION 2020 grant (IDEX/IMP/2020/14) (J.S.), Howard Hughes Medical Institute (D.T.), KU Leuven grant C14/17/109 (W.V.), the National Eye Institute Intramural Research Program (ZIA EY000511 ) at the National Institutes of Health, U.S.A. (W.V.), Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO) G0D5817N , G0B8617N , G0C1920N , G0E0520N , VS02219N (W.V.), the European Union's Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 945539 (Human Brain Project SGA3) (W.V.), Hermann and Lilly Schilling Foundation, German Research Foundation (DFG) grants WI 4046/1-1 and Research Unit GA1475-B4, KA 3726/2-1, Primate Platform of DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB) (M.W. and I.K.), Wellcome Trust ( WT092606AIA ) (C.I.P.), European Research Council Horizon 2020 (ERC CoG, MECHIDENT 724198) (C.I.P.), the Bettencourt Schueller Foundation (Ultrabrain project) (J.-F. A.), the French National Agency for Research ( ANR-10-EQPX-15 ) (J.-F. A.):and the National Institutes of Health (with Matthew Howard III: R01-DC04290 ) (C.I.P.), This work was supported by NIH-MH112142 (V.F. and E.K.), California National Primate Research Center Base Grant (P51-OD011107) (A.F.), Fondation Bettencourt Schueller, France and Human Brain Project (B.J. L.U. J.T.), Wellcome Trust (WT 110157/Z/15/Z) (A.S.M.), European Research Council (ERC StG, OptoVision, 637638) (M.C.S and M.O.R.), Chinese NSF (81430010 and 31627802) (A.W.R.), IDEXLYON ?IMPULSION 2020 grant (IDEX/IMP/2020/14) (J.S.), the National Eye Institute Intramural Research Program (ZIA EY000511) at the National Institutes of Health, U.S.A. (W.V.), Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO) G0D5817N, G0B8617N, G0C1920N, G0E0520N, VS02219N (W.V.), Wellcome Trust (WT092606AIA) (C.I.P.), the French National Agency for Research (ANR-10-EQPX-15) (J.-F. A.):and the National Institutes of Health (with Matthew Howard III: R01-DC04290) (C.I.P.), All research discussed in this work was performed in accordance with institutional and nationally approved oversight, such as the NIH Guide for Care and Use of Laboratory Animals, the U.K. Animals (Scientific Procedures) Act, 1986, and European Directive 2010/63/EU., ANR-10-EQPX-0015,ULTRABRAIN,Thérapie et Neurostimulation cérébrale de très haute précision par Ultrasons Transcraniens(2010), Institut cellule souche et cerveau (SBRI), Université de Fribourg = University of Fribourg (UNIFR), Physique pour la médecine (UMR 8063, U1273), University of California, 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, University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Subjects: Primates, Computer science, Cognitive Neuroscience, primates, Neuroimaging, Neurosciences. Biological psychiatry. Neuropsychiatry, Optogenetics, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Ultrasound, Animals, Humans, 0501 psychology and cognitive sciences, Lesion, Microstimulation, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, fMRI, [SCCO.NEUR] Cognitive science/Neuroscience, Brain, Chemogenetics, Causality, Neurology, Causal inference, Non-human, Neurological lesion, Infrared, Neuroscience, 030217 neurology & neurosurgery, RC321-571
Abstract: Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods. ispartof: NEUROIMAGE vol:235 ispartof: location:United States status: published
Published: 2021
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