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17 results on '"Federal Institute of Drugs and Medical Devices [Bonn]"'

1. Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Author: Chiesa P. A., Cavedo E., Vergallo A., Lista S., Potier M. -C., Habert M. -O., Dubois B., Thiebaut de Schotten M., Hampel H., Audrain C., Auffret A., Bakardjian H., Baldacci F., Batrancourt B., Benakki I., Benali H., Bertin H., Bertrand A., Boukadida L., Cacciamani F., Causse V., Cherif Touil S., Colliot O., Dalla Barba G., Depaulis M., Dos Santos A., Dubois M., Epelbaum S., Fontaine B., Francisque H., Gagliardi G., Genin A., Genthon R., Glasman P., Gombert F., Habert M. O., Hewa H., Houot M., Jungalee N., Kas A., Kilani M., La Corte V., Le Roy F., Lehericy S., Letondor C., Levy M., Lowrey M., Ly J., Makiese O., Masetti I., Mendes A., Metzinger C., Michon A., Mochel F., Nait Arab R., Nyasse F., Perrin C., Poirier F., Poisson C., Potier M. C., Ratovohery S., Revillon M., Rojkova K., Santos-Andrade K., Schindler R., Servera M. C., Seux L., Simon V., Skovronsky D., Uspenskaya O., Vlaincu M., Aguilar L. F., Babiloni C., Benda N., Black K. L., Bokde A. L. W., Bonuccelli U., Broich K., Cacciola F., Castrillo J., Ceravolo R., Corvol J. -C., Claudio Cuello A., Cummings J. L., Depypere H., Duggento A., Durrleman S., Escott-Price V., Federoff H., Teresa Ferretti M., Fiandaca M., Frank R. A., Garaci F., Geerts H., George N., Giorgi F. S., Graziani M., Haberkamp M., Herholz K., Karran E., Kim S. H., Koronyo Y., Koronyo-Hamaoui M., Lamari F., Langevin T., Lorenceau J., Mango D., Mapstone M., Neri C., Nistico R., O'Bryant S. E., Palermo G., Perry G., Ritchie C., Rossi S., Saidi A., Santarnecchi E., Schneider L. S., Sporns O., Toschi N., Verdooner S. R., Villain N., Welikovitch L. A., Woodcock J., Younesi E., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Treat SVD, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), sans affiliation, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre des Maladies Cognitives et Comportementales [Paris], Fraunhofer Center for Assistive Information and Communication Solutions [Porto] (Fraunhofer AICOS), Fraunhofer (Fraunhofer-Gesellschaft), Ariana Pharmaceuticals, McGill University = Université McGill [Montréal, Canada], Universidad Autonoma de Madrid (UAM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], University of Pisa - Università di Pisa, Federal Institute of Drugs and Medical Devices [Bonn], Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin, Universita degli Studi di Messina, University of Catania [Italy], University of Cambridge [UK] (CAM), Lou Ruvo Center for Brain Health [Las Vegas], Cleveland Clinic, Università degli Studi di Roma Tor Vergata [Roma], University of Pavia, Cardiff University, Universität Zürich [Zürich] = University of Zurich (UZH), University of California [Irvine] (UCI), University of California, Siemens Healthineers, Digital Services, Digital Technology and Innovation, In Silico Biosciences (ISB), Abdus Salam International Centre for Theoretical Physics [Trieste] (ICTP), University of California [San Francisco] (UCSF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Manchester [Manchester], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Abbvie Inc. [North Chicago], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Britsh Columbia [Vancouver], Cedars-Sinai Medical Center, Functional Neuromodulation, CIBER de Enfermedades Raras (CIBERER), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Brain Research Institute [Rome, Italy] (EBRI), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), 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)-Centre National de la Recherche Scientifique (CNRS), Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], University of Auckland [Auckland], University of Edinburgh, Università degli Studi di Siena = University of Siena (UNISI), Harvard Medical School [Boston] (HMS), Keck School of Medicine [Los Angeles], University of Southern California (USC), Indiana State University, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), NeuroVision Imaging, Fondation pour la Recherche sur Alzheimer, Center for Drug Evaluation and Research (CDER), European Society for Translational Medicine (EUSTM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Explorations Fonctionnelles Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Fraunhofer AICOS [Porto], McGill University, Sapienza University [Rome], University of Zürich [Zürich] (UZH), Università degli Studi di Roma 'La Sapienza' [Rome], CHU Pitié-Salpêtrière [APHP], Service de neuro-radiologie [CHU Pitié-Salpêtrière], Università degli Studi di Siena (UNISI), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Médecine nucléaire [CHU Pitié-Salpétrière], Universidad Autónoma de Madrid (UAM), 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), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Sans affiliation, 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)-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), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Messina = University of Messina (UniMe), Università degli Studi di Pavia = University of Pavia (UNIPV), University of California [Irvine] (UC Irvine), University of California (UC), University of California [San Francisco] (UC San Francisco), University of British Columbia [Vancouver], 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), Chiesa, P. A., Cavedo, E., Vergallo, A., Lista, S., Potier, M. -C., Habert, M. -O., Dubois, B., Thiebaut de Schotten, M., Hampel, H., Audrain, C., Auffret, A., Bakardjian, H., Baldacci, F., Batrancourt, B., Benakki, I., Benali, H., Bertin, H., Bertrand, A., Boukadida, L., Cacciamani, F., Causse, V., Cherif Touil, S., Colliot, O., Dalla Barba, G., Depaulis, M., Dos Santos, A., Dubois, M., Epelbaum, S., Fontaine, B., Francisque, H., Gagliardi, G., Genin, A., Genthon, R., Glasman, P., Gombert, F., Habert, M. O., Hewa, H., Houot, M., Jungalee, N., Kas, A., Kilani, M., La Corte, V., Le Roy, F., Lehericy, S., Letondor, C., Levy, M., Lowrey, M., Ly, J., Makiese, O., Masetti, I., Mendes, A., Metzinger, C., Michon, A., Mochel, F., Nait Arab, R., Nyasse, F., Perrin, C., Poirier, F., Poisson, C., Potier, M. C., Ratovohery, S., Revillon, M., Rojkova, K., Santos-Andrade, K., Schindler, R., Servera, M. C., Seux, L., Simon, V., Skovronsky, D., Uspenskaya, O., Vlaincu, M., Aguilar, L. F., Babiloni, C., Benda, N., Black, K. L., Bokde, A. L. W., Bonuccelli, U., Broich, K., Cacciola, F., Castrillo, J., Ceravolo, R., Corvol, J. -C., Claudio Cuello, A., Cummings, J. L., Depypere, H., Duggento, A., Durrleman, S., Escott-Price, V., Federoff, H., Teresa Ferretti, M., Fiandaca, M., Frank, R. A., Garaci, F., Geerts, H., George, N., Giorgi, F. S., Graziani, M., Haberkamp, M., Herholz, K., Karran, E., Kim, S. H., Koronyo, Y., Koronyo-Hamaoui, M., Lamari, F., Langevin, T., Lorenceau, J., Mango, D., Mapstone, M., Neri, C., Nistico, R., O'Bryant, S. E., Palermo, G., Perry, G., Ritchie, C., Rossi, S., Saidi, A., Santarnecchi, E., Schneider, L. S., Sporns, O., Toschi, N., Verdooner, S. R., Villain, N., Welikovitch, L. A., Woodcock, J., Younesi, E., and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Apolipoprotein E, Epidemiology, Brain activity and meditation, Precuneus, Disease, Neuropsychological Tests, Hippocampus, Cohort Studies, [SCCO]Cognitive science, 0302 clinical medicine, Medicine, Longitudinal Studies, Default mode network, ComputingMilieux_MISCELLANEOUS, Brain Mapping, Subjective memory complaints, Brain functional dynamic, Health Policy, Precision medicine, fMRI, Settore BIO/14, Brain, Brain functional dynamics, Alzheimer's disease, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, Psychiatry and Mental health, medicine.anatomical_structure, Cohort, Biomarker (medicine), Female, Amyloid, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Humans, Aged, Resting state fMRI, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, 030104 developmental biology, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Introduction The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E e4 (APOE e4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion For the first time, we demonstrated that the pleiotropic biological effect of the APOE e4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.
Published: 2019
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2. Recent advances in methodology for clinical trials in small populations the InSPiRe project

Author: Emmanuelle Comets, Martin Posch, Simon Day, A. Tournazi, Christian Röver, A. Dmitrenko, Burak Kürsad Günhan, Norbert Benda, Jason Madan, Corinne Alberti, Steffen Unkel, Nigel Stallard, Michael Pearce, Sarah Zohar, Frank Miller, Moreno Ursino, Frederike Lentz, Thomas Ondra, Tim Friede, Alexandra Graf, Gernot Wassmer, Siew Wan Hee, Troccaz, Olivier, University Medical Center Göttingen (UMG), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Medizinische Universität Wien = Medical University of Vienna, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Federal Institute of Drugs and Medical Devices [Bonn], 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), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Warwick [Coventry], Stockholm University, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), European Union [FP HEALTH 2013-602144], École Pratique des Hautes Études (EPHE), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: FOS: Computer and information sciences, Rare disease clinical trial, Statistical methods, Computer science, Population, lcsh:Medicine, Review, Statistics - Applications, 01 natural sciences, Methodology (stat.ME), 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, [STAT.AP] Statistics [stat]/Applications [stat.AP], Humans, Pharmacology (medical), Treatment effect, Applications (stat.AP), 030212 general & internal medicine, 0101 mathematics, education, Statistics - Methodology, Genetics (clinical), education.field_of_study, [STAT.AP]Statistics [stat]/Applications [stat.AP], Clinical study design, lcsh:R, Small population size, General Medicine, FP7 small populations methodology projects, R1, Data science, 3. Good health, Clinical trial, Identification (information), Research Design, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Early phase
Abstract: Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017. The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods., Comment: 9 pages, 3 figures
Published: 2018
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3. A dose finding design for seizure reduction in neonates

Author: Ursino, Moreno, Yuan, Ying, Alberti, Corinne, Comets, Emmanuelle, Favrais, Geraldine, Friede, Tim, Lentz, Frederike, Stallard, Nigel, Zohar, Sarah, 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), The University of Texas M.D. Anderson Cancer Center [Houston], Paris Diderot - Paris 7 - UFR Lettres, Arts, Langues (UPD7 UFR LAC), 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), 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), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University Medical Center Göttingen (UMG), Federal Institute of Drugs and Medical Devices [Bonn], University of Warwick [Coventry], École pratique des hautes études (EPHE), and Zohar, Sarah
Subjects: [SDV] Life Sciences [q-bio], [STAT]Statistics [stat], Time to event, Efficacy, Newborns, Phase I–II, Toxicity constraints, RJ, [SDV]Life Sciences [q-bio], [STAT] Statistics [stat]
Abstract: International audience; Clinical trials in vulnerable populations are extremely difficult to conduct. A sequential phase I–II trial aimed at finding the appropriate dose of levetiracetam for treating neonatal seizures was planned with a maximum sample size of 50 newborns. Three primary outcomes are considered: efficacy and two types of toxicity that occur at the same time but are measured at different time points. In the case of failure, physicians could add a second agent as a rescue medication.The primary outcomes were modelled via a logistic model for efficacy and a weighted likelihood with pseudo-outcomes for the two toxicities taking into account the dependences under Bayesian inference. Simulations were conducted to assess the design properties.
Published: 2018
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4. Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Biomarkers and Frailty

Author: Andrea Laslop, Eleonora Tajana Messi, Pieter D’Hooghe, René Rizzoli, Olivier Bruyère, S. Reiter-Niesert, Francis Berenbaum, Nigel K Arden, Gabriel Herrero-Beaumont, Jean-Pierre Devogelaer, Cécile Clerc, Johanne Martel-Pelletier, Giuseppe Mautone, Yannis Tsouderos, Jean-Pierre Pelletier, Cyrus Cooper, Lucio C. Rovati, Marc C. Hochberg, Stefania Maggi, Maria Luisa Brandi, Jean-Yves Reginster, F Petit-Dop, Elaine M. Dennison, Véronique Leblanc, Jaime Branco, Eric Abadie, John A. Kanis, Pascal Richette, NIHR Musculoskeletal BRU, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford [Oxford], ARUK Sports, Exercise and Osteoarthisis Centre of Excellence, Oxford, UFR Médicale, Université Paris Diderot - Paris 7 (UPD7), Fédération de rhumatologie, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MRC Epidemiology Resource Centre, University of Southampton, Department of public health, Université de Liège, Division of cardiology, Hôpital Ambroise Paré [AP-HP], CEDOC - Department of Rheumatology, Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), CHLO, EPE, Hospital De Egas Moniz, Department of internal medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoires Genevrier Antibes, Department of rheumatology, Saint Luc University Hospital, Division of rheumatology and clinical immunology, University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System, Department of orthopaedics and sport medicine, Aspetar Hospital, Doha, Qatar, Bone and Joint Research Unit, Fundacion Jimenez Diaz [Madrid] (FJD), WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield [Sheffield], Scientific Office, Austrian Agency for Health and Food Safety (AGES), Expansciences laboratoires, Courbevoie, Aging Program, National research council, Padua, Italy, Institut Biochimique SA (IBSA), Osteoarthritis Research Unit, Université de Montréal (UdeM)-Hopital Notre-Dame, Institut de Recherches Internationales Servier (IRIS), Laboratoire Servier, Federal Institute of Drugs and Medical Devices [Bonn], Service of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital and Geneva University, Clinical Research Unit, Rottapharm/Madaus, University of Oxford, Università degli Studi di Firenze = University of Florence (UniFI), CHU Pitié-Salpêtrière [AP-HP], NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), Service de Rhumatologie [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université
Subjects: medicine.medical_specialty, Osteoporosis, MEDLINE, Osteoarthritis, Disease, Bioinformatics, Pharmacotherapy, Predictive Value of Tests, Risk Factors, medicine, Humans, Pharmacology (medical), [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Current Opinion, Potential biomarkers, Predictive value of tests, ddc:618.97, Physical therapy, Disease Progression, Personalized medicine, Geriatrics and Gerontology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract: Funding: This meeting was founded by the European Society for Clinical and Economics Aspect of Osteoporosis and Osteoarthritis, a not for profit organization from Belgium. Osteoarthritis (OA), a disease affecting different patient phenotypes, appears as an optimal candidate for personalized healthcare. The aim of the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group was to explore the value of markers of different sources in defining different phenotypes of patients with OA. The ESCEO organized a series of meetings to explore the possibility of identifying patients who would most benefit from treatment for OA, on the basis of recent data and expert opinion. In the first meeting, patient phenotypes were identified according to the number of affected joints, biomechanical factors, and the presence of lesions in the subchondral bone. In the second meeting, summarized in the present article, the working group explored other markers involved in OA. Profiles of patients may be defined according to their level of pain, functional limitation, and presence of coexistent chronic conditions including frailty status. A considerable amount of data suggests that magnetic resonance imaging may also assist in delineating different phenotypes of patients with OA. Among multiple biochemical biomarkers identified, none is sufficiently validated and recognized to identify patients who should be treated. Considerable efforts are also being made to identify genetic and epigenetic factors involved in OA, but results are still limited. The many potential biomarkers that could be used as potential stratifiers are promising, but more research is needed to characterize and qualify the existing biomarkers and to identify new candidates. publishersversion published
Published: 2015
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5. A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling

Author: Stanley Durrleman, Jean-Christophe Corvol, Erfan Younesi, Bruno Dubois, Karl Broich, Simone Lista, Sid E. O'Bryant, Harald Hampel, Valentina Escott-Price, Katrine Rojkova, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), European Society for Translational Medicine (EUSTM), Cardiff University, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Federal Institute of Drugs and Medical Devices [Bonn], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), 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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and 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)-Inria de Paris
Subjects: 0301 basic medicine, MESH: Health Services Needs and Demand, medicine.medical_specialty, Pathology, Neurology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, International Cooperation, Alzheimer precision medicine initiative, Disease, MESH: Precision Medicine, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Medicine, Humans, systems medicine, Precision Medicine, Intensive care medicine, Health Services Needs and Demand, MESH: Humans, business.industry, integrative disease modeling, precision medicine initiative, Obstetrics and Gynecology, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], systems biology, General Medicine, Precision medicine, R1, 3. Good health, Clinical trial, Systems medicine, MESH: International Cooperation, 030104 developmental biology, Drug development, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], MESH: Biomarkers, Biomarker (medicine), business, Magic bullet, Alzheimer’s disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, MESH: Alzheimer Disease, Biomarkers
Abstract: International audience; After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.
Published: 2017

6. 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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7. Identification and validation of biomarkers for autism spectrum disorders

Author: Marion Haberkamp, Karl Broich, Sarah Durston, Antonio M. Persico, Luca Pani, Tony Charman, Michael V. Lombardo, Luke Mason, Sven Bölte, Declan G. Murphy, Christine Ecker, Simon Baron-Cohen, Koichi Okamoto, Emily J.H. Jones, Jordi Llinares-Garcia, Steve C.R. Williams, Lindsay Ham, Will Spooren, Spiros Vamvakas, David A. Collier, Emily Simonoff, Caroline Auriche-Benichou, Maria Isaac, Thomas Bourgeron, Valentina Mantua, Sabine Lenton, Andreas Meyer-Lindenberg, Robert Hemmings, Sitra Tauscher-Wisniewski, Mark H. Johnson, Eva Loth, Jan K. Buitelaar, Omar Khwaja, Andre Elferink, Gahan Pandina, Tobias Banaschewski, Laurence O'Dwyer, Fernando de Andres-Trelles, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], European Medicines Agency [London] (EMA), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), Medizinische Fakultät Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, University of Cambridge [UK] (CAM), Federal Institute of Drugs and Medical Devices [Bonn], Karolinska Institutet [Stockholm], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Eli Lilly and Company Limited [Windlesham], Spanish Medicines Agency and Medical Devices [Madrid] (AEMPS), University Medical Center [Utrecht], Medicines Evaluation Board [Utrecht], Centre for Brain and Cognitive Development [Birkbeck College], Birkbeck College [University of London], Italian Medicines Agency [Roma] (AIFA), University of Cyprus [Nicosia] (UCY), Radboud University Medical Center [Nijmegen], Janssen Research & Development, Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Universität Heidelberg [Heidelberg], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and University of Cyprus [Nicosia]
Subjects: Male, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], [SCCO]Cognitive science, 0302 clinical medicine, MESH: Child, Drug Discovery, Child, ComputingMilieux_MISCELLANEOUS, MESH: Autism Spectrum Disorder, Medicine (all), 05 social sciences, MESH: Endophenotypes, General Medicine, Autism spectrum disorders, Gene expression profiling, MESH: Reproducibility of Results, Autism spectrum disorder, MESH: Young Adult, Child, Preschool, Female, Identification (biology), 050104 developmental & child psychology, Adult, medicine.medical_specialty, Adolescent, Endophenotypes, Brain imaging, Computational biology, Young Adult, 03 medical and health sciences, Neuroimaging, medicine, Humans, 0501 psychology and cognitive sciences, Preschool, Psychiatry, Pharmacology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Drug Discovery3003 Pharmaceutical Science, MESH: Child, Preschool, Reproducibility of Results, MESH: Adult, medicine.disease, MESH: Male, Adolescent, Adult, Autism Spectrum Disorder, Biomarkers, Child, Child, Preschool, Endophenotypes, Female, Humans, Male, Reproducibility of Results, Young Adult, Medicine (all), Pharmacology, Drug Discovery3003 Pharmaceutical Science, Biomarkers, Endophenotype, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Biomarkers, Autism, business, MESH: Female, 030217 neurology & neurosurgery
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Published: 2015
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8. The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations

Author: Ara S. Khachaturian, Sid E. O'Bryant, Lon S. Schneider, Bruno Vellas, M. Thiebaut de Schotten, Bruno Dubois, Simone Lista, Zaven S. Khachaturian, C. R. Jack, Keith A. Johnson, Harald Hampel, William E. Klunk, Miia Kivipelto, J. Cummings, Henrik Zetterberg, Karl Herholz, Karl Broich, Sandrine Andrieu, Adriaan A. Lammertsma, Alexander Drzezga, Kaj Blennow, Reisa A. Sperling, Jean-François Mangin, Stefan J. Teipel, Olivier Colliot, Giovanni B. Frisoni, Arun L.W. Bokde, Paul S. Aisen, Philippe Amouyel, Hovagim Bakardjian, Enrica Cavedo, Radiology and nuclear medicine, NCA - neurodegeneration, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Prevent Alzheimer’s Disease 2020 [Rockville] (PAD 2020), Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Department of Radiology [Rochester], Mayo Clinic [Rochester], Center for Alzheimer Research and Treatment [Boston], Harvard Medical School [Boston] (HMS), Lou Ruvo Center for Brain Health [Las Vegas], Cleveland Clinic, Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), University of North Texas Health Science Center [Fort Worth], IRCCS San Giovanni, Laboratory of Epidemiology and Neuroimaging, Brescia, Alzheimer’s & Dementia [Rockville], Karolinska Institutet [Stockholm], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Federal Institute of Drugs and Medical Devices [Bonn], Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'épidémiologie [Toulouse], CHU Toulouse [Toulouse], Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of psychiatry-King‘s College London, Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Neuroimagerie Assistée par Ordinateur (LNAO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychosomatic Medicine [Rostock], University of Rostock, Department of Nuclear Medicine [Cologne], University Hospital of Cologne [Cologne], Institute of Neuroscience, Trinity College Dublin-Trinity College Dublin-Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin-School of Medicine [Dublin], Trinity College Dublin, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Fédération de neurologie 4, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Keck School of Medicine [Los Angeles], University of Southern California (USC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Colliot, Olivier
Subjects: Oncology, medicine.medical_specialty, prevention trials, Neuroimaging, Disease, Article, 03 medical and health sciences, ddc:616.89, 0302 clinical medicine, Atrophy, Internal medicine, Medicine, Dementia, ddc:610, Alzheimer’s Disease, Biomarker discovery, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, 030304 developmental biology, 0303 health sciences, neuroimaging, business.industry, biomarkers, Prevention Trials, molecular imaging, medicine.disease, Molecular Imaging, 3. Good health, Clinical trial, Biomarker (medicine), business, Alzheimer’s disease, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Neuroscience, Biomarkers, 030217 neurology & neurosurgery, Tractography
Abstract: Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.
Published: 2014
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9. Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Author: Lars Bertram, Hovagim Bakardjian, Stéphane Epelbaum, Alexander Drzezga, Paul S. Aisen, Robert Nisticò, Alexis Brice, Kaj Blennow, Charles Duyckaerts, Karl Broich, Stefan J. Teipel, Stéphane Lehéricy, Francesco Giuseppe Garaci, Bruno Dubois, Simone Lista, Zaven S. Khachaturian, Olivier Colliot, Harald Hampel, Henrik Zetterberg, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Department of Psychosomatic Medicine [Rostock], University of Rostock, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Department of Physiology and Pharmacology [Rome], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Vertebrate Genomics [Berlin], Max-Planck-Institut für Molekulare Genetik (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Department of Nuclear Medicine [Cologne], University Hospital of Cologne [Cologne], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Federal Institute of Drugs and Medical Devices [Bonn], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Prevent Alzheimer’s Disease 2020 [Rockville] (PAD 2020), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Department of Neurosciences [San Diego], University of California-University of California, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: CSF/blood biomarkers, Psychological intervention, Disease, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Clinical trials, alzheimer's disease, clinical trials, csf/blood biomarkers, pet imaging markers, structural/functional mri markers, Alzheimer Disease, Structural/functional MRI markers, Medicine, Humans, ddc:610, 030304 developmental biology, Pharmacology, 0303 health sciences, Alzheimer's disease, PET imaging markers, Biological Markers, Clinical Trials as Topic, Operationalization, Conceptualization, therapy [Alzheimer Disease], business.industry, Perspective (graphical), Settore BIO/14, medicine.disease, 3. Good health, Clinical trial, Clinical therapy, business, Neuroscience, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, metabolism [Alzheimer Disease], Biomarkers, metabolism [Biomarkers]
Abstract: International audience; Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.
Published: 2014
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10. Fungal respiratory infections in cystic fibrosis: a growing problem

Author: Françoise Symoens, Jean-Philippe Bouchara, R. Horré, Laurence Delhaes, Federal Institute of Drugs and Medical Devices [Bonn], University of Bonn, Mycology [Brussels], Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] (WIV-ISP), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Laboratoire de Parasitologie-Mycologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), 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), Univ Angers, Okina, and Universität Bonn = University of Bonn
Subjects: medicine.medical_specialty, Cystic Fibrosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Prevalence, Context (language use), Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Lung transplantation, Colonization, MESH: Cystic Fibrosis / microbiology, Risk factor, Intensive care medicine, MESH: Cystic Fibrosis / complications, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Aspergillus fumigatus / isolation & purification, MESH: Mitosporic Fungi / isolation & purification, MESH: Humans, Lung Diseases, Fungal, biology, 030306 microbiology, business.industry, Aspergillus fumigatus, General Medicine, MESH: Lung Diseases, Fungal / microbiology, biology.organism_classification, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, medicine.anatomical_structure, 030228 respiratory system, MESH: Mitosporic Fungi / classification, MESH: Pulmonary Aspergillosis / microbiology, Mitosporic Fungi, Pulmonary Aspergillosis, business, Exophiala dermatitidis, Respiratory tract
Abstract: tions increases as the life expectancy of patients improves. But in contrast to bacterial respiratory infections, relatively little progress has been made with regards to fungal respiratory infections. Aspergillus fumigatus is by far the most common causative agent with a reported prevalence rate varying from 5.9% to 58.3%, but a wide range of fungi may colonize the respiratory tract of CF patients. For example, other Aspergillus species like Aspergillus terreus , as well as Scedosporium spp. and Exophiala dermatitidis are increasingly described in the CF context, but their prevalence is certainly underestimated. Additionally, whether the colonization of the airways by fungi/micromycetes constitutes a clinically relevant problem is still a matter of debate. However, recent studies have clearly indicated an increase in their prevalence rate, and a relationship with increased numbers of hospital admissions. Moreover, due to their thermotolerance and to their propensity to disseminate in immunocompromised hosts, prior colonization of the airways by fi lamentous fungi constitutes a serious risk factor for invasive infections in cases of lung transplantation. The latter remains the ultimate treatment of CF patients. Numerous questions are created by fungal colonization of the airways, and basic research on the ecology of the fungi, their biochemistry, and their pathogenic mechanisms should be promoted in order to defi ne prophylactic measures or to develop more effi cient antifungal drugs. To address these questions, the International Society for Human and Animal Mycology (ISHAM) launched in October 2006, a working group on “Fungal Respiratory Infections in Cystic Fibrosis”, whose fi rst formal meeting was held in Angers, France, on June 7-8, 2009. Altogether 65 clinicians, mycologists or scientists from 14 different countries participated to this meeting, as well as numerous PhD students to guarantee dynamic discussions. Thirtyeight presentations were provided by attendees, covering a wide variety of topics, including (a) “clinical surveillance All authors are members of the ISHAM working group on Fungal Respiratory Infections in Cystic Fibrosis. Correspondence: Jean-Philippe Bouchara, Groupe d’Etude des Interactions Hote-Pathogene, UPRES-EA 3142, Laboratoire de ParasitologieMycologie, CHU, 4 rue Larrey, 49933 Angers cedex 9, France. Tel: 33 (0)2 41 35 34 72; Fax: 33 (0)2 41 35 36 16; E-mail: jean-philippe. bouchara@univ-angers.fr Fungal respiratory infections in cystic fi brosis: a growing problem
Published: 2010
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11. Association of Polymorphic Cytochrome P450 Enzyme Pathways with Falls in Multimedicated Older Adults.

Author: Just KS, Pott LM, Sommer J, Scholl C, Steffens M, Denkinger MD, Rothenbacher D, Dallmeier D, and Stingl JC
Subjects: Humans, Male, Aged, Female, Prospective Studies, Aged, 80 and over, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2C19 metabolism, Polymorphism, Genetic, Polypharmacy, Independent Living, Accidental Falls, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism
Abstract: Objectives: Dose exposure is considered relevant for drug-associated falls in older adults, pointing to an importance of drug metabolism. Aim was to analyze individual factors altering drug metabolism such as enzyme saturation by drug exposure and pharmacogenetics in the context of drug-associated falls., Design: Prospective population-based study (ActiFE-Ulm study)., Setting and Participants: Community-dwelling older adults., Methods: Focus was laid on the metabolism by polymorphic cytochrome P450 (CYP) enzymes CYP2C19, 2C9, and 2D6. Relevant variants of pharmacogenes were analyzed. Logistic binary regression analysis was used to calculate odds ratios (ORs) and 95% CIs for falls observed prospectively over a 1-year period with drug metabolism characteristics., Results: In total, 1377 participants were included in the analysis. Although the phenotype predicted by the genotype was not, the use of drugs metabolized by CYP2C19 was associated with falls. Drugs not known as fall risk-increasing drugs (FRIDs; ie, non-FRIDs), but metabolized by CYP2C19, showed an OR of 1.46 (1.11-1.93) in adjusted analysis. Significant effect modification was observed for a reduced CYP2C19 activity phenotype with non-FRIDs metabolized by CYP2C19., Conclusions and Implications: This study suggests an association between the occurrence of falls in older adults and the metabolic capacity of CYP2C19. Thus, an important step toward prevention of falls might be to personalize dosage and treatment length of the main drug classes known to be CYP2C19 substrates, such as many antidepressants, opioids, and sedatives, but also proton pump inhibitors in particular in poor and intermediate metabolizers., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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12. The new European Medicines Agency guideline on antidepressants: a guide for researchers and drug developers.

Author: Butlen-Ducuing F, Haberkamp M, Aislaitner G, Bałkowiec-Iskra E, Mattila T, Doucet M, Kollb-Sielecka M, Balabanov P, Leuchs AK, and Elferink A
Subjects: Humans, Pandemics, Antidepressive Agents adverse effects, Anxiety, Anxiety Disorders, Depressive Disorder, Major epidemiology
Abstract: According to the World Health Organization (WHO), depressive disorders are currently considered as one of the most disabling medical conditions in the world with one of the highest disability-adjusted life years [1] and this situation has apparently been further worsened during the COVID-19 pandemic [2]. Up to two thirds of patients with major depressive disorders (MDD) do not achieve full remission following an adequate first line standard of care and/or experience residual symptoms such as anxiety, impaired cognition, fatigue, sleep disturbance, or anhedonia [3]. Several attempts are often needed to find the most suitable treatment [4]. Thus, there is a need for medicinal products with better efficacy (e.g., faster onset of action, higher rates of response and remission), improved safety and/or more personalised profiles [5].
Published: 2023
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13. The therapeutic potential of psychedelics: the European regulatory perspective.

Author: Butlen-Ducuing F, McCulloch DE, Haberkamp M, Mattila T, Bałkowiec-Iskra E, Aislaitner G, Balabanov P, Lundberg J, Stenbæk DS, Elferink A, Knudsen GM, and Thirstrup S
Subjects: Humans, Hallucinogens therapeutic use
Published: 2023
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14. Green Tea Extract to Prevent Colorectal Adenomas, Results of a Randomized, Placebo-Controlled Clinical Trial.

Author: Seufferlein T, Ettrich TJ, Menzler S, Messmann H, Kleber G, Zipprich A, Frank-Gleich S, Algül H, Metter K, Odemar F, Heuer T, Hügle U, Behrens R, Berger AW, Scholl C, Schneider KL, Perkhofer L, Rohlmann F, Muche R, and Stingl JC
Subjects: Antioxidants therapeutic use, Double-Blind Method, Humans, Plant Extracts therapeutic use, Tea, Adenoma prevention & control, Colorectal Neoplasms prevention & control
Abstract: Introduction: Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum., Methods: A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization., Results: The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169)., Discussion: GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population., (Copyright © 2022 by The American College of Gastroenterology.)
Published: 2022
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15. CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System-Results From the ADRED Study.

Author: Just KS, Dormann H, Freitag M, Schurig M, Böhme M, Steffens M, Scholl C, Seufferlein T, Graeff I, Schwab M, and Stingl JC
Abstract: Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample ( n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01-1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00-1.60]). The composed CYP2D6 activity was positively associated with dizziness ( p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Just, Dormann, Freitag, Schurig, Böhme, Steffens, Scholl, Seufferlein, Graeff, Schwab and Stingl.)
Published: 2021
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16. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update.

Author: Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, and Stingl JC
Subjects: Dose-Response Relationship, Drug, Humans, Polymorphism, Genetic, Treatment Outcome, Antidepressive Agents, Tricyclic adverse effects, Antidepressive Agents, Tricyclic pharmacokinetics, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2D6 genetics, Genotyping Techniques methods, Medication Therapy Management standards, Pharmacogenomic Variants genetics
Published: 2017
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17. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

Author: Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, and Gaedigk A
Subjects: Biotransformation, Cytochrome P-450 CYP2C19 metabolism, Cytochrome P-450 CYP2D6 metabolism, Genotype, Humans, Patient Safety, Phenotype, Risk Assessment, Risk Factors, Selective Serotonin Reuptake Inhibitors adverse effects, Selective Serotonin Reuptake Inhibitors pharmacokinetics, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2D6 genetics, Drug Dosage Calculations, Pharmacogenetics standards, Polymorphism, Genetic, Selective Serotonin Reuptake Inhibitors administration & dosage
Abstract: Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org)., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)
Published: 2015
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17 results on '"Federal Institute of Drugs and Medical Devices [Bonn]"'

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17 results on '"Federal Institute of Drugs and Medical Devices [Bonn]"'

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