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2,174 results on '"Stanford School of Medicine [Stanford]"'

1. Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses

Author: University of Michigan ICPCG Group ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, University of Michigan ICPCG Group ; University of Michigan, Ann Arbor, Michigan, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah ; Division of Genetic Epidemiology, University of Utah School of Medicine, 391, Chipeta Way, Suite D, Salt Lake City, UT 84108., African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, African American Hereditary Prostate Cancer ICPCG Group ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, African American Hereditary Prostate Cancer ICPCG Group ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Translational Genomics Research Institute, Genetic Basis of Human Disease Research Division, Phoenix, Arizona, ACTANE Consortium ICPCG Group ; Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Department of Oncology, McGill University, Montreal, Quebec, Canada, ACTANE Consortium ICPCG Group ; The Norwegian Radium Hospital, Oslo, Norway, ACTANE Consortium ICPCG Group ; Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK, ACTANE Consortium ICPCG Group ; Cancer Research UK Genetic Epidemiology Unit, Cambridge, UK, ACTANE Consortium ICPCG Group ; Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, BC/CA/HI ICPCG Group ; Department of Health Research and Policy, Stanford School of Medicine, Stanford, California ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, Data Coordinating Center for the ICPCG and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, FHCRC ICPCG Group ; Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, Seattle, Washington, FHCRC ICPCG Group ; Cancer Genetics Branch, National Institutes of Health, Bethesda, Maryland, FHCRC ICPCG Group ; Institute for Systems Biology, Seattle, Washington, Johns Hopkins University ICPCG Group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, Mayo Clinic ICPCG Group and Mayo Clinic, Rochester, Minnesota, University of Tampere ICPCG Group, University of Tampere and Tampere University Hospital, Tampere, Finland, University of Ulm ICPCG Group ; Department of Urology, University of Ulm, Ulm, Germany, University of Ulm ICPCG Group ; Institute of Human Genetics, University of Ulm, Ulm, Germany, University of Ume?? ICPCG Group ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, University of Ume?? ICPCG Group ; Oncologic Centre, Ume?? University, Ume??, Sweden, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, Christensen, G. Bryce, Baffoe-Bonnie, Agnes B., George, Asha, Powell, Isaac, Bailey-Wilson, Joan E., Carpten, John D., Giles, Graham G., Hopper, John L., Severi, Gianluca, English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Lange, Ethan M., Cooney, Kathleen A., Tammela, Teuvo L. J., Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Gr??nberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M., Cannon-Albright, Lisa A., Camp, Nicola J., University of Michigan ICPCG Group ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, University of Michigan ICPCG Group ; University of Michigan, Ann Arbor, Michigan, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah ; Division of Genetic Epidemiology, University of Utah School of Medicine, 391, Chipeta Way, Suite D, Salt Lake City, UT 84108., African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, African American Hereditary Prostate Cancer ICPCG Group ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, African American Hereditary Prostate Cancer ICPCG Group ; National Human Genome Research Institute, NIH, Bethesda, Maryland, African American Hereditary Prostate Cancer ICPCG Group ; Translational Genomics Research Institute, Genetic Basis of Human Disease Research Division, Phoenix, Arizona, ACTANE Consortium ICPCG Group ; Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia, ACTANE Consortium ICPCG Group ; Department of Oncology, McGill University, Montreal, Quebec, Canada, ACTANE Consortium ICPCG Group ; The Norwegian Radium Hospital, Oslo, Norway, ACTANE Consortium ICPCG Group ; Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Surrey, UK, ACTANE Consortium ICPCG Group ; Cancer Research UK Genetic Epidemiology Unit, Cambridge, UK, ACTANE Consortium ICPCG Group ; Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, BC/CA/HI ICPCG Group ; Department of Health Research and Policy, Stanford School of Medicine, Stanford, California ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Stanford Comprehensive Cancer Center, Stanford School of Medicine, Stanford, California, BC/CA/HI ICPCG Group ; Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, Data Coordinating Center for the ICPCG and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, FHCRC ICPCG Group ; Fred Hutchinson Cancer Research Center, Divisions of Public Health Sciences, Seattle, Washington, FHCRC ICPCG Group ; Cancer Genetics Branch, National Institutes of Health, Bethesda, Maryland, FHCRC ICPCG Group ; Institute for Systems Biology, Seattle, Washington, Johns Hopkins University ICPCG Group and Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, Mayo Clinic ICPCG Group and Mayo Clinic, Rochester, Minnesota, University of Tampere ICPCG Group, University of Tampere and Tampere University Hospital, Tampere, Finland, University of Ulm ICPCG Group ; Department of Urology, University of Ulm, Ulm, Germany, University of Ulm ICPCG Group ; Institute of Human Genetics, University of Ulm, Ulm, Germany, University of Ume?? ICPCG Group ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, University of Ume?? ICPCG Group ; Oncologic Centre, Ume?? University, Ume??, Sweden, University of Utah ICPCG Group and Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah, Christensen, G. Bryce, Baffoe-Bonnie, Agnes B., George, Asha, Powell, Isaac, Bailey-Wilson, Joan E., Carpten, John D., Giles, Graham G., Hopper, John L., Severi, Gianluca, English, Dallas R., Foulkes, William D., Maehle, Lovise, Moller, Pal, Eeles, Ros, Easton, Douglas, Badzioch, Michael D., Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Xu, Jianfeng, Stanford, Janet L., Johanneson, Bo, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Thibodeau, Stephen N., McDonnell, Shannon K., Hebbring, Scott, Schaid, Daniel J., Lange, Ethan M., Cooney, Kathleen A., Tammela, Teuvo L. J., Schleutker, Johanna, Paiss, Thomas, Maier, Christiane, Gr??nberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Farnham, James M., Cannon-Albright, Lisa A., and Camp, Nicola J.
Abstract: BACKGROUND Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11???q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9???cM. CONCLUSIONS Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735???744, 2010. ?? 2010 Wiley-Liss, Inc.
Published: 2010

2. Wearables, telemedicine, and artificial intelligence in arrhythmias and heart failure: Proceedings of the European Society of Cardiology Cardiovascular Round Table

Author: Christophe Leclercq, Henning Witt, Gerhard Hindricks, Rodolphe P Katra, Dave Albert, Andrea Belliger, Martin R Cowie, Thomas Deneke, Paul Friedman, Mehdiyar Haschemi, Trudie Lobban, Isabelle Lordereau, Michael V McConnell, Leonardo Rapallini, Eigil Samset, Mintu P Turakhia, Jagmeet P Singh, Emma Svennberg, Manish Wadhwa, Franz Weidinger, CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pfizer, Leipzig University, Medtronic Inc [Minneapolis, MI, USA], Lucerne University of Applied Sciences and Arts [Luzern], King‘s College London, Royal Brompton Hospital, Mayo Clinic [Rochester], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford University School of Medicine [CA, USA], Massachusetts General Hospital [Boston], Karolinska University Hospital [Stockholm], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Medtronic [Minneapolis, MI, USA]
Subjects: Heart Failure, Artificial intelligence, Monitoring, Cardiology, Arrhythmias, Cardiac, Early detection, Telemedicine, Wearable devices, Wearable Electronic Devices, Glucose, Cardiovascular Diseases, Digital healthcare solutions, Physiology (medical), Humans, [SDV.IB]Life Sciences [q-bio]/Bioengineering, M-health, Cardiology and Cardiovascular Medicine
Abstract: Digital technology is now an integral part of medicine. Tools for detecting, screening, diagnosis, and monitoring health-related parameters have improved patient care and enabled individuals to identify issues leading to better management of their own health. Wearable technologies have integrated sensors and can measure physical activity, heart rate and rhythm, and glucose and electrolytes. For individuals at risk, wearables or other devices may be useful for early detection of atrial fibrillation or sub-clinical states of cardiovascular disease, disease management of cardiovascular diseases such as hypertension and heart failure, and lifestyle modification. Health data are available from a multitude of sources, namely clinical, laboratory and imaging data, genetic profiles, wearables, implantable devices, patient-generated measurements, and social and environmental data. Artificial intelligence is needed to efficiently extract value from this constantly increasing volume and variety of data and to help in its interpretation. Indeed, it is not the acquisition of digital information, but rather the smart handling and analysis that is challenging. There are multiple stakeholder groups involved in the development and effective implementation of digital tools. While the needs of these groups may vary, they also have many commonalities, including the following: a desire for data privacy and security; the need for understandable, trustworthy, and transparent systems; standardized processes for regulatory and reimbursement assessments; and better ways of rapidly assessing value.
Published: 2022

3. Extracting phylogenetic dimensions of coevolution reveals hidden functional signals

Author: Alexandre Colavin, Esha Atolia, Anne-Florence Bitbol, Kerwyn Casey Huang, Biophysics Program, Stanford University, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Laboratoire Jean Perrin (LJP), 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), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Institute of Bioengineering [Lausanne, Suisse], Ecole Polytechnique Fédérale de Lausanne (EPFL), Department of Microbiology and Immunology [Stanford], Department of Bioengineering [Stanford], Chan Zuckerberg BioHub [San Francisco, CA], and Gestionnaire, Hal Sorbonne Université
Subjects: hot-spots, Multidisciplinary, Models, Genetic, Science, Proteins, prediction, residue contacts, Protein function predictions, mutations, Article, information, Evolution, Molecular, protein-kinase cascades, evolutionary trace, Protein structure predictions, identification, Medicine, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], actin, domains, Phylogeny, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Coevolution
Abstract: Despite the structural and functional information contained in the statistical coupling between pairs of residues in a protein, coevolution associated with function is often obscured by artifactual signals such as genetic drift, which shapes a protein’s phylogenetic history and gives rise to concurrent variation between protein sequences that is not driven by selection for function. Here, we introduce a background model for phylogenetic contributions of statistical coupling that separates the coevolution signal due to inter-clade and intra-clade sequence comparisons and demonstrate that coevolution can be measured on multiple phylogenetic timescales within a single protein. Our method, nested coevolution (NC), can be applied as an extension to any coevolution metric. We use NC to demonstrate that poorly conserved residues can nonetheless have important roles in protein function. Moreover, NC improved the structural-contact predictions of several coevolution-based methods, particularly in subsampled alignments with fewer sequences. NC also lowered the noise in detecting functional sectors of collectively coevolving residues. Sectors of coevolving residues identified after application of NC were more spatially compact and phylogenetically distinct from the rest of the protein, and strongly enriched for mutations that disrupt protein activity. Thus, our conceptualization of the phylogenetic separation of coevolution provides the potential to further elucidate relationships among protein evolution, function, and genetic diseases.
Published: 2022

4. Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis

Author: Julien Stackowicz, Caitlin M. Gillis, Ophélie Godon, Bruno Iannascoli, Eva Conde, Edouard Leveque, William P. M. Worrall, Stephen J. Galli, Pierre Bruhns, Laurent L. Reber, Friederike Jönsson, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, This work was supported by a Jeunes Chercheuses/Jeunes Chercheurs grant from the Agence National de la Recherche (ANR-16-CE15-0012, to FJ). The Phenomin project receives funds from the ANR under the framework 'Investissements d'Avenir' labelled ANR-10-INBS-07 PHENOMIN. PB acknowledges support from the European Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616,050), Institut Pasteur and INSERM (Institut National de la Santé et de la Recherche Médicale), SJG from NIH grant R01 AI165373, CMG was supported by a stipend from the Pasteur – Paris University (PPU) International PhD program and by the Institut Carnot Pasteur Maladies Infectieuses, and LLR from an ATIP-Avenir grant from the INSERM and the Fondation pour la Recherche Médicale (FRM EQU202103012566)., ANR-16-CE15-0012,PlanA,Rôle des plaquettes et leurs interactions dans les réactions anaphylactiques(2016), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), and European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: International audience; No abstract available
Published: 2023

5. Insights from an autism imaging biomarker challenge: Promises and threats to biomarker discovery

Author: Monique Elmaleh, Freddy Cliquet, Nicolas Guigui, David Germanaud, Ayoub Ghriss, Balázs Kégl, Anita Beggiato, Roberto Toro, Richard Delorme, Amicie de Pierrefeu, Valentina Zantedeschi, Joris Van den Bossche, Nicolas Traut, Laurent Bonasse-Gahot, Alexandre Boucaud, Alban Bethegies, Guillaume Lemaitre, Thomas Bourgeron, Katja Heuer, Meng Wang, Gael Varauquaux, Weidong Cai, Stanislas Chambon, Institut Pasteur [Paris], Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Méthodes computationnelles et mathématiques pour comprendre la société et la santé à partir de données (SODA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Paris-Saclay, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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, hosa.io, Centre d'Analyse et de Mathématique sociales (CAMS), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, rythm.co, University of Colorado [Boulder], University of Chinese Academy of Sciences [Beijing] (UCAS), Institute of Automation - Chinese Academy of Sciences, Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), HUAWEI Technologies France (HUAWEI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Département de Neuroscience - Department of Neuroscience, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris sciences et lettres (PSL), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Huawei Technologies France, Huawei Technologies France [Boulogne-Billancourt], Lassailly-Bondaz, Anne, and Laboratoire Hubert Curien (LHC)
Subjects: Imaging biomarker, Computer science, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Autism Spectrum Disorder, Autism, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, diagnostic, Overfitting, computer.software_genre, MESH: Magnetic Resonance Imaging, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], benchmark, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Biomarker discovery, MESH: Autism Spectrum Disorder, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Brain, Replicate, Magnetic Resonance Imaging, machine learning, Neurology, Autism spectrum disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive Neuroscience, MESH: Autistic Disorder, Machine learning, MESH: Brain, overfit, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, Modalities, MESH: Humans, business.industry, prediction, [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG], medicine.disease, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Sample size determination, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Biomarkers, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, Biomarkers
Abstract: MRI has been extensively used to identify anatomical and functional differences in Autism Spectrum Disorder (ASD). Yet, many of these findings have proven difficult to replicate because studies rely on small cohorts and are built on many complex, undisclosed, analytic choices. We conducted an international challenge to predict ASD diagnosis from MRI data, where we provided preprocessed anatomical and functional MRI data from > 2,000 individuals. Evaluation of the predictions was rigorously blinded. 146 challengers submitted prediction algorithms, which were evaluated at the end of the challenge using unseen data and an additional acquisition site. On the best algorithms, we studied the importance of MRI modalities, brain regions, and sample size. We found evidence that MRI could predict ASD diagnosis: the 10 best algorithms reliably predicted diagnosis with AUC∼0.80 – far superior to what can be currently obtained using genotyping data in cohorts 20-times larger. We observed that functional MRI was more important for prediction than anatomical MRI, and that increasing sample size steadily increased prediction accuracy, providing an efficient strategy to improve biomarkers. We also observed that despite a strong incentive to generalise to unseen data, model development on a given dataset faces the risk of overfitting: performing well in cross-validation on the data at hand, but not generalising. Finally, we were able to predict ASD diagnosis on an external sample added after the end of the challenge (EU-AIMS), although with a lower prediction accuracy (AUC=0.72). This indicates that despite being based on a large multisite cohort, our challenge still produced biomarkers fragile in the face of dataset shifts.
Published: 2022

6. Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Author: Eric Frost, Pascale B. Beauregard, Adam Plotka, Abdelouahed Khalil, Jacek M. Witkowski, Arnold R. Eiser, Anis Larbi, Tamas Fulop, Annelise E. Barron, Francois P.J. Bernier, Serafim Rodrigues, Katsuiku Hirokawa, Shreyansh Tripathi, Ton Bunt, Benoit Laurent, Christian Bocti, Mathieu Desroches, Centre de recherche sur le vieillissement - CSSS-UIGS (Université de Sherbrooke), University of Delhi, Basque Center for Applied Mathematics (BCAM), Basque Center for Applied Mathematics, Ikerbasque - Basque Foundation for Science, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Izumi Biosciences Inc., Leonard Davis Institute of Health Economics, University of Pennsylvania, Morinaga Milk Industry Co., Université de Sherbrooke / Sherbrooke University (UdS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Medical University of Gdańsk, Tokyo Medical and Dental University [Japan] (TMDU), and Agency for science, technology and research [Singapore] (A*STAR)
Subjects: brain, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Review, Disease, neuroinflammation, 03 medical and health sciences, mild cognitive impairment, 0302 clinical medicine, Immune system, Immunity, medicine, Dementia, Risk factor, ComputingMilieux_MISCELLANEOUS, Neuroinflammation, antimicrobial immunity, treatment, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Neurodegeneration, medicine.disease, 030227 psychiatry, Immunology, Etiology, business, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract: Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.
Published: 2021

7. Modeling the Pulmonary Circulation in CHD: Clinical Concepts, Engineering Applications, and an Integrated Medico-Engineering Approach

Author: Weiguang Yang, Jeffrey A. Feinstein, Irene E. Vignon-Clementel, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires (SIMBIOTX ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), and European Project: ERC CoG 615220,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),MoDeLLiver(2020)
Subjects: [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, CHD, Surgical planning, Pulmonary circulation, Multiscale modeling, Peripheral pulmonary artery stenosis, CFD, Blood flow simulations, Clinical application, [SPI.MECA.MEFL]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Fluids mechanics [physics.class-ph]
Abstract: International audience; he pulmonary circulation is comprised of the pulmonary vascular tree (arteries, capillaries, veins), the pulmonary parenchyma, and the process during which deoxygenated blood traverses the pulmonary vascular tree to become oxygenated before returning to the left heart. In contrast to the systemic circulation, the pulmonary circulation exists at a pressure one-sixth that of the systemic circulation. A variety of forms of congenital heart disease (CHD) include abnormalities of the pulmonary circulation, some of which may result in serious symptoms. Mathematical modeling has been increasingly used to characterize the pulmonary circulation and improve our understanding of pulmonary hemodynamics in acquired and congenital heart disease. This chapter presents the state-of-the-art considerations of and methods for modeling the pulmonary circulation. A brief introduction of the pulmonary circulation’s physiology is followed by a clinical overview of CHD-related pulmonary vascular abnormalities, a summary of current mathematical modeling techniques, and example of real-world application of these techniques.
Published: 2022

8. A data compendium associating the genomes of 12,289 Mycobacterium tuberculosis isolates with quantitative resistance phenotypes to 13 antibiotics

Author: Brankin, Alice, Malone, Kerri, Barilar, Ivan, Battaglia, Simone, Borroni, Emanuele, Pires Brandao, Angela, Cabibbe, Andrea Maurizio, Carter, Joshua, Chetty, Darren, Cirillo, Daniela María, Claxton, Pauline, Clifton, David, Cohen, Ted, Coronel, Jorge, Crook, Derrick, Dreyer, Viola, Earle, Sarah, Escuyer, Vincent, Ferrazoli, Lucilaine, Gāo, George Fú, Gardy, Jennifer, Gharbia, Saheer, Teixeira Ghisi, Kelen, Ghodousi, Arash, Gibertoni Cruz, Ana Lúıza, Grandjean, Louis, Grazian, Clara, Groenheit, Ramona, Guthrie, Jennifer, He, Wencong, Hoffmann, Harald, J., Sarah, Hunt, Martin, Ismail, Nazir Ahmed, Jarrett, Lisa, Joseph, Lavania, Jou, Ruwen, Kambli, Priti, Khot, Rukhsar, Knaggs, Jeff, Koch, Anastasia, Kohlerschmidt, Donna, Kouchaki, Samaneh, Lachapelle, Alexander, Lalvani, Ajit, Grandjean Lapierre, Simon, Laurenson, Ian, Letcher, Brice, Lin, Wan-Hsuan, Liu, Chunfa, Liu, Dongxin, Mandal, Ayan, Mansjö, Mikael, Matias, Daniela, Meintjes, Graeme, de Freitas Mendes, Flávia, Merker, Matthias, Mihalic, Marina, Millard, James, Miotto, Paolo, Mistry, Nerges, Moore, David, Musser, Kimberlee A., Ngcamu, Dumisani, Ngoc Nhung, Hoang, Niemann, Stefan, Soli Nilgiriwala, Kayzad, Nimmo, Camus, O'Donnell, Max, Okozi, Nana, Siqueira Oliveira, Rosangela, Omar, Shaheed Vally, Paton, Nicholas, Peto, Timothy Ea, Watanabe Pinhata, Juliana Maira, Plesnik, Sara, Puyen, Zully, Rabodoarivelo, Marie, Rakotosamimanana, Niaina, Rancoita, Paola, Rathod, Priti, Robinson, Esther, Rodger, Gillian, Rodrigues, Camilla, Rodwell, Timothy, Roohi, Aysha, Santos-Lazaro, David, Shah, Sanchi, Kohl, Thomas Andreas, Smith, Grace, Solano, Walter, Spitaleri, Andrea, Supply, Philip, Steyn, Adrie, Surve, Utkarsha, Tahseen, Sabira, Thuong, Nguyen, Thwaites, Guy, Todt, Katharina, Trovato, Alberto, Utpatel, Christian, van Rie, Annelies, Vijay, Srinivasan, Walker, Timothy, Walker, A. Sarah, Warren, Robin M., Werngren, Jim, Wijkander, Maria, Wilkinson, Robert, Wilson, Daniel, Wintringer, Penelope, Xiao, Yu-Xin, Yang, Yang, Zhao, Yanlin, Yao, Shen-Yuan, Zhu, Baoli, Fowler, Philip, Iqbal, Zamin, Consortium, The CRyPTIC, University of Oxford, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Forschungszentrum Borstel - Research Center Borstel, IRCCS San Raffaele Scientific Institute [Milan, Italie], Casa de Oswaldo Cruz [Rio de Janeiro] (COC), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Instituto Adolfo Lutz [São Paulo, Brazil], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Africa Health Research Institute [Durban/Mtubatuba] (AHRI), University of Edinburgh, Yale School of Public Health (YSPH), Universidad Peruana de Ciencias Aplicadas (Lima) (UPC), Wadsworth Center, New York State Department of Health [Albany], Chinese Center for Disease Control and Prevention, Bill & Melinda Gates Foundation [Seattle], UK Health Security Agency [London] (UKHSA), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University College of London [London] (UCL), University of New South Wales [Sydney] (UNSW), Public Health Agency of Sweden, University of British Columbia [Vancouver], Public Health Ontario - Santé publique Ontario, Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, National Institute for Communicable Diseases [Johannesburg] (NICD), Taipei Medical University, PD Hinduja Hospital & Research Institute, Mumbai, University of Cape Town, University of Surrey (UNIS), Imperial College London, Université de Montréal (UdeM), PRA Health sciences [Mumbai], London School of Hygiene and Tropical Medicine (LSHTM), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Columbia University Irving Medical Center (CUIMC), National University of Singapore (NUS), Socios En Salud [Lima, Peru], Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Foundation for Innovative New Diagnostics (FIND), University of California [San Diego] (UC San Diego), University of California (UC), Universidad Peruana Cayetano Heredia (UPCH), 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), National TB control Program [Islamabad, Pakistan], University of Antwerp (UA), Stellenbosch University, Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, The Francis Crick Institute [London], Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences [Beijing] (CAS), and Wellcome Trust (200205/Z/15/Z)Bill and Melinda Gates Foundation (OPP1133541)National Institute for Health Research Oxford Biomedical Research CentreNational Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial ResistanceWellcome Trust (203919/Z/16/Z)National Mega Project on Major Infectious Disease Prevention (2018ZX10103001)H2020 Marie Skłodowska-Curie Actions (EIPOD3)Unitaid (2019-32-FIND MDR)FAPESP (17/16082-7)FAPESP (2012/51756-5)National Natural Science Foundation of China (81991534)Beijing Municipal Science and Technology Commission (Z201100005520041)Wellcome Trust International Intermediate Fellowship (206724/Z/17/Z)Wellcome TrustSouth African Medical Research Councilthe Rhodes Trust and Stanford Medical Scientist Training Program (T32 GM007365)National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections at Imperial College LondonFonds de Recherche en Santé du QuébecWellcome Trust (203583/Z/16/Z)Research Foundation Flanders (G0F8316N)Wellcome Trust (98316)Wellcome Trust (214321/Z/18/Z)Wellcome Trust (203135/Z/16/Z)National Research Foundation South Africa (64787)Wellcome Trust (201470/Z/16/Z)National Institute of Allergy and Infectious Diseases (1R01AI146338)GOSH (1R01AI146338)GOSH/ICH Biomedical Research CentreOxford Medical Research Council Doctoral Training Partnership (NDM Prize Studentship)Nuffield Department of Clinical MedicineSir Henry Dale Fellowship (101237/Z/13/B)The Robertson FoundationNIHRWellcome Trust (214560/Z/18/Z)Rhodes TrustWellcome Trust (FC0010218)UK Research and Innovation (FC0010218)Cancer Research UK (FC0010218)National Institutes of HealthCenters for Disease Control and PreventionUSAIDBill and Melinda Gates FoundationWellcome Trust (203141/Z/16/Z)NIHR Oxford Biomedical Research Centre (BRC BRC-1215-20008)Deutsches Zentrum für InfektionsforschungPublic Health ScotlandCenters for Disease Control and Prevention (U60OE000103)Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI-117312)
Subjects: General Immunology and Microbiology, General Neuroscience, Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, Microbial Sensitivity Tests, Mycobacterium tuberculosis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, General Biochemistry, Genetics and Molecular Biology, Phenotype, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Resistance, Multiple, Bacterial, Mutation, Tuberculosis, Multidrug-Resistant, Humans, Rifampin, General Agricultural and Biological Sciences
Abstract: The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.
Published: 2022

9. The cargo adaptor protein CLINT1 is phosphorylated by the Numb-associated kinase BIKE and mediates dengue virus infection

Author: Stanford Schor, Szuyuan Pu, Vlad Nicolaescu, Siavash Azari, Mardo Kõivomägi, Marwah Karim, Patricia Cassonnet, Sirle Saul, Gregory Neveu, Andrew Yueh, Caroline Demeret, Jan M. Skotheim, Yves Jacob, Glenn Randall, Shirit Einav, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Illinois [Chicago] (UIC), University of Illinois System, Stanford University, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and We thank investigators who have provided plasmids (see Methods). We thank Dr. Ryan Leib, Dr. Fang Liu, and the Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University Mass Spectrometry (http://mass-spec.stanford.edu) for help with relevant experiments.
Subjects: dengue virus (DENV), intracellular trafficking, [SDV]Life Sciences [q-bio], education, virus assembly, CLINT1, Cell Biology, Dengue Virus, host-pathogen interaction, Virus Replication, Biochemistry, Dengue, proteomics, Two-Hybrid System Techniques, Animals, Humans, cell signaling, NAK kinase, Phosphorylation, BIKE, Molecular Biology, human activities
Abstract: International audience; The signaling pathways and cellular functions regulated by the four Numb-associated kinases (NAKs) are largely unknown. We previously reported that AAK1 and GAK control intracellular trafficking of RNA viruses, and recently revealed a requirement for BIKE in early and late stages of dengue virus (DENV) infection. However, the downstream targets phosphorylated by BIKE in this process have not yet been identified. Here, to identify BIKE substrates, we conducted a barcode fusion genetics-yeast two-hybrid screen and retrieved publicly available data generated via affinity-purification mass spectrometry. We subsequently validated 19 of 47 putative BIKE interactors using mammalian cell-based protein-protein interaction assays. We found that CLINT1, a cargo-specific adaptor implicated in bidirectional Golgi-to-endosome trafficking, emerged as a predominant hit in both screens. Our experiments indicated that BIKE catalyzes phosphorylation of a threonine 294 (T294) CLINT1 residue both in vitro and in cell culture. Our findings revealed that CLINT1 phosphorylation mediates its binding to the DENV nonstructural 3 protein and subsequently promotes DENV assembly and egress. In addition, using live-cell imaging we revealed that CLINT1 cotraffics with DENV particles and is involved in mediating BIKE's role in DENV infection. Finally, our data suggest that additional cellular BIKE interactors implicated in the host immune and stress responses and the ubiquitin proteasome system might also be candidate phosphorylation substrates of BIKE. In conclusion, these findings reveal cellular substrates and pathways regulated by the understudied NAK enzyme BIKE, a mechanism for CLINT1 regulation, and control of DENV infection via BIKE signaling, with potential implications for cell biology, virology, and host-targeted antiviral design.
Published: 2022

10. Mere end lugtesans - COVID-19 er associeret med svær påvirkning af lugtesansen, smagssansen og mundfølelsen

Author: Parma, Valentina, Ohla, Kathrin, Veldhuizen, Maria G, Niv, Masha Y, Kelly, Christine E, Bakke, Alyssa J, Cooper, Keiland W, Bouysset, Cédric, Pirastu, Nicola, Dibattista, Michele, Kaur, Rishemjit, Liuzza, Marco Tullio, Pepino, Marta Y, Schöpf, Veronika, Pereda-Loth, Veronica, Olsson, Shannon B, Gerkin, Richard C, Rohlfs Domínguez, Paloma, Albayay, Javier, Farruggia, Michael C, Bhutani, Surabhi, Fjaeldstad, Alexander W, Kumar, Ritesh, Menini, Anna, Bensafi, Moustafa, Sandell, Mari, Konstantinidis, Iordanis, Di Pizio, Antonella, Genovese, Federica, Öztürk, Lina, Thomas-Danguin, Thierry, Frasnelli, Johannes, Boesveldt, Sanne, Saatci, Özlem, Saraiva, Luis R, Lin, Cailu, Golebiowski, Jérôme, Hwang, Liang-Dar, Ozdener, Mehmet Hakan, Guàrdia, Maria Dolors, Laudamiel, Christophe, Ritchie, Marina, Havlícek, Jan, Pierron, Denis, Roura, Eugeni, Navarro, Marta, Nolden, Alissa A, Lim, Juyun, Whitcroft, Katherine L, Colquitt, Lauren R, Ferdenzi, Camille, Brindha, Evelyn V, Altundag, Aytug, Macchi, Alberto, Nunez-Parra, Alexia, Patel, Zara M, Fiorucci, Sébastien, Philpott, Carl M, Smith, Barry C, Lundström, Johan N, Mucignat, Carla, Parker, Jane K, van den Brink, Mirjam, Schmuker, Michael, Fischmeister, Florian Ph S, Heinbockel, Thomas, Shields, Vonnie D C, Faraji, Farhoud, Santamaría, Enrique, Fredborg, William E A, Morini, Gabriella, Olofsson, Jonas K, Jalessi, Maryam, Karni, Noam, D’Errico, Anna, Alizadeh, Rafieh, Pellegrino, Robert, Meyer, Pablo, Huart, Caroline, Chen, Ben, Soler, Graciela M, Alwashahi, Mohammed K, Welge-Lüssen, Antje, Freiherr, Jessica, de Groot, Jasper H B, Klein, Hadar, Okamoto, Masako, Singh, Preet Bano, Hsieh, Julien W, Abdulrahman, Olagunju, Dalton, Pamela, Yan, Carol H, Voznessenskaya, Vera V, Chen, Jingguo, Sell, Elizabeth A, Walsh-Messinger, Julie, Archer, Nicholas S, Koyama, Sachiko, Deary, Vincent, Roberts, S Craig, Yanık, Hüseyin, Albayrak, Samet, Nováková, Lenka Martinec, Croijmans, Ilja, Mazal, Patricia Portillo, Moein, Shima T, Margulis, Eitan, Mignot, Coralie, Mariño, Sajidxa, Georgiev, Dejan, Kaushik, Pavan K, Malnic, Bettina, Wang, Hong, Seyed-Allaei, Shima, Yoluk, Nur, Razzaghi-Asl, Sara, Justice, Jeb M, Restrepo, Diego, Reed, Danielle R, Hummel, Thomas, Munger, Steven D, Hayes, John E, Indústries Alimentàries, Qualitat i Tecnologia Alimentària, Tecnologia Alimentària, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, Mersin University, The Hebrew University of Jerusalem (HUJ), AbScent, Pennsylvania State University (Penn State), Penn State System, University of California [Irvine] (UC Irvine), University of California (UC), Université Côte d'Azur (UCA), University of Edinburgh, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Central Scientific Instruments Organisation (CSIR), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Medizinische Universität Wien = Medical University of Vienna, Groupement scientifique de Biologie et de Medecine Spatiale (GSBMS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES), Tata Institute for Fundamental Research (TIFR), Arizona State University [Tempe] (ASU), Universidad de Extremadura - University of Extremadura (UEX), Università degli Studi di Padova = University of Padua (Unipd), Yale School of Medicine [New Haven, Connecticut] (YSM), San Diego State University (SDSU), Aarhus University [Aarhus], University of Hertfordshire [Hatfield] (UH), Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), Neurosciences Sensorielles Comportement Cognition, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Turku, Aristotle University of Thessaloniki, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Monell Chemical Senses Center, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Montréal (UdeM), Wageningen University and Research Centre (WUR), Medical Science University, Sidra Medicine [Doha, Qatar], Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), University of Southern Queensland (USQ), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), DreamAir Llc, Charles University [Prague] (CU), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Massachusetts System (UMASS), Oregon State University (OSU), Ear Institute, UCL, Lyon Neuroscience Research center, Karunya University, Biruni University, Assi Sette Llaghi Varese, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of East Anglia [Norwich] (UEA), California Department of Food and Agriculture (CDFA), Unité mixte de recherche interactions plantes-microorganismes, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Maastricht University [Maastricht], Institute for Biology - Neurobiology, Freie Universität Berlin, Karl-Franzens-Universität Graz, Howard University College of Medicine, Towson University, University of California [San Diego] (UC San Diego), Proteomics, Center for Applied Medical Research (CIMA), Stockholm University, University of Gastronomic Sciences, Iran University of Medical Sciences, Goethe Universität Frankfurt, University of Tennessee, IBM T.J. Watson Research Center, Université libre de Bruxelles (ULB), Guangzhou Medical University, Buenos Aires University and GEOG (Grupo de Estudio de Olfato y Gusto), Sultan Qaboos University (SQU), Federal University of Technology of Akure (FUTA), A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences [Moscow] (RAS), Hospital of Xi'an Jiaotong University, University of Pennsylvania, University of Dayton, CSIRO Agriculture and Food (CSIRO), Indiana University [Bloomington], Indiana University System, University of Northumbria at Newcastle [United Kingdom], University of Stirling, Middle East Technical University [Ankara] (METU), Utrecht University [Utrecht], Instituto Universitario del Hospital Italiano [Buenos Aires, Argentina], Institute for Research in Fundamental Sciences [Tehran] (IPM), Hebrew University of Jerusalem, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Terrazas del Club Hipico, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Tata Institute of Fundamental Research [Bangalore], Universidade de São Paulo = University of São Paulo (USP), University of Florida [Gainesville] (UF), University of Colorado Anschutz [Aurora], Center for Smell and Taste, Department of Food Science, Pennsylvania State University., Julien, Sabine, Tıp Fakültesi, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'oto-rhino-laryngologie, Department of Food and Nutrition, Senses and Food, Research Center Jülich, University of California [Irvine] (UCI), University of California, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi 'Magna Graecia' di Catanzaro [Catanzaro, Italie] (UMG), University of Extremadura, University of Padova, Yale University School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, University of Helsinki, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institute of Agrifood Research and Technology (IRTA), Universita degli Studi di Padova, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Karl-Franzens-Universität [Graz, Autriche], University of California San Diego Health, University of Brussels, University of Pennsylvania [Philadelphia], Tata Institute of Fundamental Research, University of São Paulo (USP), UCL - SSS/IONS - Institute of NeuroScience, FSE Campus Venlo, and RS: FSE UCV
Subjects: Male, Taste, Physiology, Smagstab, Audiology, AcademicSubjects/SCI01180, Settore BIO/09 - Fisiologia, Behavioral Neuroscience, chemistry.chemical_compound, Olfaction Disorders, Taste Disorders, 0302 clinical medicine, RATINGS, Hyposmia, Surveys and Questionnaires, CHEMOSENSITIVITY, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Viral, PALADAR, 030223 otorhinolaryngology, Sensory Science and Eating Behaviour, media_common, TASTE, US NATIONAL-HEALTH, [SDV.IDA] Life Sciences [q-bio]/Food engineering, Middle Aged, Biological Sciences, 16. Peace & justice, Sensory Systems, 3. Good health, Smell, GCCR Group Author, ddc:540, Smell loss, Female, Original Article, medicine.symptom, Corrigendum, Coronavirus Infections, olfaction, Adult, somatosensation, medicine.medical_specialty, 663/664, Coronavirus disease 2019 (COVID-19), OLFACTORY DISORDERS, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), media_common.quotation_subject, Pneumonia, Viral, head and neck surgery, Aged, Betacoronavirus, COVID-19, Humans, Pandemics, SARS-CoV-2, Self Report, Somatosensory Disorders, Young Adult, Anosmia, Sensory system, Olfaction, 03 medical and health sciences, Chemesthesis, Physiology (medical), Perception, medicine, Neurology & Neurosurgery, Behaviour Change and Well-being, business.industry, R-PACKAGE, 3112 Neurosciences, Pneumonia, Parosmia, COMPONENT, Smagssans, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Sensoriek en eetgedrag, chemistry, Lugtetab, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Lugtesans
Abstract: Correction: Chemical Senses, Volume 46, 2021, bjab050, https://doi.org/10.1093/chemse/bjab050 Published: 08 December 2021 Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change +/- 100) revealed a mean reduction of smell (-79.7 +/- 28.7, mean +/- standard deviation), taste (-69.0 +/- 32.6), and chemesthetic (-37.3 +/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis.The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
Published: 2020

11. Specific Considerations for Venovenous Extracorporeal Membrane Oxygenation During Coronavirus Disease 2019 Pandemic

Author: Maïra Gaillard, Clark G. Owyang, Florent Laverdure, Olaf Mercier, Guillaume Lebreton, Jai Madhok, Antoine Girault, Julien Guihaire, Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Weill Cornell Medicine [New York], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Chirurgie cardiaque et thoracique [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), Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, ARDS, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], medicine.medical_treatment, Pneumonia, Viral, Biomedical Engineering, Biophysics, Bioengineering, Acute respiratory distress, 030204 cardiovascular system & hematology, Biomaterials, Betacoronavirus, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Pandemic, Extracorporeal membrane oxygenation, Coagulopathy, Humans, Medicine, Pandemics, Respiratory Distress Syndrome, Heparin, SARS-CoV-2, business.industry, Anticoagulants, COVID-19, Thrombosis, General Medicine, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], surgical procedures, operative, 030228 respiratory system, Anesthesia, High blood flow, Female, Coronavirus Infections, business, Limited resources
Abstract: International audience; Extracorporeal membrane oxygenation (ECMO) is recognized as organ support for potentially reversible acute respiratory distress syndrome (ARDS). However, limited resource during the outbreak and the coagulopathy associated with coronavirus disease 2019 (COVID-19) make the utilization of venovenous (VV) ECMO highly challenging. We herein report specific considerations for cannulation configurations and ECMO management during the pandemic. High blood flow and anticoagulation at higher levels than usual practice for VV ECMO may be required because of thrombotic hematologic profile of COVID-19. Among our first 24 cases (48.8 ± 8.9 years), 17 patients were weaned from ECMO after a mean duration of 19.0 ± 10.1 days and 16 of them have been discharged from ICU.
Published: 2020

12. Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns

Author: Stephen J. Galli, Mindy Tsai, Nicolas Gaudenzio, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Immunology, mast cells, Inflammation, Adaptive Immunity, Immunoglobulin E, Mrgprb2, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Animals, Humans, Immunology and Allergy, innate immunity, 030304 developmental biology, 0303 health sciences, Innate immune system, biology, allergy, Mast cell, Acquired immune system, Immunity, Innate, cytokines, 3. Good health, acquired immunity, Disease Models, Animal, medicine.anatomical_structure, chemistry, inflammation, tissue remodeling, test cells, biology.protein, MRGPRX2, Disease Susceptibility, Inflammation Mediators, Antibody, medicine.symptom, signaling, basophils, Biomarkers, Histamine, Signal Transduction, 030215 immunology
Abstract: International audience; Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochordate Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral proteases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that these cells can have beneficial as well as detrimental functions, both innately and as participants in adaptive immune responses. We also discuss aspects of mast cell heterogeneity and comment on how the plasticity of this lineage may provide insight into its roles in health and disease. Finally, we consider some currently open questions that are yet unresolved.
Published: 2020

13. Adéquation de l’apport en protéines et acides aminés dans les régimes végétariens

Author: François Mariotti, Christopher D. Gardner, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: 2. Zero hunger, 0303 health sciences, 03 medical and health sciences, Nutrition and Dietetics, 030309 nutrition & dietetics, Medicine (miscellaneous), [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS
Abstract: Resume Dans cette revue de la litterature, nous etudions l’adequation des apports en proteines et en acides amines des regimes vegetariens chez les adultes des pays occidentaux, en rassemblant des donnees indirectes et directes de statut nutritionnel. Nous concluons que les aliments riches en proteines, tels que les legumineuses, les noix et les graines, sont suffisants pour assurer un apport satisfaisant en proteines chez les vegetariens et vegetaliens, et que la question de l’insuffisance d’acides amines specifiques a ete tres largement exageree. Nous nous penchons aussi specifiquement sur le cas des personnes âgees, ou les questions liees a l’adequation proteique des regimes vegetariens sont plus complexes, et sur la situation des enfants ou, au contraire, il n’y a pas de preoccupations particulieres concernant l’adequation proteique, les besoins energetiques etant tres eleves par rapport aux besoins proteiques. Etant donne les recommandations et les mutations actuelles vers des regimes vegetalises, il est necessaire de continuer a etudier en detail sur des bases scientifiques rationnelles l’adequation proteique des regimes vegetariens et vegetaliens, mais aussi, et surtout, d’elargir a des criteres generaux de qualite nutritionnelle et de sante.
Published: 2020

14. Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Author: Jennifer E. Flythe, Tara I. Chang, Martin P. Gallagher, Elizabeth Lindley, Magdalena Madero, Pantelis A. Sarafidis, Mark L. Unruh, Angela Yee-Moon Wang, Daniel E. Weiner, Michael Cheung, Michel Jadoul, Wolfgang C. Winkelmayer, Kevan R. Polkinghorne, Teresa Adragão, Samaya J. Anumudu, Christopher T. Chan, Alfred K. Cheung, Maria Rosa Costanzo, Indranil Dasgupta, Andrew Davenport, Simon J. Davies, Marijke J.E. Dekker, Laura M. Dember, Daniel Gallego, Rafael Gómez, Carmel M. Hawley, Manfred Hecking, Kunitoshi Iseki, Vivekanand Jha, Jeroen P. Kooman, Csaba P. Kovesdy, Eduardo Lacson, Adrian Liew, Charmaine E. Lok, Christopher W. McIntyre, Rajnish Mehrotra, Dana C. Miskulin, Ezio Movilli, Fabio Paglialonga, Roberto Pecoits-Filho, Jeff Perl, Carol A. Pollock, Miguel C. Riella, Patrick Rossignol, Rukshana Shroff, Laura Solá, Henning Søndergaard, Sydney C.W. Tang, Allison Tong, Yusuke Tsukamoto, Suzanne Watnick, Matthew R. Weir, James B. Wetmore, Caroline Wilkie, Martin Wilkie, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, The George Institute for Global Health [Sydney] (GIGH), The University of Sydney, Concord Repatriation General Hospital [Sydney, Australia] (CRGH), Leeds Teaching Hospitals NHS Trust, Instituto Nacional de Cardiologia Ignacio Chavez, Aristotle University of Thessaloniki, The University of New Mexico [Albuquerque], The University of Hong Kong (HKU), Tufts Medical Center [Boston], KDIGO, Cliniques Universitaires Saint-Luc [Bruxelles], Université Catholique de Louvain = Catholic University of Louvain (UCL), Baylor College of Medicine (BCM), Baylor University, Monash University [Clayton], Baylor College of Medecine, York University [Toronto], Australian Catholic University (ACU), Institut de Gestion de Rennes - Institut d'Administration des Entreprises - Rennes (IGR-IAE Rennes), Université de Rennes (UR), University of Delhi, University College of London [London] (UCL), Perelman School of Medicine, University of Pennsylvania, 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 ), UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, 030232 urology & nephrology, Psychological intervention, Article, Peritoneal dialysis, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), residual kidney function, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Medical prescription, Intensive care medicine, Dialysis, patient-reported outcome measures, hemodialysis, business.industry, medicine.disease, 030104 developmental biology, Blood pressure, peritoneal dialysis, quality of life, Nephrology, Hemodialysis, business, Kidney disease
Abstract: International audience; Blood pressure (BP) and volume control are critical components of dialysis care and have substantial impacts on patient symptoms, quality of life, and cardiovascular complications. Yet, developing consensus best practices for BP and volume control have been challenging, given the absence of objective measures of extracellular volume status and the lack of high-quality evidence for many therapeutic interventions. In February of 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference titled Blood Pressure and Volume Management in Dialysis to assess the current state of knowledge related to BP and volume management and identify opportunities to improve clinical and patient-reported outcomes among individuals receiving maintenance dialysis. Four major topics were addressed: BP measurement, BP targets, and pharmacologic management of suboptimal BP; dialysis prescriptions as they relate to BP and volume; extracellular volume assessment and management with a focus on technology-based solutions; and volume-related patient symptoms and experiences. The overarching theme resulting from presentations and discussions was that managing BP and volume in dialysis involves weighing multiple clinical factors and risk considerations as well as patient lifestyle and preferences, all within a narrow therapeutic window for avoiding acute or chronic volume-related complications. Striking this challenging balance requires individualizing the dialysis prescription by incorporating comorbid health conditions, treatment hemodynamic patterns, clinical judgment, and patient preferences into decision-making, all within local resource constraints.
Published: 2020

15. Rapid identification of human mast cell degranulation regulators using functional genomics coupled to high-resolution confocal microscopy

Author: Ralph Stadhouders, Marcus Maurer, Rudi W. Hendriks, Stephen J. Galli, Jelle Folkerts, Nicolas Gaudenzio, See-Ying Tam, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), 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), Pulmonary Medicine, and Cell biology
Subjects: CHO, Bright-field Microscopy, single cell imaging, confocal microscopy, Cell Degranulation, law.invention, Small hairpin RNA, Mice, 0302 clinical medicine, law, RNA interference, ShRNA Knockdown, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cricetinae, Gene expression, Mast Cells, Statistical Calculation, degranulation regulator, Recombinant Protein Expression, 0303 health sciences, Stem Cell Factor, Microscopy, Confocal, Chemistry, Degranulation, Cricetulus griseus, Transfection, Genomics, Mast cell, mast cell degranulation, 3. Good health, Cell biology, medicine.anatomical_structure, RNA Interference, CRISPR-Cas9, Functional genomics, functional genomics, Image Analysis, CHO Cells, General Biochemistry, Genetics and Molecular Biology, Article, Gene Knockout, 03 medical and health sciences, Cricetulus, Confocal microscopy, Cell Separation And Isolation, medicine, Genome Editing, Fiji, Mus musculus, Animals, Humans, Gene Knockdown, 030304 developmental biology, degranulation, Gene Expression Data Analysis, Homo sapiens, Human mast cell, high-resolution confocal microscopy, Cell And Tissue Culture, High-throughput Screening, mast cell, single-cell imaging, 030217 neurology & neurosurgery, Cross-linking, primary cell culture
Abstract: Targeted functional genomics represents a powerful approach for studying gene function in vivo and in vitro. However, its application to gene expression studies in human mast cells has been hampered by low yields of human mast cell cultures and their poor transfection efficiency. We developed an imaging system in which mast cell degranulation can be visualized in single cells subjected to shRNA knockdown or CRISPR-Cas 9 gene editing. By using high resolution confocal microscopy and a fluorochrome-labeled avidin probe, one can directly assess the suppression of functional responses, i.e. degranulation, in single human mast cells. The elimination of a drug or marker selection step avoids the use of potentially toxic treatment procedures and the short hands-on time of the functional analysis step enables the high-throughput screening of shRNA or CRISPR-Cas9 constructs to identify genes that regulate human mast cell degranulation. The ability to analyse single cells significantly reduces the total number of cells required, and allows for the parallel visualization of the degranulation profile of both edited and non-edited mast cells, offering a consistent internal control not found in other protocols. Moreover, our protocol offers a flexible choice between RNA interference and CRISPR-Cas9 genome editing for perturbation of gene expression using our human mast cell single-cell imaging system. Perturbation of gene expression, acquisition of microscopy data, and image analysis can be completed within 5 days, requiring only standard laboratory equipment and expertise., EDITORIAL SUMMARY This protocol presents an an imaging system in which mast cell degranulation can be visualized in single cells subjected to shRNA knockdown or CRISPR-Cas 9 gene editing using high resolution confocal microscopy with a fluorochrome-labeled avidin probe.
Published: 2020

16. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021

17. TU-F-CAMPUS-T-05: A Cloud-Based Monte Carlo Dose Calculation for Electron Cutout Factors

Author: Bush, K [Stanford School of Medicine, Stanford, CA (United States)]
Published: 2015
Full Text: View/download PDF

18. SU-E-T-622: Identification and Improvement of Patients Eligible for Dose Escalation with Matched Plans

Author: King, M [Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA (United States)]
Published: 2014
Full Text: View/download PDF

19. Suppression de him-14(it44ts) par une insertion transgénique exprimant GFP:COSA-1

Author: Girard, Chloé, Akerib, Chantal, Villeneuve, Anne, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics
Abstract: Formation of crossovers (COs) during meiosis depends on the coordinated activities of multiple pro-CO factors, including the MutSγ complex and COSA-1, that become concentrated at the sites of CO-designated recombination intermediates in an interdependent manner (Yokoo et al. 2012; Woglar and Villeneuve 2018). The MutSγ complex is a heterodimer comprising the conserved proteins MSH-5 and MSH-4 (aka HIM-14, encoded by the him-14 gene) (Zalevsky et al. 1999; Kelly et al. 2000). COSA-1 is a member of the cyclin superfamily and is hypothesized to function as part of a cyclin-dependent protein kinase (CDK) complex (Yokoo et al. 2012). The MutSγ complex was suggested to be a potential target for this hypothesized COSA-1 dependent CDK activity, as MSH-5 has multiple potential CDK phosphorylation sites and can be phosphorylated in vitro by a mammalian CDK. These and other data led to a model in which COSA-1-dependent phosphorylation boosts the activity of MutSγ as part of a positive feedback loop that concentrates pro-CO factors at CO sites (Yokoo et al. 2012).
Published: 2021

20. Linear and nonlinear profiles of weak behavioral and neural differentiation between numerical operations in children with math learning difficulties

Author: Lang Chen, Teresa Iuculano, Percy K. Mistry, Vinod Menon, Jonathan Nicholas, Yuan Zhang, Université de Paris (UP), Laboratoire de psychologie du développement et de l'éducation de l'enfant (LaPsyDÉ - UMR 8240), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Faculté des Sciences humaines et sociales - Sorbonne (UPD5 SHS), Université Paris Descartes - Paris 5 (UPD5), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Cognitive Neuroscience, education, Individuality, Experimental and Cognitive Psychology, Intraparietal sulcus, behavioral disciplines and activities, 050105 experimental psychology, Article, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Cognition, Arithmetic problem-solving, Similarity (psychology), Feature (machine learning), Humans, Representational similarity analysis, 0501 psychology and cognitive sciences, Child, Categorical variable, ComputingMilieux_MISCELLANEOUS, Problem Solving, Temporal cortex, Cerebral Cortex, Fusiform gyrus, [SCCO.NEUR]Cognitive science/Neuroscience, Math learning difficulties, 05 social sciences, Subtraction, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Psychology, Insula, psychological phenomena and processes, 030217 neurology & neurosurgery, Mathematics, Cognitive psychology
Abstract: International audience; Mathematical knowledge is constructed hierarchically during development from a basic understanding of addition and subtraction, two foundational and inter-related, but semantically distinct, numerical operations. Early in development, children show remarkable variability in their numerical problem-solving skills and difficulties in solving even simple addition and subtraction problems are a hallmark of math learning difficulties. Here, we use novel quantitative analyses to investigate whether less distinct representations are associated with poor problem-solving abilities in children during the early stages of math-skill acquisition. Crucially, we leverage dimensional and categorical analyses to identify linear and nonlinear neurobehavioral profiles of individual differences in math skills. Behaviorally, performance on the two different numerical operations was less differentiated in children with low math abilities, and lower problem-solving efficiency stemmed from weak evidence-accumulation during problem-solving. Children with low numerical abilities also showed less differentiated neural representations between addition and subtraction operations in multiple cortical areas, including the fusiform gyrus, intraparietal sulcus, anterior temporal cortex and insula. Furthermore, analysis of multi-regional neural representation patterns revealed significantly higher network similarity and aberrant integration of representations within a fusiform gyrus-intraparietal sulcus pathway important for manipulation of numerical quantity. These findings identify the lack of distinct neural representations as a novel neurobiological feature of individual differences in children's numerical problem-solving abilities, and an early developmental biomarker of low math skills. More generally, our approach combining dimensional and categorical analyses overcomes pitfalls associated with the use of arbitrary cutoffs for probing neurobehavioral profiles of individual differences in math abilities.
Published: 2021

21. Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Author: Jean-Pierre Bellenger, Benoit Laurent, Nabil Bosco, Tamas Fulop, Katsuiku Hirokawa, Eric Frost, Pascale B. Beauregard, Abdelouahed Khalil, David Dumoulin, Weili Xu, Mathieu Desroches, Simon Lévesque, Stephen C. Cunnane, Annelise E. Barron, Anis Larbi, Charles Ramassamy, Michael Catanzaro, Serafim Rodrigues, Usma Munawara, Crystal Tze Ying Tan, Jacek M. Witkowski, Centre de recherche sur le vieillissement - CSSS-UIGS (Université de Sherbrooke), Università degli Studi di Pavia = University of Pavia (UNIPV), Agency for science, technology and research [Singapore] (A*STAR), Tokyo Medical and Dental University [Japan] (TMDU), Nestlé Institute of Health Sciences SA [Lausanne, Switzerland], Université de Sherbrooke / Sherbrooke University (UdS), INRS-Centre Armand-Frappier Sante Biotechnologie, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Ikerbasque - Basque Foundation for Science, Basque Center for Applied Mathematics (BCAM), Basque Center for Applied Mathematics, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), and Medical University of Gdańsk
Subjects: 0301 basic medicine, Aging, Immunology, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], free radicals, Systemic inflammation, Peripheral blood mononuclear cell, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Dementia, Macrophage, Neuroinflammation, MCI neuroinflammation, Microglia, business.industry, Monocyte, Research, [SCCO.NEUR]Cognitive science/Neuroscience, RC952-954.6, phagocytosis, RC581-607, medicine.disease, cytokines, 3. Good health, macrophages, 030104 developmental biology, medicine.anatomical_structure, Geriatrics, Immunologic diseases. Allergy, medicine.symptom, business, monocytes, signaling, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract: Background Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. Objectives AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. Results We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Conclusion Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.
Published: 2021

22. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author: Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (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), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California
Subjects: 0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Published: 2019

23. Effects of Sarilumab on Rheumatoid Arthritis as Reported by Patients Using the Rheumatoid Arthritis Impact of Disease Scale

Author: Toshio Kimura, Hubert van Hoogstraten, Sophie Guillonneau, Laure Gossec, Chieh-I Chen, E.K. Mangan, Clare Proudfoot, M. Reaney, Vibeke Strand, Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: Adult, Male, medicine.medical_specialty, Immunology, Disease, Antibodies, Monoclonal, Humanized, Placebo, Severity of Illness Index, Gastroenterology, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, Adalimumab, medicine, Humans, Immunology and Allergy, In patient, 030212 general & internal medicine, RHEUMATOID ARTHRITIS, Aged, 030203 arthritis & rheumatology, business.industry, Minimal clinically important difference, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, RHEUMATOID ARTHRITIS IMPACT OF DISEASE SCALE, 3. Good health, Sarilumab, Treatment Outcome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Rheumatoid arthritis, Drug Therapy, Combination, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Antirheumatic drugs, medicine.drug
Abstract: Objective.We evaluated the effect of sarilumab on patient-perceived impact of rheumatoid arthritis (RA) using the 7-domain RA Impact of Disease (RAID) scale.Methods.Two phase III, randomized, controlled trials of sarilumab in patients with active, longstanding RA were analyzed: (1) sarilumab 150 mg and 200 mg every 2 weeks plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARD) versus placebo + csDMARD [TARGET (NCT01709578)]; and (2) sarilumab 200 mg versus adalimumab (ADA) 40 mg monotherapy [MONARCH (NCT02332590)]. Least-squares mean (LSM) differences in RAID total score (range 0–10) and 7 key RA symptoms, including pain and fatigue (baseline to Weeks 12 and 24), were compared. “Responders” by RAID total score were defined by improvements from baseline ≥ minimal clinically important difference (MCID), and ≥ patient-acceptable symptom-state (PASS) at endpoint.Results.Sarilumab 150 mg and 200 mg + csDMARD were nominally superior (p < 0.05) versus placebo + csDMARD and 200 mg sarilumab versus ADA 40 mg in LSM differences for RAID total score at weeks 12 (−0.93 and −1.13; −0.49, respectively) and 24 (−0.75 and −1.01; −0.78), and all effects of RA (except functional impairment in MONARCH Week 12). Effects were greater in physical domains (e.g., pain) than mental domains (e.g., emotional well-being). More patients receiving sarilumab versus placebo or ADA reported improvements ≥ MCID and PASS in total RAID scores at both assessments.Conclusion.Based on the RAID, sarilumab + csDMARD or as monotherapy reduced the effect of RA on patients’ lives to a greater extent than placebo + csDMARD or ADA monotherapy. (ClinicalTrials.gov: NCT01709578 and NCT02332590)
Published: 2019

24. Aspergillus-Pseudomonas interaction, relevant to competition in airways

Author: Paolo Visca, Gabriele Sass, Karl V. Clemons, Shajia R Ansari, John C. Penner, Eric Déziel, David A. Stevens, Hasan Nazik, Hemi Shah, Hubertus Haas, Anna-Maria Dietl, Marie-Christine Groleau, California Institute for Medical Research (CIMR), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Istanbul University, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Innsbruck Medical University [Austria] (IMU), Roma Tre University, These studies were partially supported by a gift from John Flatley, CIMR no. 3770 and by a grant from the Child Health Research Institute, Stanford Transdisciplinary Initiatives Program, CIMR no. 3777. This work was partially supported by the Austrian Science Fund/Infect-ERA program (FWF grant I1616/Infect-ERA project AspMetNet to HH). A-M.D. is an associate student of the HOROS doctoral program (W1253), The authors thank Marife Martinez for excellent technical support, Sass, Gabriele, Nazik, Hasan, Penner, John, Shah, Hemi, Ansari, Shajia R, Clemons, Karl V, Groleau, Marie-Christine, Dietl, Anna-Maria, Visca, Paolo, Haas, Hubertu, Déziel, Eric, and Stevens, David A
Subjects: MESH: Aspergillus fumigatus/growth & development, Siderophore, MESH: Respiratory Tract Infections/pathology, medicine.disease_cause, Aspergillus fumigatus, cystic fibrosis, chemistry.chemical_compound, skin and connective tissue diseases, Respiratory Tract Infections, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Oligopeptides/metabolism, 0303 health sciences, Pyoverdine, biology, pyoverdine, MESH: Pseudomonas aeruginosa/growth & development, Pseudomonas, MESH: Pseudomonas aeruginosa/genetics, General Medicine, 3. Good health, Infectious Diseases, Pseudomonas aeruginosa, Oligopeptides, MESH: Mutation, Virulence Factors, Virulence, MESH: Aspergillosis/microbiology, Microbiology, microbial interaction, 03 medical and health sciences, MESH: Respiratory Tract Infections/microbiology, MESH: Virulence Factors/genetics, medicine, Aspergillosis, Humans, Pseudomonas Infections, MESH: Pseudomonas Infections/microbiology, cystic fibrosi, 030304 developmental biology, MESH: Aspergillosis/pathology, MESH: Humans, MESH: Oligopeptides/genetics, 030306 microbiology, MESH: Pseudomonas Infections/pathology, Biofilm, MESH: Virulence Factors/metabolism, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, biology.organism_classification, MESH: Microbial Interactions, Quorum sensing, chemistry, Mutation, Aspergillus fumigatu, Microbial Interactions
Abstract: International audience; In airways of immunocompromised patients and individuals with cystic fibrosis, Pseudomonas aeruginosa and Aspergillus fumigatus are the most common opportunistic bacterial and fungal pathogens. Both pathogens form biofilms and cause acute and chronic illnesses. Previous studies revealed that P. aeruginosa is able to inhibit A. fumigatus biofilms in vitro. While numerous P. aeruginosa molecules have been shown to affect A. fumigatus, there never has been a systematic approach to define the principal causative agent. We studied 24 P. aeruginosa mutants, with deletions in genes important for virulence, iron acquisition, or quorum sensing, for their ability to interfere with A. fumigatus biofilms. Cells, planktonic or biofilm culture filtrates of four P. aeruginosa mutants, pvdD-pchE-, pvdD-, lasR-rhlR-, and lasR-, inhibited A. fumigatus biofilm metabolism or planktonic A. fumigatus growth significantly less than P. aeruginosa wild type. The common defect of these four mutants was a lack in the production of the P. aeruginosa siderophore pyoverdine. Pure pyoverdine affected A. fumigatus biofilm metabolism, and restored inhibition by the above mutants. In lungs from cystic fibrosis patients, pyoverdine production and antifungal activity correlated. The key inhibitory mechanism for pyoverdine was iron-chelation and denial of iron to A. fumigatus. Further experiments revealed a counteracting, self-protective mechanism by A. fumigatus, based on A. fumigatus siderophore production.
Published: 2019

25. Mutations in PERP Cause Dominant and Recessive Keratoderma

Author: Vanessa Gildenstern, Keith A. Choate, Young H. Lim, Patrick Nitschké, Alain Hovnanian, Yolanda R. Helfrich, Richard P. Lifton, Christine Bole-Feysot, S. Duchatelet, Raúl de Lucas, Leonard M. Milstone, Lynn M. Boyden, Laura D. Attardi, Fernando Santos-Simarro, Laure Guibbal, Akemi Ishida-Yamamoto, Jing Zhou, Ronghua Hu, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Yale University School of Medicine, Asahikawa Medical College, University of Michigan System, Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Dermatology, Biology, Biochemistry, Article, Loss of heterozygosity, Young Adult, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Keratoderma, Palmoplantar, Keratin, Cell Adhesion, medicine, Humans, Genes, Tumor Suppressor, Child, Frameshift Mutation, Keratoderma, Molecular Biology, Gene, chemistry.chemical_classification, integumentary system, Homozygote, Membrane Proteins, Desmosomes, Exons, Cell Biology, medicine.disease, Cell biology, Microscopy, Electron, 030104 developmental biology, Palmoplantar keratoderma, chemistry, OLMSTED SYNDROME, Codon, Nonsense, Child, Preschool, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols, Female, Epidermis, Intracellular
Abstract: Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.
Published: 2019

26. Processive flow by biased polymerization mediates the slow axonal transport of actin

Author: Christophe Leterrier, Nilaj Chakrabarty, Yong Tang, Archan Ganguly, Subhojit Roy, Peter Jung, Pankaj Dubey, Kelsey Ladt, Ohio University, University of Wisconsin-Madison, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of California [San Diego] (UC San Diego), University of California, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California (UC), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, Models, Neurological, Primary Cell Culture, macromolecular substances, Biology, Axonal Transport, Hippocampus, Polymerization, 03 medical and health sciences, Mice, 0302 clinical medicine, Microtubule, Live cell imaging, Slow axonal transport, Report, medicine, Animals, Computer Simulation, Axon, Cytoskeleton, education, Actin, Research Articles, 030304 developmental biology, Neurons, 0303 health sciences, education.field_of_study, Cell Biology, Embryo, Mammalian, Actins, Rats, medicine.anatomical_structure, Animals, Newborn, Axoplasmic transport, Biophysics, 030217 neurology & neurosurgery
Abstract: Chakrabarty et al. propose a model in which slow axonal transport of actin can occur by a biased polymerization of actin filaments along the axon shaft without the involvement of microtubules (MTs) or MT-based motors. These dynamics are distinct from polymer sliding—the canonical mechanism thought to convey cytoskeletal cargoes in slow transport., Classic pulse-chase studies have shown that actin is conveyed in slow axonal transport, but the mechanistic basis for this movement is unknown. Recently, we reported that axonal actin was surprisingly dynamic, with focal assembly/disassembly events (“actin hotspots”) and elongating polymers along the axon shaft (“actin trails”). Using a combination of live imaging, superresolution microscopy, and modeling, in this study, we explore how these dynamic structures can lead to processive transport of actin. We found relatively more actin trails elongated anterogradely as well as an overall slow, anterogradely biased flow of actin in axon shafts. Starting with first principles of monomer/filament assembly and incorporating imaging data, we generated a quantitative model simulating axonal hotspots and trails. Our simulations predict that the axonal actin dynamics indeed lead to a slow anterogradely biased flow of the population. Collectively, the data point to a surprising scenario where local assembly and biased polymerization generate the slow axonal transport of actin without involvement of microtubules (MTs) or MT-based motors. Mechanistically distinct from polymer sliding, this might be a general strategy to convey highly dynamic cytoskeletal cargoes.
Published: 2019

27. Secukinumab provides sustained PASDAS-defined remission in psoriatic arthritis and improves health-related quality of life in patients achieving remission: 2-year results from the phase III FUTURE 2 study

Author: Coates, L, Gladman, D, Nash, P, Fitzgerald, O, Kavanaugh, A, Kvien, T, Gossec, L, Strand, V, Rasouliyan, L, Pricop, L, Ding, K, Jugl, S, Gaillez, C, Group, Future 2 Study, University of Oxford [Oxford], University of Toronto, University of Queensland [Brisbane], University College Dublin [Dublin] (UCD), UC San Diego School of Medicine, Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, and Novartis Pharma AG
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Remission, [SDV]Life Sciences [q-bio], Health Status, Population, Placebo, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Quality of life, Double-Blind Method, Internal medicine, Post-hoc analysis, Medicine, Humans, Patient Reported Outcome Measures, education, Secukinumab, Interleukin-17A, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Research, Arthritis, Psoriatic, Remission Induction, Repeated measures design, Antibodies, Monoclonal, PASDAS, FUTURE 2 study, Middle Aged, medicine.disease, Rheumatology, 3. Good health, 030104 developmental biology, Treatment Outcome, Antirheumatic Agents, Quality of Life, Female, lcsh:RC925-935, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Secukinumab has demonstrated sustained improvement in the signs and symptoms of psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). This post hoc analysis assessed the ability of secukinumab to achieve Psoriatic Arthritis Disease Activity Score (PASDAS)-based remission or low disease activity (LDA) through 2 years among patients with PsA in the FUTURE 2 study. PASDAS (cut-off scores: remission ≤ 1.9; LDA > 1.9 and
Published: 2018

28. Stoichiometry Controls the Dynamics of Liquid Condensates of Associative Proteins

Author: Pierre Ronceray, Ned Wingreen, Yaojun Zhang, Xichong Liu, Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS), Princeton University, Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: [PHYS]Physics [physics], 0303 health sciences, Viscosity, FOS: Physical sciences, General Physics and Astronomy, Proteins, Condensed Matter - Soft Condensed Matter, Molecular Dynamics Simulation, Biophysical Phenomena, 03 medical and health sciences, 0302 clinical medicine, Models, Chemical, Biological Physics (physics.bio-ph), Soft Condensed Matter (cond-mat.soft), Physics - Biological Physics, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Multivalent associative proteins with strong complementary interactions play a crucial role in phase separation of intracellular liquid condensates. We study the internal dynamics of such "bond-network" condensates comprising two complementary proteins via scaling analysis and molecular dynamics. We find that when stoichiometry is balanced, relaxation slows down dramatically due to a scarcity of alternative binding partners following bond breakage. This microscopic slow-down strongly affects the bulk diffusivity, viscosity, and mixing, which provides a means to experimentally test this prediction.
Published: 2021

29. Impact of delayed patient flow on surgical outcomes after hip fracture

Author: Da Costa, Ines, Belnou, Pierre, Soulier, Anne, Lapidus, Nathanaël, Sung Tsai, Eileen, Bourcier, Elsa, Laura, Moisi, Sautet, Alain, Bonnet, Francis, Lescot, Thomas, Verdonk, Franck, Service des Soins Intensifs [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de santé publique [CHU Saint-Antoine], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de Chirurgie Orthopédique et Traumatologie [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2021

30. Correction: Determination of the phylogenetic origins of the Árpád Dynasty based on Y chromosome sequencing of Béla the Third

Author: Péter L. Nagy, Judit Olasz, Endre Neparáczki, Nicholas Rouse, Karan Kapuria, Samantha Cano, Huijie Chen, Julie Di Cristofaro, Goran Runfeldt, Natalia Ekomasova, Zoltán Maróti, János Jeney, Sergey Litvinov, Murat Dzhaubermezov, Lilya Gabidullina, Zoltán Szentirmay, György Szabados, Dragana Zgonjanin, Jacques Chiaroni, Doron M. Behar, Elza Khusnutdinova, Peter A. Underhill, Miklós Kásler, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: 0303 health sciences, 03 medical and health sciences, [SDV]Life Sciences [q-bio], 030305 genetics & heredity, Genetics, 10. No inequality, Genetics (clinical), ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

31. The human gut microbiome and health inequities

Author: Erika C. Claud, Erin C. Hanlon, Carlijn E Bruggeling, Katherine R. Amato, Corinne F. Maurice, Meghan B. Azad, Christopher W. Kuzawa, Liping Zhao, Ali Keshavarzian, Geoffrey A. Preidis, Michael T. Bailey, Bas E. Dutilh, Elizabeth K. Costello, Laure Ségurel, Josiane L. Broussard, Burton H. Singer, Wrenetha Julion, Holly A. Swain Ewald, Marie-Claire Arrieta, Gregory E. Miller, Paul W. Ewald, Emily R. Davenport, Sathish Subramanian, Northwestern University [Evanston], University of Calgary, Children's Hospital Research Institute of Manitoba [Winnipeg, Canada], University of Manitoba [Winnipeg], Center for Microbial Pathogenesis [Columbus], Ohio State University [Columbus] (OSU), Colorado State University [Fort Collins] (CSU), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Chicago, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Huck Institutes of the Life Sciences [University Park], Utrecht University [Utrecht], Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, University of Louisville, Rush University [Chicago], Rush University Medical Center [Chicago], McGill University = Université McGill [Montréal, Canada], Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Éco-Anthropologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), University of Florida [Gainesville] (UF), Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Shanghai Jiao Tong University [Shanghai], Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Theoretical Biology and Bioinformatics, and Sub Bioinformatics
Subjects: Population health, Structural racism|health disparities|chronic disease|DOHad|policy, 03 medical and health sciences, Race (biology), 0302 clinical medicine, Human gut, Development economics, Taverne, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Humans, Disease, Microbiome, General, Socioeconomic status, Health policy, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Sexual identity, Multidisciplinary, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Publications, Health Status Disparities, Health equity, 3. Good health, Gastrointestinal Microbiome, Mental Health, Health, Perspective, Psychology, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 235695.pdf (Publisher’s version ) (Closed access) Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.
Published: 2021

32. Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease

Author: Moore, Ursula, Gordish, Heather, Diaz-Manera, Jordi, James, Meredith K, Mayhew, Anna G, Guglieri, Michela, Fernandez-Torron, Roberto, Rufibach, Laura E, Feng, Jia, Blamire, Andrew M, Carlier, Pierre G, Spuler, Simone, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Lowes, Linda Pax, Mendell, Jerry R, Bushby, Kate, Straub, Volker, Jain COS Consortium, Newcastle University [Newcastle], Georgetown University [Washington] (GU), CIBER de Enfermedades Raras (CIBERER), Hospital de la Santa Creu i Sant Pau, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, The University of Sydney, National Institutes of Health [Bethesda] (NIH), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Ludwig-Maximilians-Universität München (LMU), Hospital Universitario Virgen del Rocío [Sevilla], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Padova = University of Padua (Unipd), Abigail Wexner Research Institute, Nationwide Children's Hospital, Centre de référence des maladies rares neuromusculaires, 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), Universita degli Studi di Padova, Jain Foundation, and International Centre for Genomic Medicine in Neuromuscular Diseases
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Disease, Clinical trials methodology, 0302 clinical medicine, [185] Muscle disease, Child, Genetics (clinical), Muscle disease, Muscle Weakness, medicine.diagnostic_test, [21] Clinical trials methodology, Anatomy, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Limb girdle weakness, Muscular Atrophy, Phenotype, Neurology, Child, Preschool, Disease Progression, Female, Function and Dysfunction of the Nervous System, Cohort study, Adult, Dysferlinopathy, Miyoshi myopathy, Adolescent, [54] Cohort study, Lower limb weakness, [16] Clinical neurology examination, 03 medical and health sciences, Young Adult, medicine, Humans, Clinical neurology examination, [176] All neuromuscular disease, business.industry, Infant, Newborn, Infant, Magnetic resonance imaging, medicine.disease, Clinical trial, Distal Myopathies, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, All neuromuscular disease
Abstract: The Jain COS Consortium., This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. Volker Straub was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.
Published: 2021

33. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)

Author: Boris Keren, Femke Latta, Elise Brimble, Hester Y. Kroes, Maria Szczepańska, Maria I. Tejada, Rutger A.J. Nievelstein, Maria Ruzhnikov, David Germanaud, Dominik N. Müller, Karl-Peter Schlingmann, Martin Konrad, Gijs A C Franken, Anne-Claude Tabet, Cyril Mignot, Martin Ćuk, Joost G. J. Hoenderop, René J. M. Bindels, Luis Alfonso Martínez-Cruz, Jeroen H. F. de Baaij, Jonathan I. Levy, Felix Claverie-Martin, Radboud University Medical Center [Nijmegen], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Service de Génétique Cytogénétique et Embryologie [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), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidade de Mogi das Cruces = University of Mogi das Cruzes (UMC), Utrecht University [Utrecht], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Hospital Universitario N.S. de Candelaria [Santa Cruz de Tenerife, Spain], Silesian Medical University, Katowice, Poland, University Hospital Centre Zagreb, Partenaires INRAE, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), and Biocruces Bizkaia Health Research Institute [Baracaldo]
Subjects: Oncology, medicine.medical_specialty, Heterozygote, obesity, HSMR, Biology, Hypomagnesemia, 03 medical and health sciences, hypomagnesemia, Internal medicine, Cyclins, Intellectual disability, Genetics, medicine, Humans, Gene, Cation Transport Proteins, CNNM2, Genetics (clinical), Research Articles, 030304 developmental biology, Cyclin, 0303 health sciences, 030305 genetics & heredity, medicine.disease, Obesity, Phenotype, 3. Good health, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], intellectual disability, Cohort, Speech delay, Mutation, medicine.symptom, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. 25Mg2+ uptake assays demonstrated loss‐of‐function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44–0.72 mmol/L), which could not be fully corrected by Mg2+ supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR., Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with hypomagnesemia. Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome, caused by CNNM2 mutations
Published: 2021

34. IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcus aureus

Author: Frédéric Fontaine, Lukas Stulik, Stephen J. Galli, Nicolas Gaudenzio, Karin Lakovits, Thomas Marichal, Riccardo Sibilano, Arvand Haschemi, Manuel R. Amieva, Martin L. Watzenboeck, Sylvia Knapp, Philipp Starkl, Lauren M. Popov, Laurent L. Reber, Anastasiya Hladik, André C. Mueller, Sophie Zahalka, Mariem Radhouani, Research Center for Molecular Medicine of the Austrian Academy of Sciences, University of Vienna [Vienna], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of California [Berkeley], University of California, Medizinische Universität Wien = Medical University of Vienna, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, 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), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Stanford University, and X4 Pharmaceuticals
Subjects: 0301 basic medicine, Allergy, Staphylococcus aureus, Immunology, Biology, Adaptive Immunity, Immunoglobulin E, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Immunity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Hypersensitivity, Immunology and Allergy, Animals, allergy module, Mast Cells, bacteria, 030304 developmental biology, Skin, degranulation, 0303 health sciences, Effector, Degranulation, type 2 immunity, Allergens, Staphylococcal Infections, allergy, Acquired immune system, medicine.disease, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Infectious Diseases, 030228 respiratory system, host defense, 030220 oncology & carcinogenesis, biology.protein, Female, Staphylococcal Skin Infections, IgE, Antibody, basophils
Abstract: International audience; Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
Published: 2020

35. External Beam Radiation Therapy Enhances Local Control in Pigmented Villonodular Synovitis

Author: Donaldson, Sarah [Department of Radiation Oncology, Stanford Cancer Center, Stanford School of Medicine, Stanford, CA (United States)]
Published: 2009
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36. Preserving equipoise and performing randomized trials for COVID-19 social distancing interventions

Author: John P. A. Ioannidis, Ioana A. Cristea, Florian Naudet, Università degli Studi di Pavia = University of Pavia (UNIPV), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Meta-Research Innovation Center at Stanford (METRICS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University-Stanford Medicine, Stanford University-Stanford University, METRICS is supported by a grant from the Laura andJohn Arnold Foundation. The work of JPAI is supported by an unrestrictedgift from Sue and Bob O’Donnell., Jonchère, Laurent, Università degli Studi di Pavia, 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: Research design, Epidemiology, [SDV]Life Sciences [q-bio], Pneumonia, Viral, Applied psychology, Randomisation, randomised-controlled trials, research design and methods, statistics, Psychological intervention, 030204 cardiovascular system & hematology, Special Article, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Credibility, Design choice, Humans, 030212 general & internal medicine, Pandemics, Randomized Controlled Trials as Topic, Therapeutic Equipoise, SARS-CoV-2, Social distance, Public Health, Environmental and Occupational Health, COVID-19, 3. Good health, Coronavirus, [SDV] Life Sciences [q-bio], Intervention (law), Psychiatry and Mental health, Psychological Distance, Research Design, Social Conditions, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Coronavirus Infections, Psychology
Abstract: In the coronavirus disease 2019 (COVID-19) pandemic, a large number of non-pharmaceutical measures that pertain to the wider group of social distancing interventions (e.g. public gathering bans, closures of schools, workplaces and all but essential business, mandatory stay-at-home policies, travel restrictions, border closures and others) have been deployed. Their urgent deployment was defended with modelling and observational data of spurious credibility. There is major debate on whether these measures are effective and there is also uncertainty about the magnitude of the harms that these measures might induce. Given that there is equipoise for how, when and if specific social distancing interventions for COVID-19 should be applied and removed/modified during reopening, we argue that informative randomised-controlled trials are needed. Only a few such randomised trials have already been conducted, but the ones done to-date demonstrate that a randomised trials agenda is feasible. We discuss here issues of study design choice, selection of comparators (intervention and controls), choice of outcomes and additional considerations for the conduct of such trials. We also discuss and refute common counter-arguments against the conduct of such trials.
Published: 2020

37. Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes

Author: Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, Levy CJ, Pinsker JE, Wadwa RP, Dassau E, Doyle FJ, Anderson SM, Church MM, Dadlani V, Ekhlaspour L, Forlenza GP, Isganaitis E, Lam DW, Kollman C, Beck RW, Trial Research Group. iDCL, University of Virginia [Charlottesville], Department of Molecular Medicine [Tampa], University of South Florida [Tampa] (USF), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Mayo Clinic [Rochester], Harvard Medical School [Boston] (HMS), and Université de Lorraine (UL)
Subjects: Adult, Blood Glucose, Male, Pancreas, Artificial, Pediatrics, medicine.medical_specialty, Adolescent, Insulin delivery, 030204 cardiovascular system & hematology, law.invention, Young Adult, 03 medical and health sciences, Insulin Infusion Systems, 0302 clinical medicine, Randomized controlled trial, law, Diabetes mellitus, Multicenter trial, medicine, Humans, Hypoglycemic Agents, Insulin, MESH: Diabetes Mellitus, Type 1/drug therapy, Hypoglycemic Agents/administration & dosage, Insulin/administration & dosage, Pancreas, Artificial/adverse effects, In patient, 030212 general & internal medicine, Aged, Glycemic, Glycated Hemoglobin, Type 1 diabetes, business.industry, Equipment Design, General Medicine, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, 3. Good health, Diabetes Mellitus, Type 1, Multicenter study, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring.A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was70 mg per deciliter or54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group.In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).
Published: 2020

38. Impact of Regional Block Failure in Ambulatory Hand Surgery on Patient Management: A Cohort Study

Author: Franck Verdonk, Lucile Picard, Thomas Lescot, Eileen Sung Tsai, Nathanael Lapidus, Pierre Belnou, Alain Sautet, Francis Bonnet, Julien Gaillard, Claire Debes, Service des Soins Intensifs [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de Chirurgie Orthopédique et Traumatologie [CHU Saint-Antoine], Hôpital Américain de Paris, Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)
Subjects: medicine.medical_specialty, Multivariate analysis, lcsh:Medicine, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Article, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, medicine, risk factors, ambulatory surgery, patient management, business.industry, Incidence (epidemiology), lcsh:R, 030208 emergency & critical care medicine, Hand surgery, Retrospective cohort study, General Medicine, block failure, medicine.disease, 3. Good health, Patient management, Substance abuse, Emergency medicine, Ambulatory, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, regional anesthesia, Cohort study
Abstract: Regional anesthesia (RA) is an anesthetic technique essential for the performance of ambulatory surgery. Failure rates range from 6% to 20%, and the consequences of these failures have been poorly investigated. We determined the incidence and the impact of regional block failure on patient management in the ambulatory setting. This retrospective cohort study includes all adult patients who were admitted to a French University Hospital (H&ocirc, pital Saint-Antoine, AP-HP) between 1 January 2016 and 31 December 2017 for unplanned ambulatory distal upper limb surgery. Univariate and stepwise multivariate analyses were performed to determine factors associated with block failure. Among the 562 patients included, 48 (8.5%) had a block failure. RA failure was associated with a longer surgery duration (p = 0.02), more frequent intraoperative analgesics administration (p &lt, 0.01), increased incidence of unplanned hospitalizations (p &lt, 0.001), and a 39% prolongation of Post-Anesthesia Care Unit (PACU) length of stay (p &lt, 0.0001). In the multivariate analysis, the risk factors associated with block failure were female sex (p = 0.04), an American Society of Anesthesiologists (ASA) score &gt, 2 (p = 0.03), history of substance abuse (p = 0.01), and performance of the surgery outside of the specific ambulatory surgical unit (p = 0.01). Here, we have documented a significant incidence of block failure in ambulatory hand surgery, with impairment in the organization of care. Identifying patients at risk of failure could help improve their management, especially by focusing on providing care in a dedicated ambulatory circuit.
Published: 2020

39. Targeting Infectious Agents as a Therapeutic Strategy in Alzheimer’s Disease

Author: Francois P.J. Bernier, Mathieu Desroches, Usma Munawara, Jacek M. Witkowski, Tamas Fulop, Michele Catanzaro, Anis Larbi, Katsuiku Hirokawa, Eric Frost, Pascale B. Beauregard, Jean-Philippe Bellenger, Serafim Rodrigues, Abdelouahed Khalil, David Dumoulin, Andrea Guidolin, Annelise E. Barron, Centre de recherche sur le vieillissement - CSSS-UIGS (Université de Sherbrooke), Agency for science, technology and research [Singapore] (A*STAR), University of Tunis El Manar, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Ikerbasque - Basque Foundation for Science, Basque Center for Applied Mathematics (BCAM), Basque Center for Applied Mathematics, Morinaga Milk Industry Co., Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Tokyo Medical and Dental University [Japan] (TMDU), Université de Sherbrooke / Sherbrooke University (UdS), and Medical University of Gdańsk
Subjects: Senescence, Amyloid, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Plaque, Amyloid, Systemic inflammation, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Anti-Infective Agents, Alzheimer Disease, medicine, Dementia, Humans, Pharmacology (medical), Microbiome, Neuroinflammation, ComputingMilieux_MISCELLANEOUS, Inflammation, Innate immune system, Amyloid beta-Peptides, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Neurodegeneration, medicine.disease, Immunity, Innate, 030227 psychiatry, Psychiatry and Mental health, Immunology, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Alzheimer’s disease (AD) is the most prevalent dementia in the world. Its cause(s) are presently largely unknown. The most common explanation for AD, now, is the amyloid cascade hypothesis, which states that the cause of AD is senile plaque forma- tion by the amyloid β peptide, and the formation of neurofibrillary tangles by hyperphosphorylated tau. A second, burgeoning theory by which to explain AD is based on the infection hypothesis. Much experimental and epidemiological data support the involvement of infections in the development of dementia. According to this mechanism, the infection either directly or via microbial virulence factors precedes the formation of amyloid β plaques. The amyloid β peptide, possessing antimicrobial properties, may be beneficial at an early stage of AD, but becomes detrimental with the progression of the disease, concomi- tantly with alterations to the innate immune system at both the peripheral and central levels. Infection results in neuroinflam- mation, leading to, and sustained by, systemic inflammation, causing eventual neurodegeneration, and the senescence of the immune cells. The sources of AD-involved microbes are various body microbiome communities from the gut, mouth, nose, and skin. The infection hypothesis of AD opens a vista to new therapeutic approaches, either by treating the infection itself or modulating the immune system, its senescence, or the body’s metabolism, either separately, in parallel, or in a multi-step way., Basque Government under the grant “Artificial Intelligence in BCAM number EXP. 2019/00432”
Published: 2020

40. Variability in the analysis of a single neuroimaging dataset by many teams

Author: Richard C. Reynolds, Jeremy Hogeveen, Joseph T. McGuire, Vittorio Iacovella, Gregory R. Samanez-Larkin, Cemal Koba, Paolo Avesani, Mikella A. Green, Margaret L. Schlichting, Claudio Toro-Serey, Tristan Glatard, Phui Cheng Lim, Emily A. Yearling, Simon B. Eickhoff, Katherine L. Bottenhorn, Susanne Weis, Andrew Erhart, Doris Pischedda, Mauricio R. Delgado, William A. Cunningham, Robert Langner, Matthew B. Wall, Amr Eed, Jorge Moll, Jeffrey B. Dennison, Wouter D. Weeda, Annabel B. Losecaat Vermeer, Anthony C. Juliano, Felix Hoffstaedter, Julia A. Camilleri, Nadège Bault, Cristian Buc Calderon, Xu Zhang, Gustav Tinghög, Vuong Truong, Leah Bakst, Stephan Heunis, Bertrand Thirion, Colin F. Camerer, Bradley C. Love, Tom Verguts, Luca Cecchetti, Patricia A. Reuter-Lorenz, Camille Maumet, Gabrielle Herman, Giacomo Handjaras, Michalis Kassinopoulos, Anthony Romyn, Xiangzhen Kong, Michael Notter, Nina Lauharatanahirun, Claire Donnat, Norberto Malpica, Jelle J. Goeman, Kamalaker Dadi, Michael Mack, Joke Durnez, Alberto De Luca, Margaret A. Sheridan, Shruti Ray, Colin Hawco, Enrico Glerean, J. Paul Hamilton, Qiang Shen, Sebastian Bobadilla-Suarez, Andrea Leo, David Wisniewski, Ayse Ilkay Isik, Lei Zhang, Bharat B. Biswal, Rotem Botvinik-Nezer, Flora Li, Bronson Harry, Andrew Jahn, Elise Lesage, Jean M. Vettel, Marco Barilari, Adrian I. Onicas, Susan Holmes, Khoi Vo, Aahana Bajracharya, Matthew Hughes, Rui Yuan, Nuri Erkut Kucukboyaci, Remi Gau, Sangsuk Yoon, Hongmi Lee, Alexandru D. Iordan, John Thorp, Russell A. Poldrack, Anna Dreber, Joshua E. Zosky, Dylan M. Nielson, Adriana S. Méndez Leal, Erin W. Dickie, Roeland Hancock, Tiago Bortolini, Kaustubh R. Patil, Monica Y.C. Li, Kristin N. Meyer, Fu Shiguang, Kenny Skagerlund, Juan Carlos de la Torre, Jennifer A. Silvers, R. Alison Adcock, Gustav Nilsonne, Zachary J. Cole, Emilio Sanz-Morales, Charles P. Davis, Michael Joseph, Sangil Lee, Tom Johnstone, Peder M. Isager, Jonathan E. Peelle, Emiliano Ricciardi, Scott A. Huettel, G. Matthew Fricke, Leonardo Tozzi, Brice A. Kuhl, Sagana Vijayarajah, Alexander Bowring, Jeanette A. Mumford, Blazej M. Baczkowski, Shabnam Hakimi, Sebastian Kupek, Michael Kirchler, Yanina Prystauka, Niall W. Duncan, Anna van 't Veer, Emily G. Brudner, Jamil P. Bhanji, Sarah M. Tashjian, Senne Braem, Paolo Papale, Simon R. Steinkamp, Georgios D. Mitsis, Kenneth S. L. Yuen, Magnus Johannesson, David J. White, Alec Smith, Krzysztof J. Gorgolewski, Alexander Leemans, Robert W. Cox, Emanuele Olivetti, Luca Turella, Juergen Huber, Tom Schonberg, David V. Smith, Lysia Demetriou, Peter Sokol-Hessner, Juergen Dukart, Glad Mihai, Taylor Salo, Jean-Baptiste Poline, Angela R. Laird, Sergej A.E. Golowin, Sarah Genon, Adriana Galván, Claus Lamm, Joseph W. Kable, Roni Iwanir, Theo Marins, Matthew R. Johnson, Anais Rodriguez-Thompson, Benjamin Meyer, Stefan Czoschke, Loreen Tisdall, Douglas H. Schultz, Evan N. Lintz, Derek Beaton, Peer Herholz, Olivia Guest, Jenny R. Rieck, Laura Fontanesi, Ekaterina Dobryakova, Alexandre Pérez, Olivier Collignon, Xin Di, Ruud Berkers, Sheryl B. Ball, Carlos González-García, Schuyler W. Liphardt, Edna C. Cieslik, Roland G. Benoit, João F. Guassi Moreira, Helena Melero, Jaime J. Castrellon, Hayley R. Brooks, Chuan-Peng Hu, Felix Holzmeister, Cheryl L. Grady, Thomas E. Nichols, Alba Xifra-Porxas, Steven H. Tompson, Kelsey McDonald, Julia Beitner, Timothy R. Koscik, Tel Aviv University (TAU), Dartmouth College [Hanover], Leopold Franzens Universität Innsbruck - University of Innsbruck, California Institute of Technology (CALTECH), Stockholm School of Economics (SSE), University of Wisconsin-Madison, Duke University [Durham], Fondazione Bruno Kessler [Trento, Italy] (FBK), University of Trento [Trento], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Washington University in Saint Louis (WUSTL), Boston University [Boston] (BU), Virginia Tech [Blacksburg], Université Catholique de Louvain = Catholic University of Louvain (UCL), Plymouth University, Rotman Research Institute at the Baycrest Centre (RRI), University of Amsterdam [Amsterdam] (UvA), Goethe-University Frankfurt am Main, Rutgers University [Newark], Rutgers University System (Rutgers), New Jersey Institute of Technology [Newark] (NJIT), University of Electronic Science and Technology of China [Chengdu] (UESTC), University College of London [London] (UCL), D'Or Institute for Research and Education [Rio de Janeiro], Florida International University [Miami] (FIU), University of Oxford, Vrije Universiteit Brussel (VUB), Universiteit Gent = Ghent University (UGENT), University of Denver, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Jülich Research Centre, School for Advanced Studies Lucca (IMT), University of Nebraska–Lincoln, University of Nebraska System, National Institutes of Health [Bethesda] (NIH), University of Toronto, Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), 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 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)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Lancashire Teaching Hospital, University of Connecticut (UCONN), University Medical Center [Utrecht], Imperial College London, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Kessler Foundation [East Hanover], Stanford University, Taipei Medical University, TMU-ShuangHo Hospital [New Taipei City], Instituto de Neurociencias de Alicante, University of Basel (Unibas), The University of New Mexico [Albuquerque], Zhejiang University of Technology, University of California [Los Angeles] (UCLA), University of California (UC), Université catholique de Lille (UCL), Concordia University [Montreal], Aalto University, Leiden University Medical Center (LUMC), Universiteit Leiden, Linköping University (LIU), Western Sydney University, Centre for Addiction and Mental Health [Toronto] (CAMH), McGill University = Université McGill [Montréal, Canada], Eindhoven University of Technology [Eindhoven] (TU/e), Epilepsy Centre Kempenhaeghe [Heeze], Leibniz-Institut für Resilienzforschung [Mainz] (LIR), Swinburne University of Technology (Hawthorn campus), University of Michigan [Ann Arbor], University of Michigan System, Max Planck Institute for Empirical Aesthetics [Frankfurt am Main], University of Pennsylvania, Max Planck Institute for Psycholinguistics, Carver College of Medicine, University of Iowa, Rutgers New Jersey Medical School (NJMS), University of Oregon [Eugene], University of Vienna [Vienna], Johns Hopkins University (JHU), Nanjing University (NJU), Haskins Laboratories, The Alan Turing Institute, Universidad Rey Juan Carlos [Madrid] (URJC), 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)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), 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), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Karolinska Institutet [Stockholm], Stockholm University, Université de Lausanne = University of Lausanne (UNIL), Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Technical University of Berlin / Technische Universität Berlin (TU), University of California [Berkeley] (UC Berkeley), Columbia University [New York], Human Research and Engineering Directorate [Aberdeen Proving Ground], Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of California [Santa Barbara] (UC Santa Barbara), University of Dayton, Maumet, Camille, Technische Universität Berlin (TU), Leiden University, European Commission, Fundación 'la Caixa', Tel Aviv University [Tel Aviv], University of Innsbruck, University of Electronic Science and Technology of China (UESTC), University of Oxford [Oxford], Universiteit Gent = Ghent University [Belgium] (UGENT), University of Nebraska [Lincoln], Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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, University of California, University of Pennsylvania [Philadelphia], Empenn, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Lausanne (UNIL), Humboldt-Universität zu Berlin, University of California [Berkeley], University of California [Santa Barbara] (UCSB), Signal Processing Systems, and Human Technology Interaction
Subjects: Data Analysis, Male, Scientific community, Computer science, Decision, Datasets as Topic, Variation (game tree), Field (computer science), 0302 clinical medicine, Multidisciplinary approach, Data Science/methods, Models, Meta-Analysis as Topic, 0303 health sciences, Multidisciplinary, medicine.diagnostic_test, Brain, Magnetic Resonance Imaging, Research Personnel, Datasets as Topic/statistics & numerical data, Neurological, Female, ddc:500, Research Personnel/organization & administration, Models, Neurological, BF, Article, 03 medical and health sciences, Neuroimaging, Functional neuroimaging, Human behaviour, medicine, Humans, 030304 developmental biology, Statistical hypothesis testing, Flexibility (engineering), [SCCO.NEUR]Cognitive science/Neuroscience, Functional Neuroimaging, [SCCO.NEUR] Cognitive science/Neuroscience, Data Science, Reproducibility of Results, Brain/diagnostic imaging, Pipeline (software), Data science, Workflow, Logistic Models, Functional magnetic resonance imaging, Decision making, 030217 neurology & neurosurgery, Software
Abstract: Botvinik-Nezer, Rotem et al., Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed., European Union’s Horizon 2020 research and innovation programme (https://ec.europa.eu/programmes/horizon2020/en) under the Marie Skłodowska-Curie grant agreement no. 665501. A. Eed was supported by a predoctoral fellowship La Caixa-Severo Ochoa from Obra Social La Caixa. S.B.E. was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 785907 (HBP SGA2).
Published: 2020

41. Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma

Author: Sattva S. Neelapu, Theodore F. Logan, Izidore S. Lossos, Vincent Ribrag, Charles Herbaux, Walter J. Urba, Yoshinobu Koguchi, John M. Timmerman, Caron A. Jacobson, Satyendra Suryawanshi, John E. Godwin, Ronald Levy, Roch Houot, Andrew D. Zelenetz, Cecilia Carpio, Deanne Lathers, Gilles Salles, Jaclyn Neely, Yali Liu, Radhakrishnan Ramchandren, Institut Català de la Salut, [Timmerman J] UCLA Medical Center, Los Angeles, California. [Herbaux C] Centre Hospitalier Régional Universitaire de Lille, Lille, France. [Ribrag V] Institut Gustave Roussy, Villejuif, France. [Zelenetz AD] Memorial Sloan Kettering Cancer Center, New York, New York. [Houot R] CHU Rennes, Service Hématologie Clinique, Rennes, France. INSERM, Unité dʼInvestigation Clinique, Rennes, France. [Neelapu SS] The University of Texas MD Anderson Cancer Center, Houston, Texas. [Carpio C] Vall dʼHebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, California State University [Los Angeles] (CAL STATE LA), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Gustave Roussy (IGR), Memorial Sloane Kettering Cancer Center [New York], CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of Texas M.D. Anderson Cancer Center [Houston], Indiana University System, University of Miami Leonard M. Miller School of Medicine (UMMSM), Providence Cancer Center, Hospices Civils de Lyon (HCL), Dana-Farber Cancer Institute [Boston], Universitat Autònoma de Barcelona (UAB), Bristol-Myers Squibb Company, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Bristol-Myers SquibbBristol-Myers Squibb, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Follicular lymphoma, Medicaments antineoplàstics - Ús terapèutic, Gastroenterology, 0302 clinical medicine, Antineoplastic Agents, Immunological, immune system diseases, hemic and lymphatic diseases, Other subheadings::/therapeutic use [Other subheadings], Research Articles, biology, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Antibodies, Monoclonal, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Progression-Free Survival, 3. Good health, neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso [ENFERMEDADES], 030220 oncology & carcinogenesis, Rituximab, Female, Lymphoma, Large B-Cell, Diffuse, Antibody, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.drug, Research Article, medicine.medical_specialty, Cèl·lules B - Tumors - Tractament, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Refractory, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse [DISEASES], Internal medicine, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Humans, In patient, Progression-free survival, Aged, business.industry, Otros calificadores::/uso terapéutico [Otros calificadores], [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Lymphoma, Discontinuation, biology.protein, business, 030215 immunology
Abstract: Limfoma de cèl·lules B; Urelumab Linfoma de células B; Urelumab B-cell lymphoma; Urelumab Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care. Research funding from Bristol-Myers Squibb, Kite/Gilead, Merck, and Spectrum Pharmaceuticals.
Published: 2020

42. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author: Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), 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), 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 ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Dánartíðni, Epidemiology, LOCI, 45/43, General Physics and Astronomy, Muscle Proteins, Genome-wide association study, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, DISEASE, Ventricular Function, Left, Coronary artery disease, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, IMPUTATION, Medicine, Blóðrásarsjúkdómar, 692/308/174, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, Microfilament Proteins, article, Atrial fibrillation, Mendelian Randomization Analysis, CATALOG, 3. Good health, OBESITY, Erfðarannsóknir, Cardiomyopathies, Medical Genetics, Cyclin-Dependent Kinase Inhibitor p21, Science, 631/208/205/2138, Heart failure, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/443/592/2727, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, RESOURCE, Humans, Mortality, METAANALYSIS, Genetic association, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Heart Failure, HYPERTENSION, business.industry, Case-control study, Klinisk medicin, 692/699/75/230, General Chemistry, Cardiovascular genetics, medicine.disease, R1, 030104 developmental biology, Case-Control Studies, lcsh:Q, Morbidity, Clinical Medicine, business, Apoptosis Regulatory Proteins, Carrier Proteins, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.
Published: 2020

43. Quantitative modeling links in vivo microstructural and macrofunctional organization of human and macaque insular cortex, and predicts cognitive control abilities

Author: Weidong Cai, Gallardo Guillermo, Van Dang Nguyen, Jing-Rebecca Li, Mark A. Pinsk, Vinod Menon, Demian Wassermann, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Max-Planck-Institut, Princeton University, Division of Computational Science and Technology [Stockholm] (CST), Royal Institute of Technology [Stockholm] (KTH ), Shape reconstruction and identification (DeFI ), Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Stanford School of Medicine [Stanford], Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), 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 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)-Inria Saclay - Ile de France, LargeBrainNets, LargeSmallBrainNets, Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: 0303 health sciences, biology, behavior, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Cognition, Insular cortex, behavioral disciplines and activities, Macaque, insula, 03 medical and health sciences, 0302 clinical medicine, VEN, nervous system, biology.animal, circuits, salience network, cognitive control, neural, Control (linguistics), Psychology, Neuroscience, Biological sciences, Insula, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The human insular cortex is a heterogenous brain structure which plays an integrative role in guiding behavior. The cytoarchitectonic organization of the human insula has been investigated over the last century using postmortem brains but there has been little progress in noninvasive in vivo mapping of its microstructure and large-scale functional circuitry. Quantitative modeling of multi-shell diffusion MRI (dMRI) data from 440 HCP participants revealed that human insula microstructure differs significantly across its functionally defined dorsal anterior, ventral anterior, and posterior insula subdivisions that serve distinct cognitive and affective functions. The microstructural organization of the insula was mirrored in its functionally interconnected circuits with the anterior cingulate cortex that anchor the salience network, a system important for adaptive switching of cognitive control systems. Novel validation of the human insula findings came from quantitative dMRI modeling in macaques which revealed microstructural features consistent with known primate insula cytoarchitecture. Theoretical analysis and computer simulations, using realistic 3-dimensional models of neuronal morphology from postmortem tissue, demonstrated that dMRI signals reflect the cellular organization of cortical gray matter, and that these signals are sensitive to cell size and the presence of large neurons such as the von Economo neurons. Crucially, insular microstructural features were linked to behavior and predicted individual differences in cognitive control ability. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular cortex dysfunction, including autism, schizophrenia, and fronto-temporal dementia.Statement of SignificanceThe human insular cortex is a heterogenous brain structure which plays an integrative role in identifying salient sensory, affective, and cognitive cues for guiding attention and behavior. It is also is one of the most widely activated brain regions in all of human neuroimaging research. Here we use novel quantitative tools with in vivo diffusion MRI in large group (N=440) of individuals to uncover several unique microstructural features of the human insula and its macrofunctional circuits. Crucially, microstructural properties of the insular cortex predicted human cognitive control abilities, in agreement with its crucial role in adaptive human behaviors. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular dysfunction, including autism, schizophrenia, and fronto-temporal dementia.
Published: 2020

44. Ketamine/xylazine and barbiturates modulate microglial morphology and motility differently in a mouse model

Author: Ines Hristovska, Fabrice Chrétien, Franck Verdonk, Eileen S. Tsai, Jean-Christophe Comte, Jérôme Honnorat, Virginie Desestret, Olivier Pascual, Bodescot, Myriam, Régulation de la plasticité synaptique par les microglies : un travail de nuit ? - - Micromem2017 - ANR-17-CE16-0008 - AAPG2017 - VALID, Synaptopathies et Autoanticorps [Lyon] (SynatAc), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Forgetting Processes and Cortical Dynamics (FORGETTING), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, Université Sorbonne Paris Cité (USPC), Laboratoire Hospitalo-Universitaire de Neuropathologie [Paris], Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IH was funded by the French ministry for research. This work was also supported by the Foundation des Gueules Cassées and the SFAR (Société Française d’Anesthésie-Réanimation), ANR MICROMEM # R17136CC and INSERM., ANR-17-CE16-0008,Micromem,Régulation de la plasticité synaptique par les microglies : un travail de nuit ?(2017), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Université de Paris (UP), Processus d'oubli et Dynamique Corticale [Lyon], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: Male, Xylazine, 0301 basic medicine, Cytoplasm, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Mice, 0302 clinical medicine, Animal Cells, Anesthesiology, Cell Movement, Medicine and Health Sciences, Premovement neuronal activity, Anesthesia, Pentobarbital, Clinical Neurophysiology, Brain Mapping, Multidisciplinary, Microglia, Pharmaceutics, Chemistry, Drugs, Brain, Electroencephalography, Electrophysiology, Cell Motility, Bioassays and Physiological Analysis, medicine.anatomical_structure, Brain Electrophysiology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Medicine, Ketamine, Cellular Types, Anatomy, Cellular Structures and Organelles, Research Article, medicine.drug, Imaging Techniques, Science, Neurophysiology, Motility, Glial Cells, Neuroimaging, Mice, Transgenic, Research and Analysis Methods, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Drug Therapy, In vivo, medicine, Pain Management, Animals, Thiopental, GABA Modulators, Microglial Cells, Anesthetics, Pharmacology, Electrophysiological Techniques, Neurotoxicity, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology and Life Sciences, Cell Biology, medicine.disease, 030104 developmental biology, Anesthetic, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Clinical Medicine, Neuroscience, 030217 neurology & neurosurgery, Ex vivo
Abstract: International audience; Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.
Published: 2020

45. Learning disabilities: Developmental dyscalculia

Author: Teresa Iuculano, Elisa Castaldi, Manuela Piazza, Université Paris Descartes - Faculté des Sciences humaines et sociales - Sorbonne (UPD5 SHS), Université Paris Descartes - Paris 5 (UPD5), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, and Centre National de la Recherche Scientifique (CNRS)
Subjects: 05 social sciences, Numerical cognition, Cognition, Number sense, medicine.disease, 050105 experimental psychology, [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, Learning disability, Developmental Dyscalculia, Dyscalculia, medicine, 0501 psychology and cognitive sciences, medicine.symptom, 10. No inequality, Everyday life, Psychology, Neurocognitive, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: Developmental dyscalculia (DD) is a developmental learning disability that manifests as a persistent difficulty in comprehending even the most basic numeric and arithmetic concepts, despite normal intelligence and schooling opportunities. Given the predominant use of numbers in modern society, this condition can pose major challenges in the sufferer's everyday life, both in personal and professional development. Since, to date, we still lack a universally recognized and psychometrically driven definition of DD, its diagnosis has been applied to a wide variety of cognitive profiles. In this chapter, we review the behavioral and neural characterization of DD as well as the different neurocognitive and etiologic accounts of this neurodevelopmental disorder. We underline the multicomponential nature of this heterogeneous disability: different aspects of mathematical competence can be affected by both the suboptimal recruitment of general cognitive functions supporting mathematical cognition (such as attention, memory, and cognitive control) and specific deficits in mastering numeric concepts and operations. Accordingly, both intervention paradigms focused on core numeric abilities and more comprehensive protocols targeting multiple neurocognitive systems have provided evidence for effective positive outcomes.
Published: 2020

46. Virtual Reality for PEripheral Regional Anesthesia (VR-PERLA Study)

Author: Camille Alaterre, Siham Zriouel, Francis Bonnet, Franck Verdonk, Thomas Lescot, Eileen Sung Tsai, Baptiste Duceau, Service des Soins Intensifs [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, and Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Hemodynamics, lcsh:Medicine, Virtual reality, anesthesia, Article, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Distraction, medicine, 030212 general & internal medicine, ambulatory surgery, business.industry, lcsh:R, satisfaction, General Medicine, Perioperative, anxiety, 3. Good health, 030220 oncology & carcinogenesis, Anesthesia, Ambulatory, Anxiety, virtual reality, Observational study, medicine.symptom, business, regional anesthesia, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: When used as an add-on to regional anesthesia, virtual reality (VR) has been reported to provide anxiety-reducing benefits and sedation-sparing effects. However, its impact on patient satisfaction is still a matter of controversy. We investigated the feasibility and benefits of implementing intraoperative VR distraction in a French University Hospital (H&ocirc, pital Saint-Antoine, AP-HP). This monocentric observational before&ndash, after study included 100 patients who underwent ambulatory upper limb surgery under peripheral nerve block in January 2019, 50 before and 50 after implementation of an intraoperative VR distraction protocol. Primary outcome was patient self-rated satisfaction score evaluated right after surgery. Secondary outcomes included 2-month patient-reported satisfaction score, perioperative self-rated anxiety and intraoperative hemodynamic changes. Compared to former standard care, VR distraction was associated with significantly higher postoperative satisfaction scores (10 [IQR 9, 10] vs. 9 [8, 10], p &lt, 0.001) still reported two months after surgery (10 [10, 10] vs. 10 [8.5, 10], p = 0.06). Patient median intraoperative anxiety score was lower in the VR group, compared to Standard Care group (0 [0, 2] vs. 3 [0.25, 7], p &lt, 0.001), and occurrence of intraoperative hemodynamic changes was also lessened in the VR group (2% vs. 16%, 0R = 0.11[95% CI 0.002&ndash, 0.87], p = 0.031). The present findings suggest that VR distraction program in the operating room could effectively improve patient satisfaction with anxiety-reduction and hemodynamic benefits.
Published: 2020

47. Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness

Author: Kikuti, Carlos, Houdusse, Anne, Gyimesi, Máté, Horváth, Ádám, Túrós, Demeter, Suthar, Sharad Kumar, Pénzes, Máté, Kurdi, Csilla, Canon, Louise, Ruppel, Kathleen, Trivedi, Darshan, Spudich, James, Lőrincz, István, Rauscher, Anna, Kovács, Mihály, Pál, Endre, Komoly, Sámuel, Málnási-Csizmadia, András, Rauscher, Anna Á., Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Pecs, Eötvös Loránd University (ELTE), Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University
Subjects: Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Muscle Fibers, Skeletal, unmet medical need, Sarcomere, Mice, Drug Delivery Systems, 0302 clinical medicine, Myosin, Protein Isoforms, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Skeletal Muscle Myosins, artificial intelligence, stroke, 3. Good health, medicine.anatomical_structure, Muscle relaxation, Muscle Spasticity, Female, medicine.symptom, force, Muscle Contraction, Muscle contraction, Adult, Spastic gait, Myosins, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, motor protein, medicine, Animals, Humans, musculoskeletal disorder, blebbistatin, Spasticity, Rats, Wistar, Muscle, Skeletal, crystallography, 030304 developmental biology, deep learning, Skeletal muscle, Muscle stiffness, medicine.disease, Rats, sarcomere, Cardiac Myosins, Neuroscience, human activities, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.
Published: 2020

48. A high-stringency blueprint of the human proteome

Author: Ruedi Aebersold, Edouard C. Nice, Mathias Uhlén, Seong Beom Ahn, Joshua LaBaer, Joshua L Justice, Yves Vandenbrouck, Gilbert S. Omenn, Stephen R. Pennington, Jennifer E. Van Eyk, Emma Lundberg, Peipei Ping, J. C. Waddington, Sara A. Wennersten, Sanjeeva Srivastava, Robert L. Moritz, Marc R. Wilkins, Amos Marc Bairoch, Rebekah L. Gundry, Ulrike Kusebauch, György Marko-Varga, Maggie P.Y. Lam, Fuchu He, Susan T. Weintraub, Peter Stewart, Markus Kostrzewa, Cecilia Lindskog, Christopher M. Overall, Nuno Bandeira, Mark S. Baker, Juan Antonio Vizcaíno, Fernando J. Corrales, Sudhir Srivastava, Jochen M. Schwenk, Subash Adhikari, Eric W. Deutsch, Ileana M. Cristea, Charles Pineau, Gilberto B. Domont, Magnus Palmblad, Lydie Lane, Henry Rodriguez, Fábio C. S. Nogueira, Daniel W. Chan, Young Ki Paik, Michael Snyder, Instituto de Salud Carlos III, Comunidad de Madrid, National Institutes of Health (US), Canada Research Chairs, Wellcome Trust, Knut and Alice Wallenberg Foundation, Fundaçao Capes (Brasil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Cancer Council NSW (Australia), Cancer Institute NSW (Australia), Stanford University, Macquarie University, Monash University [Melbourne], Institute for Systems Biology [Seattle] (ISB), Centre médical universitaire de Genève (CMU), University of Michigan [Ann Arbor], University of Michigan System, University College Dublin [Dublin] (UCD), Yonsei University, University of British Columbia (UBC), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Princeton University, Cedars-Sinai Medical Center, Royal Institute of Technology [Stockholm] (KTH ), Uppsala University, Johns Hopkins University School of Medicine [Baltimore], Arizona State University [Tempe] (ASU), National Institutes of Health [Bethesda] (NIH), National Cancer Institute [Bethesda] (NCI-NIH), Bruker Daltonik GmbH, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Nebraska Medical Center, University of Nebraska System, Indian Institute of Technology Bombay (IIT Bombay), Pontifícia Universidade Católica do Rio de Janeiro (PUC-Rio), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), University of Colorado Anschutz [Aurora], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of New South Wales [Sydney] (UNSW), University of California [San Diego] (UC San Diego), University of California (UC), Department of Computer Science and Engineering [Univ California San Diego] (CSE - UC San Diego), Lund University [Lund], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Leiden University Medical Center (LUMC), Universiteit Leiden, Stanford University School of Medicine [CA, USA], Universität Zürich [Zürich] = University of Zurich (UZH), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, HAL UR1, Admin, Biocomputing Unit [Madrid], University of California-University of California, University of California, Department of Computer Science and Engineering [San Diego] (CSE-UCSD), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Proteomics, Proteome, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Proteomic analysis, Genomics, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Blueprint, Human Genome Project, Human proteome project, Humans, Disease, lcsh:Science, ddc:616, Multidisciplinary, 030102 biochemistry & molecular biology, Molecular medicine, Extramural, Biochemistry and Molecular Biology, General Chemistry, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Perspective, lcsh:Q, Biokemi och molekylärbiologi
Abstract: © The Author(s) 2020, The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases., Parts of this work were supported by grants to ProteoRed PRB3-ISCIII, PT17/0019/0001 Comunidad de Madrid Grant B2017/BMD-3817 (F.J.C.); Korean Ministry of Health and Welfare HI13C2098 and HI16C0257 (Y.K.P.); NIH grants P30ES017885 and U24CA210967 (G.S.O.), 5U01HL-13104204, PADOM-SPO11347 and PARYB-SPO112285 (M.P.S.); NCI CPTAC U24CA210985 and NCI EDRN U24CA115102 (D.W.C.); NIH National Institute of General Medical Sciences R01GM087221 (E.W.D./R.L.M.) and R24GM127667 (E.W.D.); NIH National Institute on Aging U19AG023122 (R.L.M.); NSF DBI-1933311 (E.W.D.); CIHR COVID-19 Rapid Research Funding (F20-01013), CIHR Foundation Grant FDN:14840 and Canada Research Chair (C.M.O.); Investissement d’Avenir Infrastructures Nationales en Biologie et Santé ANR-10-INBS-08 (Proteomics French Infrastructure ProFI (Y.V.); Wellcome Trust WT101477MA and 208391/Z/17/Z (J.A.V.); Knut and Alice Wallenberg Foundation (M.U., C.L., J.M.S., E.L.); Brazilian CAPES 88887.130697, CNPq 440613/2016-7, FAPERJ E-26/210.173/2018 (G.B.D.) and FAPERJ E-26/202.650/2018 (F.C.S.N.), Australian Commonwealth NCRIS (M.S.B.); NHMRC 1010303 (M.S.B., E.C.N.); Cancer Council NSW RG19-04 (M.S.B., S.B.A., E.C.N.); Cancer Institute NSW Fellowship 15/ECF/1-38 (S.B.A.), Sydney Vital CINSW Translational Cancer Research Centre grant (M.S.B., S.B.A., S.A.), ‘Fight on the Beaches’ (M.S.B., S.B.A., E.C.N., S.A.) funding and an International Macquarie Research Excellence Scholarship (S.A.). M.S.B. thanks the Faculty of Medicine, Stanford University for a sabbatical visiting professorship.
Published: 2020

49. De novo protein design enables the precise induction of RSV-neutralizing antibodies

Author: Sean Ervin, Jean-François Eléouët, Sabrina Vollers, Marie-Anne Rameix-Welti, Marie Galloux, Stéphane Rosset, Jean-Philippe Julien, Xiaolin Wen, Yuxing Li, Johannes T. Cramer, Che Yang, Jaume Bonet, Thomas Krey, Theodore S. Jardetzky, Patricia Corthésy, Yimeng Wang, Sabine Riffault, Chi-I Chiang, Iga Kucharska, Delphyne Descamps, Elie Dheilly, Sandrine Georgeon, Giacomo Castoro, Mélanie Villard, Charles-Adrien Richard, Teresa C. Delgado, Fabian Sesterhenn, Elisa Oricchio, Vicente Mas, Luciano A. Abriata, Bruno E. Correia, John T. Bates, Instituto de Salud Carlos III, European Research Council, Swiss National Science Foundation, Stavros Niarchos Foundation, EPFL Postdoctoral Fellows, German Center for Infection Research (Alemania), Deutsche Forschungsgemeinschaft (Alemania), Federal Ministry of Education & Research (Alemania), Canada Research Chairs, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Hannover Medical School [Hannover] (MHH), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Maryland [Baltimore], The Hospital for sick children [Toronto] (SickKids), Department of Biochemistry [University of Toronto], University of Toronto, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Swiss Institute for Experimental Cancer Research - Lausanne (ISREC), Swiss Institute for Experimental Cancer Research, Centro Nacional de Microbiología [ISCIII, Madrid, Spain] (CNM), Instituto de Salud Carlos III [Madrid] (ISC), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wake Forest Baptist Medical Center, University of Mississippi Medical Center (UMMC), University of Maryland School of Medicine, University of Maryland System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), University of Luebeck, INSTITUT FUR ANGEWANDTE BODENBIOLOGIE GMBH HAMBURG DEU, 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), European Project: 716058,DeNovoImmunoDesign, Université de Lausanne = University of Lausanne (UNIL), and European Project: 716058,EXCELLENT SCIENCE - European Research Council (ERC),ERC-2016-STG - ERC Starting Grant,DeNovoImmunoDesign(2017)
Subjects: Immunogen, medicine.drug_class, Protein Conformation, Recombinant Fusion Proteins, Protein design, Amino Acid Motifs, computational design, Computational biology, Biology, Monoclonal antibody, Protein Engineering, Epitope, Article, Affinity maturation, 03 medical and health sciences, 0302 clinical medicine, Antigen, backbone, medicine, Respiratory Syncytial Virus Vaccines, Humans, b-cells, 030304 developmental biology, affinity maturation, 0303 health sciences, epitope, Multidisciplinary, dengue virus, Immunodominant Epitopes, Computational Biology, fusion-glycoprotein vaccine, Single-Domain Antibodies, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Fusion protein, Antibodies, Neutralizing, 3. Good health, nmr structure determination, Respiratory Syncytial Virus, Human, biology.protein, potent, Antibody, influenza, 030217 neurology & neurosurgery
Abstract: De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs. This work was supported by the swiss initiative for systems biology (SystemsX.ch), the European Research Council (Starting grant - 716058), the Swiss National Science Foundation (310030_163139) and the EPFL’s Catalyze4Life initiative. F.S. was supported by an SNF/Innosuisse BRIDGE Proof-of-Concept grant. J.B. was supported by the EPFL Fellows postdoctoral fellowship. T.K. received funding from the German Center of Infection Research (DZIF) and the Cluster of Excellence RESIST (EXC 2155) of the German Research foundation. J.T.C. was funded by the ERA-Net PrionImmunity project 01GM1503 (Federal Ministry of Education and Research, Germany). V.M. received funding from “AESI-18” (Instituto de Salud Carlos III), grant MPY 375/18. J.PJ. was funded by the Canada Research Chairs program (J.P.J.), T.J. and X.W. were funded by the NIH NIAID (R01 AI137523). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí
Published: 2020

50. The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

Author: Perrine Janiaud, Cathrine Axfors, Janneke van't Hooft, Ramon Saccilotto, Arnav Agarwal, Christian Appenzeller-Herzog, Despina G. Contopoulos-Ioannidis, Valentin Danchev, Ulrich Dirnagl, Hannah Ewald, Gerald Gartlehner, Steven N. Goodman, Noah A. Haber, Angeliki Diotima Ioannidis, John P. A. Ioannidis, Mark P. Lythgoe, Wenyan Ma, Malcolm Macleod, Mario Malički, Joerg J. Meerpohl, Yan Min, David Moher, Blin Nagavci, Florian Naudet, Christiane Pauli-Magnus, Jack W. O'Sullivan, Nico Riedel, Jan A. Roth, Mandy Sauermann, Stefan Schandelmaier, Andreas M. Schmitt, Benjamin Speich, Paula R. Williamson, Lars G. Hemkens, HAL UR1, Admin, University of Basel (Unibas), Meta-Research Innovation Center at Stanford (METRICS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University-Stanford Medicine, Stanford University-Stanford University, Stanford University, Uppsala University, Universiteit van Amsterdam (UvA), University of Toronto, Stanford University School of Medicine [CA, USA], Berlin Institute of Health (BIH), Danube University Krems, University of California [Los Angeles] (UCLA), University of California (UC), Imperial College London, University of Edinburgh, University of Freiburg [Freiburg], Ottawa Hospital Research Institute [Ottawa] (OHRI), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], University Hospital Basel [Basel], McMaster University [Hamilton, Ontario], University of Oxford, University of Liverpool, Laura and John Arnold Foundation, 31CA30_196190, Schweizerischer Nationalfonds zur F&#x00F6, rderung der Wissenschaftlichen Forschung, Obstetrics and Gynaecology, University of California, 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), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, China, clinical research agenda, hydroxychloroquine, Pneumonia, Viral, 0601 Biochemistry and Cell Biology, General Biochemistry, Genetics and Molecular Biology, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, 1112 Oncology and Carcinogenesis, 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Pandemics, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Clinical Trials as Topic, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, General Immunology and Microbiology, SARS-CoV-2, covid 19, COVID-19, 1103 Clinical Sciences, Articles, General Medicine, 16. Peace & justice, 3. Good health, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Health Services Research, Coronavirus Infections, Research Article
Abstract: Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.
Published: 2020

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