Accès ouvert déclaré 2022 article

Stroke genetics informs drug discovery and risk prediction across ancestries

Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel Posner, Frederick Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K. Georgakis, Ilana Caro, Kristi Krebs, Yi‐Ching Liaw, Felix Vaura, Kuang Lin, Bendik S. Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee‐Joon Bae, Ganesh Chauhan, Michael Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V. Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel‐Márquez, Marianne Nygaard, Hampton L. Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J. Knol, Adam Lewis, Renae Judy, Tetsuro Ago, Philippe Amouyel, Nicole D. Armstrong, Mark K. Bakker, Traci M. Bartz, David A. Bennett, Joshua C. Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M. Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W. Cole, Phil L. de Jager, Rafael de Cid, Matthias Endres, Leslie Ecker Ferreira, Mirjam I. Geerlings, Natalie C. Gasca, Vilmundur Guðnason, Jun Hata, Jing He, Alicia K. Heath, Yuk‐Lam Ho, Aki S. Havulinna, Jemma C. Hopewell, Hyacinth I. Hyacinth, Michael Inouye, Mina A. Jacob, Christina Jeon, Christina Jern, Masahiro Kamouchi, Keith L. Keene, Takanari Kitazono, Steven J. Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J. Launer, Keon‐Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S. Markus, Nicholas A. Marston, Thomas Meitinger, Braxton D. Mitchell, Felipe A. Montellano, Takayuki Morisaki, Thomas H. Mosley, Mike A. Nalls, Børge G. Nordestgaard, Martin O’Donnell, Yukinori Okada, N. Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M. Psaty, Stephen S. Rich, Jonathan Rosand, Marc S. Sabatine, Ralph L. Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L. Satizábal, Carsten Oliver Schmidt, Atsushi Shimizu, Nicholas Smith, Kelly L. Sloane, Yoichi Sutoh, Yan V. Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P. Torres‐Aguila, Hemant K. Tiwari, David‐Alexandre Trégouët, Stella Trompet, Anil M Tuladhar, Anne Tybjærg‐Hansen, Marion van Vugt, Riina Vibo, Shefali S. Verma, Kerri L. Wiggins, Patrik Wennberg, Daniel Woo, Peter W. F. Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Joshua C. Bis, Jin‐Moo Lee, Yu‐Ching Cheng, James F. Meschia, Wei Min Chen, Michèle M. Sale, Alan B. Zonderman, Michele K. Evans, James G. Wilson, Adolfo Correa, Matthew Traylor, Cathryn M. Lewis, Cara L. Carty, Alexander Reiner, Jeffrey Haessler, Carl D. Langefeld, Rebecca F. Gottesman, Kristine Yaffe, Yong Mei Liu, Charles Kooperberg, Leslie A. Lange, Karen L. Furie, Donna K. Arnett, Oscar R. Benavente, Raji P. Grewal, Leema Reddy Peddareddygari, Kristian Hveem, Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack Pattee, Ben M. Brumpton, Pierre Suchon, Ming‐Huei Chen, Kelly A. Frazer, Constance Turman, Marine Germain, James W. MacDonald, Sigrid K. Brækkan, Sebastian M. Armasu, Nathan Pankratz, Rebecca D. Jackson, Jonas B. Nielsen, Franco Giulianini, Marja K. Puurunen, Manal Ibrahim, Susan R. Heckbert, Theo K. Bammler, Bryan M. McCauley, Kent D. Taylor, James S. Pankow, Alex P. Reiner, Maiken E. Gabrielsen, Jean-François Deleuze, Chris O’Donnell, Jihye Kim, Barbara McKnight, Peter Kraft, John‐Bjarne Hansen, Frits R. Rosendaal, John A. Heit, Weihong Tang, Pierre‐Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, Ewoud J. van Dijk, Peter J. Koudstaal, Gert-Jan Luijckx, Paul J. Nederkoorn, Robert J van Oostenbrugge, Marieke C. Visser, Marieke J.H. Wermer, L. Jaap Kappelle, Tõnu Esko, Andres Metspalu, Reedik Mägi, Mari Nelis, Marguerite R. Irvin, Christopher Levi, Jane Maguire, Jordi Jiménez‐Conde, Pankaj Sharma, Cathie Sudlow, Kristiina Rannikmäe, Reinhold Schmidt, Agnieszka Slowik, Joanna Pera, Vincent Thijs, Andreea Ilinca, Olle Melander, Gunnar Engström, Kathryn M. Rexrode, Peter M. Rothwell, Tara M. Stanne, Julie A. Johnson, John Danesh, Adam S. Butterworth, Laura Heitsch, Giorgio B. Boncoraglio, Michiaki Kubo, Alessandro Pezzini, Arndt Rolfs, Anne‐Katrin Giese, David R. Weir, Owen A. Ross, Robin Lemmons, Martin Söderholm, Mary Cushman, Katarina Jood, Caitrin W. McDonough, Steven Bell, Birgit Linkohr, Tsong-Hai Lee, Jukka Putaala, Oscar L. Lopez, Xueqiu Jian, Ulf Schminke, Natàlia Cullell, Pilar Delgado, Laura Ibáñez, Jerzy Krupiński, Vasileios Lioutas, Koichi Matsuda, Joan Montaner, Elena Muiño, Jaume Roquer, Chloé Sarnowski, Naveed Sattar, Gerli Sibolt, Alexander Teumer, Loes C.A. Rutten‐Jacobs, Masahiro Kanai, Sólveig Grétarsdóttir, Natalia S. Rost, Salim Yusuf, Peter Almgren, Hakan Ay, Steve Bevan, Robert D. Brown, Caty Carrera, Julie E. Buring, Wei‐Min Chen, Ioana Cotlarciuc, Paul I. W. de Bakker, Anita L. DeStefano, Marcel den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Stefan Gustafsson, Ahamad Hassan, Elizabeth G. Holliday, George Howard, Fang‐Chi Hsu, Erik Ingelsson, Tamara B. Harris, Brett Kissela, Dawn Kleindorfer, Claudia Langenberg, Robin Lemmens, Didier Leys, Wei‐Yu Lin, Erik Lorentzen, Patrik K. E. Magnusson, Patrick F. McArdle, Sara L. Pulit, Kenneth Rice, Saori Sakaue, Bishwa R. Sapkota, Christian Tanislav, Gudmar Thorleifsson, U. Thorsteinsdottir, Christophe Tzourio, Cornelia M. van Duijn, James Walters, Nicholas J. Wareham, Najaf Amin, Hugo J. Aparicio, John Attia, Alexa Beiser, Claudine Berr, Mariana Bustamante, Valeria Caso, Seung Hoan Choi, Ayesha Chowhan, Jean‐François Dartigues, Hossein Delavaran, Marcus Dörr, Ian Ford, Wander S. Gurpreet, Anders Hamsten, Atsushi Hozawa, Martin Ingelsson, Motoki Iwasaki, Sara Kaffashian, Lalit Kalra, Ólafur Kjartansson, Manja Kloß, Daniel Labovitz, Cathy C. Laurie, Linxin Li, Lars Lind, Cecilia M. Lindgren, Makoto Hirata, Naoko Minegishi, Andrew P. Morris, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio Parati, Nancy L. Pedersen, Markus Perola, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, José R. Romero, Anthony G. Rudd, Antti-Pekka Sarin, Sarju Ralhan, Mamoru Satoh, Norie Sawada, Ásgeir Sigurðsson, Albert V. Smith, O. Colin Stine, David J. Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Emmanuel Touzé, Shoichiro Tsugane, André G. Uitterlinden, Einar Már Valdimarsson, Sven J. van der Lee, Kenji Wakai, Stephen R. Williams, Charles Wolfe, Quenna Wong, Taiki Yamaji, Dharambir K. Sanghera, Kari Stefansson, Nicolas Martinez‐Majander, Kenji Sobue, Carolina Soriano‐Tárraga, Henry Völzke, Onoja Akpa, Fred Stephen Sarfo, Albert Akpalu, Reginald Obiako, Kolawole Wahab, Godwin Osaigbovo, Lukman Owolabi, Morenikeji Komolafe, Carolyn Jenkins, Oyedunni Arulogun, Godwin Ogbole, Abiodun M. Adeoye, Joshua Akinyemi, Atinuke Agunloye, Adekunle Fakunle, Ezinne Uvere, Abimbola Olalere, Olayinka Adebajo, Junshi Chen, Robert Clarke, Rory Collins, Yu Guo, Chen Wang, Jun Lv, Richard Peto, Yiping Chen, Zammy Fairhurst-Hunter, Michael Hill, Alfred Pozarickij, Dan Schmidt, Becky Stevens, Iain Turnbull, Canqing Yu, Akiko Nagai, Yoishinori Murakami, Eric J. Shiroma, Sigurður Sigurðsson, Mohsen Ghanbari, Eric Boerwinkle, Bernard Fongang, Ruiqi Wang, M. Kamran Ikram, Uwe Völker, Karlijn F. de Laat, Anouk G.W. van Norden, Paul L.M. de Kort, Sarah E. Vermeer, Paul J.A.M. Brouwers, Rob A.R. Gons, Tom den Heijer, Gert W. van Dijk, Frank G. W. van Rooij, Anne Hege Aamodt, Anne Heidi Skogholt, Cristen J. Willer, Ingrid Heuch, Knut Hagen, Lars G. Fritsche, Linda M. Pedersen, Hanne Ellekjær, Wei Zhou, Amy E. Martinsen, Espen Saxhaug Kristoffersen, Laurent F. Thomas, Christoph Kleinschnitz, Stefan Frantz, Kathrin Ungethüm, Cristina Gallego-Fábrega, Miquel Lledós, Laia Llucià‐Carol, Tomás Sobrino, Francisco Campos, José Castillo, Juan F. Arenillas, Vı́ctor Obach, José Álvarez‐Sabín, Carlos A. Molina, Marc Ribó, Lucía Muñoz-Narbona, Elena López‐Cancio, Mónica Millán, Rosa Díaz-Navarro, Cristòfol Vives-Bauzá, Gemma Serrano‐Heras, Tomás Segura, Rajat Dhar, Raquel Delgado‐Mederos, Pol Camps‐Renom, Natàlia Blay, Lauro Sumoy, Joan Martí‐Fábregas, Peter Schnohr, Gorm Boje Jensen, Marianne Benn, Shoaib Afzal, Pia R. Kamstrup, Jessica van Setten, Sander W. van der Laan, Jet M. J. Vonk, Bong‐Jo Kim, Sami Curtze, Marjaana Tiainen, Janne Kinnunen, Vilas Menon, Chengran Yang, Florence Saillour-Glenisson, Simon Gravel, Iona Y. Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J. Grabe, J. Wouter Jukema, Ina L. Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M. M. Howson, Hieab H.H. Adams, Sylvia Wassertheil‐Smoller, Kaare Christensen, M. Arfan Ikram, Tatjana Rundek, Bradford B. Worrall, G.M. Lathrop, Moeen Riaz, Eleanor M. Simonsick, Janika Kõrv, Paulo Henrique Condeixa de França, Ramin Zand, Kameshwar Prasad, Ruth Frikke‐Schmidt, Thomas Liman, Karl Georg Hæusler, Ynte M. Ruigrok, Peter U. Heuschmann, W. T. Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M. Damrauer, Daniel I. Chasman, Jerome I. Rotter, John‐Anker Zwart, Teemu Niiranen, Myriam Fornage, Yung‐Po Liaw, Sudha Seshadri, Israel Fernández‐Cadenas, Robin Walters, Christian T. Ruff, Mayowa Owolabi, Jennifer E. Huffman, Lili Milani, Martin Dichgans, Stéphanie Debette

636Citations signalées, ce qui n’est pas une note de qualité

294Institutions déclarées

31Pays d’affiliation déclarés

Rattachement africain : fr, de, jp, ee, us, tw, fi, gb, no, kr, in, ca, Nigéria, nl, il, dk, es, br, is, au, se, ch, cn, ie, id, at, pl, it, be, Ghana, cl. Niveau de preuve : code pays fourni par la source.

Le résumé fourni par la source

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.

Le contrôle bibliographique ouvert

DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.

Titre Crossref: Stroke genetics informs drug discovery and risk prediction across ancestries
Date Crossref: 30/09/2022
Éditeur: Springer Science and Business Media LLC
Type: journal-article

Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.

Les institutions déclarées

Université de Bordeaux Inserm Bordeaux Population Health LMU Klinikum Institut für Schlaganfall- und Demenzforschung Ludwig-Maximilians-Universität München Iwate Medical University Tohoku Medical Megabank Organization University of Tartu The University of Osaka VA Boston Healthcare System Brigham and Women's Hospital Harvard University Thrombolysis in Myocardial Infarction Study Group Tokyo Medical University The University of Tokyo Broad Institute Massachusetts General Hospital Massachusetts Institute of Technology Chung Shan Medical University Hospital Chung Shan Medical University University of Turku Finnish Institute for Health and Welfare University of Oxford Oslo University Hospital Norwegian University of Science and Technology University of Alabama at Birmingham Seoul National University Bundang Hospital Rajendra Institute of Medical Sciences Thrombosis and Atherosclerosis Research Institute McMaster University University of Helsinki Helsinki University Hospital University of Ibadan Erasmus MC Hebrew University of Jerusalem Copenhagen University Hospital Rigshospitalet Pennsylvania State University Geisinger Health System Universitat Autònoma de Barcelona Hospital de Sant Pau University of Southern Denmark Odense University Hospital National Institutes of Health Data Tecnica International (United States)National Institute on Aging University of Virginia University of Cambridge Novo Nordisk (United Kingdom)Vanderbilt University Medical Center University of Pennsylvania Kyushu University Université de Lille Institut Pasteur de Lille Centre Hospitalier Universitaire de Lille Utrecht University University Medical Center Utrecht University of Washington Rush University Medical Center University of Oslo Washington University in St. Louis University of Maryland, Baltimore VA Maryland Health Care System Columbia University Irving Medical Center Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol German Center for Neurodegenerative Diseases German Centre for Cardiovascular Research Charité - Universitätsmedizin Berlin Universidade da Região de Joinville University of Iceland Icelandic Heart Association Imperial College London Institute for Molecular Medicine Finland University of Cincinnati Medical Center Baker Heart and Diabetes Institute Health Data Research UK Radboud University Nijmegen Radboud University Medical Center Los Angeles County Department of Public Health Sahlgrenska University Hospital University of Gothenburg East Carolina University Monash University Korea University Medical Center SIB Swiss Institute of Bioinformatics University of Lausanne Peking University Helmholtz Munich Technical University of Munich University of Würzburg Universitätsklinikum Würzburg Jackson Memorial Hospital University of Mississippi Medical Center University of Copenhagen Gentofte Hospital Ollscoil na Gaillimhe – University of Galway RIKEN Center for Integrative Medical Sciences University of California, San Francisco Zimmer Biomet (Germany)University of Miami Columbia University Stiftelsen Norsk Luftambulanse The University of Texas at San Antonio Health Science Center Institute for Neurodegenerative Disorders Universitätsmedizin Greifswald Kaiser Permanente Washington Health Research Institute VA Office of Research and Development Emory University Atlanta VA Health Care System Leiden University Medical Center Umeå University Boston University Korea National Institute of Health Jacksonville College Mayo Clinic in Florida Queen Mary University of London William Harvey Research Institute King's College London Washington State University Fred Hutch Cancer Center Wake Forest University Johns Hopkins University Johns Hopkins Medicine National Institute of Neurological Disorders and Stroke University of Colorado Anschutz Brown University University of Kentucky University of British Columbia Saint Francis Medical Center St Olav's University Hospital University of California San Diego Rady Children's Hospital-San Diego UiT The Arctic University of Norway University of Minnesota University of Bristol MRC Epidemiology Unit Aix-Marseille Université Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement Hôpital de la Timone University Hospital of North Norway The Ohio State University Statens Serum Institut University of Michigan The Lundquist Institute UCLA Medical Center Harbor–UCLA Medical Center Commissariat à l'Énergie Atomique et aux Énergies Alternatives Fondation Jean Dausset-CEPH Centre National de Recherche en Génomique Humaine Direction de la Recherche Fondamentale University of Pembangunan Nasional Veteran Jawa Timur Assistance Publique Hôpitaux de Marseille University Medical Center Groningen Amsterdam University Medical Centers University of Amsterdam Maastricht University John Hunter Hospital Hunter Medical Research Institute University of Technology Sydney Universitat Pompeu Fabra Municipal Institute for Medical Research Hospital del Mar Research Institute Royal Holloway University of London Ashford and St Peter's Hospitals NHS Foundation Trust University of Edinburgh Medical University of Graz Jagiellonian University The University of Melbourne Florey Institute of Neuroscience and Mental Health Austin Health Lund University Skåne University Hospital University of Florida Wellcome Sanger Institute Genomics (United Kingdom)Fondazione IRCCS Istituto Neurologico Carlo Besta National Institute for Health and Care Research University of Brescia University of Rostock KU Leuven University of Vermont Region Västra Götaland VIB-KU Leuven Center for Brain & Disease Research Chang Gung Memorial Hospital University of Pittsburgh Vall d'Hebron Institut de Recerca University Hospital Mútua de Terrassa Mútua Terrassa Hospital Universitario Virgen Macarena Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío Universidad de Sevilla Beth Israel Deaconess Medical Center The University of Texas Health Science Center at Houston University of Glasgow deCODE Genetics (Iceland)Population Health Research Institute University of Lincoln Mayo Clinic in Arizona Athinoula A. Martinos Center for Biomedical Imaging Fundación Atapuerca Uppsala University Science for Life Laboratory University of North Carolina at Chapel Hill University of Basel University Hospital of Basel Felix Platter-Hospital Yale University Leeds General Infirmary Leeds Teaching Hospitals NHS Trust University of Newcastle Australia Stanford University Berlin Institute of Health at Charité - Universitätsmedizin Berlin Karolinska Institutet MRC Biostatistics Unit University of Oklahoma Health Sciences Center Justus-Liebig-Universität Gießen Université de Montpellier Center for Research in Environmental Epidemiology University of Perugia Dayanand Medical College & Hospital University Health Network University of Toronto Ontario Brain Institute National University Hospital of Iceland Heidelberg University University Hospital Heidelberg Albert Einstein College of Medicine Montefiore Medical Center Centre for Human Genetics BioBank Japan University of Liverpool Mario Negri Institute for Pharmacological Research Universitat de Barcelona Centro de Investigación Biomédica en Red de Salud Mental Guy's and St Thomas' NHS Foundation Trust Aichi Cancer Center Université de Caen Normandie Nagoya University Reykjavík University Oklahoma City University Hospital Del Mar Kwame Nkrumah University of Science and Technology University of Ghana Ahmadu Bello University University of Ilorin Teaching Hospital Jos University Teaching Hospital Aminu Kano Teaching Hospital Obafemi Awolowo University Medical University of South Carolina China National Center for Food Safety Risk Assessment Chinese Academy of Medical Sciences & Peking Union Medical College Peking Union Medical College Hospital Baylor College of Medicine Haga Hospital Amphia Ziekenhuis Elisabeth-TweeSteden Ziekenhuis Rijnstate Hospital Medisch Spectrum Twente Catharina Ziekenhuis Sint Franciscus Gasthuis Canisius-Wilhelmina Ziekenhuis Medisch Centrum Leeuwarden Akershus University Hospital University of Duisburg-Essen Institut d'Investigacions Biomèdiques de Barcelona Instituto de Investigación Sanitaria de Santiago BioCruces Health research Institute Universidad de Valladolid Hospital Clínic de Barcelona Consorci Institut D'Investigacions Biomediques August Pi I Sunyer Vall d'Hebron Hospital Universitari Hospital Universitari Germans Trias i Pujol Hospital Universitario Central de Asturias Health Research Institute of the Balearic Islands Hospital General Universitario de Albacete Frederiksberg Hospital McGill University Netherlands Heart Institute Adolfo Ibáñez University Erasmus University Rotterdam McGill Genome Centre Geisinger Neuroscience Institute Carl von Ossietzky Universität Oldenburg Yonsei University Korea Health Promotion Institute Impact Philadelphia VA Medical Center Turku University Hospital Munich Cluster for Systems Neurology Centre Hospitalier Universitaire de Bordeaux Institut des Maladies Neurodégénératives Brown Foundation

Une affiliation ne permet pas de déduire la nationalité d’un auteur.

Les sujets associés

Genetic Associations and EpidemiologyBioinformatics and Genomic NetworksLipoproteins and Cardiovascular Health

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