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Biol Psychiatry. 2018 Nov 1;84(9):644-654. doi: 10.1016/j.biopsych.2018.04.023. Epub 2018 May 14.

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

van Erp TGM1, Walton E2, Hibar DP3, Schmaal L4, Jiang W5, Glahn DC6, Pearlson GD6, Yao N6, Fukunaga M7, Hashimoto R8, Okada N9, Yamamori H10, Bustillo JR11, Clark VP12, Agartz I13, Mueller BA14, Cahn W15, de Zwarte SMC15, Hulshoff Pol HE15, Kahn RS15, Ophoff RA16, van Haren NEM17, Andreassen OA18, Dale AM19, Doan NT20, Gurholt TP21, Hartberg CB20, Haukvik UK18, Jørgensen KN21, Lagerberg TV22, Melle I18, Westlye LT23, Gruber O24, Kraemer B24, Richter A24, Zilles D25, Calhoun VD12, Crespo-Facorro B26, Roiz-Santiañez R26, Tordesillas-Gutiérrez D27, Loughland C28, Carr VJ29, Catts S30, Cropley VL31, Fullerton JM32, Green MJ33, Henskens FA34, Jablensky A35, Lenroot RK33, Mowry BJ36, Michie PT37, Pantelis C38, Quidé Y33, Schall U39, Scott RJ40, Cairns MJ40, Seal M41, Tooney PA42, Rasser PE43, Cooper G43, Shannon Weickert C33, Weickert TW33, Morris DW44, Hong E45, Kochunov P45, Beard LM46, Gur RE46, Gur RC46, Satterthwaite TD46, Wolf DH46, Belger A47, Brown GG48, Ford JM49, Macciardi F50, Mathalon DH49, O'Leary DS51, Potkin SG50, Preda A50, Voyvodic J52, Lim KO14, McEwen S53, Yang F54, Tan Y54, Tan S54, Wang Z54, Fan F54, Chen J54, Xiang H55, Tang S55, Guo H56, Wan P56, Wei D57, Bockholt HJ58, Ehrlich S59, Wolthusen RPF60, King MD61, Shoemaker JM61, Sponheim SR62, De Haan L63, Koenders L63, Machielsen MW63, van Amelsvoort T64, Veltman DJ65, Assogna F66, Banaj N67, de Rossi P68, Iorio M67, Piras F66, Spalletta G69, McKenna PJ70, Pomarol-Clotet E70, Salvador R70, Corvin A71, Donohoe G44, Kelly S72, Whelan CD73, Dickie EW74, Rotenberg D74, Voineskos AN74, Ciufolini S75, Radua J76, Dazzan P77, Murray R75, Reis Marques T75, Simmons A75, Borgwardt S78, Egloff L78, Harrisberger F78, Riecher-Rössler A78, Smieskova R78, Alpert KI79, Wang L80, Jönsson EG81, Koops S15, Sommer IEC82, Bertolino A83, Bonvino A84, Di Giorgio A84, Neilson E85, Mayer AR61, Stephen JM61, Kwon JS86, Yun JY87, Cannon DM88, McDonald C88, Lebedeva I89, Tomyshev AS89, Akhadov T90, Kaleda V89, Fatouros-Bergman H91, Flyckt L91; Karolinska Schizophrenia Project, Busatto GF92, Rosa PGP92, Serpa MH92, Zanetti MV92, Hoschl C93, Skoch A94, Spaniel F93, Tomecek D95, Hagenaars SP96, McIntosh AM97, Whalley HC85, Lawrie SM85, Knöchel C98, Oertel-Knöchel V98, Stäblein M98, Howells FM99, Stein DJ100, Temmingh HS99, Uhlmann A101, Lopez-Jaramillo C102, Dima D103, McMahon A73, Faskowitz JI73, Gutman BA104, Jahanshad N73, Thompson PM73, Turner JA105.

Author information

1
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California. Electronic address: tvanerp@uci.edu.
2
Imaging Genetics and Neuroinformatics Lab, Georgia State University, Atlanta, Georgia.
3
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, California; Janssen Research & Development, San Diego, California.
4
Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, Victoria, Australia; Centre for Youth Mental Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Psychiatry and Neuroscience, VU University Medical Center, Amsterdam, The Netherlands.
5
Department of Psychology, Georgia State University, Atlanta, Georgia.
6
Department of Psychiatry, Yale University, New Haven, Connecticut; Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut.
7
Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
8
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
9
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
10
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
11
Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico.
12
Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico; Mind Research Network, Albuquerque, New Mexico.
13
Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
14
Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
15
Department of Psychiatry and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
16
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California; Department of Psychiatry and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
17
Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Psychiatry and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
18
Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
19
Center for Translational Imaging and Precision Medicine, San Diego, California; Department of Neurosciences, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California; Department of Psychiatry, University of California, San Diego, La Jolla, California; Department of Cognitive Science, University of California, San Diego, La Jolla, California.
20
Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway.
21
Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
22
Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
23
Department of Psychology, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
24
Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany; Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry, Georg August University, Göttingen, Germany.
25
Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry, Georg August University, Göttingen, Germany; Department of Psychiatry, University Medical Center Göttingen, Göttingen, Germany.
26
Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, Marqués de Valdecilla Research Institute (IDIVAL), University of Cantabria, Santander, Spain; Centro Investigación Biomédica en Red de Salud Mental, Santander, Spain.
27
Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, Marqués de Valdecilla Research Institute (IDIVAL), University of Cantabria, Santander, Spain; Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute, Marqués de Valdecilla Research Institute (IDIVAL), University of Cantabria, Santander, Spain; Centro Investigación Biomédica en Red de Salud Mental, Santander, Spain.
28
Priority Research Centre for Brain & Mental Health, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia; Hunter New England Local Health District, Newcastle, New South Wales, Australia.
29
Department of Psychiatry, Monash University, Melbourne, Victoria, Australia; School of Psychiatry, University of New South Wales, New South Wales, Australia.
30
Discipline of Psychiatry, School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
31
Neuropsychiatry Centre, University of Melbourne, Melbourne, Victoria, Australia.
32
School of Medical Sciences, University of New South Wales, New South Wales, Australia; Neuroscience Research Australia, Sydney, New South Wales, Australia.
33
School of Psychiatry, University of New South Wales, New South Wales, Australia; Neuroscience Research Australia, Sydney, New South Wales, Australia.
34
Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia; School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
35
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia.
36
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia; Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia.
37
School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia.
38
Neuropsychiatry Centre, University of Melbourne, Melbourne, Victoria, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
39
Priority Research Centre for Brain & Mental Health, University of Newcastle, Newcastle, New South Wales, Australia; Grow Up Well, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
40
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
41
Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
42
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia; Priority Research Centre for Brain & Mental Health, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
43
Priority Research Centre for Brain & Mental Health, University of Newcastle, Newcastle, New South Wales, Australia.
44
Centre for Neuroimaging & Cognitive Genomics, Clinical Neuroimaging Laboratory, National Centre for Biomedical Engineering (NCBES) Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; School of Psychology, and Department of Biochemistry, National University of Ireland Galway, Galway, Ireland; Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
45
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland.
46
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
47
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
48
Department of Psychiatry, University of California, San Diego, La Jolla, California.
49
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, California; San Francisco Veterans Affairs Medical Center, San Francisco, California.
50
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California.
51
Department of Psychiatry, University of Iowa, Iowa City, Iowa.
52
Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
53
Department of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California.
54
Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China.
55
Chongqing Three Gorges Central Hospital, Chongqing, China.
56
Zhumadian Psychiatry Hospital, Henan Province, Zhumadian, China.
57
Luoyang Fifth People's Hospital, Henan Province, Luoyang, China.
58
Mind Research Network, Albuquerque, New Mexico; Department of Psychiatry, University of Iowa, Iowa City, Iowa; Advanced Biomedical Informatics Group, LLC, Iowa City, Iowa.
59
Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts; Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
60
Social Neuroscience Laboratory, Charlestown, Massachusetts; Psychiatric Neuroimaging Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
61
Mind Research Network, Albuquerque, New Mexico.
62
Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota; Minneapolis VA Health Care System, Minneapolis, Minnesota.
63
Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
64
Department of Psychiatry & Psychology, Maastricht University, Maastricht, The Netherlands.
65
Department of Psychiatry, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
66
Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Centro Fermi, Museo Storico della Fisica e Centro Studi e Ricerche "Enrico Fermi", Rome, Italy.
67
Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
68
Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso (NESMOS), Faculty of Medicine and Psychology, and Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
69
Beth K. and Stuart C. Yudofsky Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas; Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
70
Fundación para la Investigación y Docencia Maria Angustias Giménez (FIDMAG) Germanes Hospitalaries Research Foundation, Barcelona, Spain; Centro Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
71
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
72
Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
73
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, California.
74
Centre for Addiction and Mental Health, Toronto, Canada.
75
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
76
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Fundación para la Investigación y Docencia Maria Angustias Giménez (FIDMAG) Germanes Hospitalaries Research Foundation, Barcelona, Spain; Centro Investigación Biomédica en Red de Salud Mental, Barcelona, Spain; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
77
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, United Kingdom.
78
University of Basel Psychiatric Hospital, Basel, Switzerland.
79
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
80
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
81
Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
82
Department of Neuroscience, University Medical Center Groningen, Rijks Universiteit Groningen, Groningen, The Netherlands; Department of Psychiatry, University Medical Center Groningen, Rijks Universiteit Groningen, Groningen, The Netherlands.
83
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari "Aldo Moro," Bari, Italy.
84
Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
85
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
86
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
87
Yeongeon Student Support Center, Seoul National University College of Medicine, Seoul, Republic of Korea; Seoul National University Hospital, Seoul, Republic of Korea.
88
Centre for Neuroimaging & Cognitive Genomics, Clinical Neuroimaging Laboratory, National Centre for Biomedical Engineering (NCBES) Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
89
Mental Health Research Center, Moscow, Russia.
90
Children's Clinical and Research Institute of Emergency Surgery and Trauma, Moscow, Russia.
91
Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Services, Stockholm County Council, Stockholm, Sweden.
92
Laboratory of Psychiatric Neuroimaging, Laboratórios de Investigação Médica 21, Department of Psychiatry, Faculty of Medicine, and Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, São Paulo, Brazil.
93
National Institute of Mental Health, Klecany, Czech Republic.
94
National Institute of Mental Health, Klecany, Czech Republic; MR Unit, Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
95
National Institute of Mental Health, Klecany, Czech Republic; Institute of Computer Science, Czech Academy of Sciences, Czech Technical University in Prague, Prague, Czech Republic; Faculty of Electrical Engineering, Czech Technical University in Prague, Prague, Czech Republic.
96
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
97
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
98
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
99
Department of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
100
Department of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
101
Department of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
102
Research Group in Psychiatry, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellin, Colombia.
103
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychology, City, University of London, London, United Kingdom.
104
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois.
105
Imaging Genetics and Neuroinformatics Lab, Georgia State University, Atlanta, Georgia; Mind Research Network, Albuquerque, New Mexico.

Abstract

BACKGROUND:

The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

METHODS:

The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.

RESULTS:

Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.

CONCLUSIONS:

The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

KEYWORDS:

Cortical; Imaging; Meta-analysis; Schizophrenia; Surface area; Thickness

PMID:
29960671
PMCID:
PMC6177304
[Available on 2019-11-01]
DOI:
10.1016/j.biopsych.2018.04.023
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