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Genomic investigations of unexplained acute hepatitis in children
Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, Laura Atkinson, José Afonso Guerra‐Assunção, Mahdi Moradi Marjaneh, Riccardo Zennezini Chiozzi, Nathaniel Storey, Luis Campos, J. Ciaran Hutchinson, John R. Counsell, Gabriele Pollara, Sunando Roy, Cristina Venturini, Juan F. Antinao Diaz, Ala’a Siam, Luke J. Tappouni, Zeinab Asgarian, Joanne Ng, Killian S. Hanlon, Alexander Lennon, Andrew McArdle, Agata Czap, Joshua Rosenheim, Catarina Andrade, Glenn Anderson, Jack C. D. Lee, Rachel Williams, Charlotte A. Williams, Helena J. Tutill, Nadua Bayzid, Luz Marina Martin Bernal, Hannah Macpherson, Kylie-Ann Montgomery, Catherine Moore, Kate Templeton, Claire Neill, Matthew T. G. Holden, Rory Gunson, Samantha J. Shepherd, Priyen Shah, Samantha Cooray, Marie Voice, M.A. Steele, Colin G. Fink, Thomas E. Whittaker, Giorgia Santilli, Paul Gissen, Benedikt B. Kaufer, Jana Reich, Julien Andréani, Peter Simmonds, Dimah K. Alrabiah, Sergi Castellano, Primrose Chikowore, Miranda Odam, Tommy Rampling, Catherine Houlihan, Katja Höschler, Tiina Talts, Cristina Celma, Suam Gonzalez, Eileen Gallagher, Ruth Simmons, Conall Watson, Sema Mandal, Maria Zambon, Meera Chand, James Hatcher, Surjo De, J. Kenneth Baillie, Malcolm G. Semple, Evangelos Bellos, Claire Broderick, Samuel Channon‐Wells, Tisham De, Giselle D’Souza, Leire Estramiana Elorrieta, Diego Estrada‐Rivadeneyra, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Harsita Patel, Ivana Pennisi, Oliver Powell, Ruth Reid, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Michael J. Carter, Shane M. Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, A.R. Jennings, Shankar-Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Matthew Seal, Saul N. Faust, Dan Owen, Ruth Ensom, Sarah McKay, Diana Mondo, Mariya Shaji, Rachel Schranz, Prita Rughnani, Amutha Anpananthar, Susan Liebeschuetz, Anna Riddell, Nosheen Khalid, Ivone Lancoma Malcolm, Teresa Simagan, Mark Peters, Alasdair Bamford, Nazima Pathan, Esther Daubney, Deborah L. White, Melissa Heightman, Sarah Eisen, Terry Segal, Lucy Wellings, Simon B. Drysdale, Nicole Branch, Lisa Hamzah, Heather Jarman, Lisa Capozzi, Emma Gardiner, Robert J. Moots, Magda Nasher, Anita Hanson, Michelle Linforth, Séan O’Riordan, Donna Ellis, Iván Caro, Fiona Shackley, Arianna Bellini, Stuart Gormley, Samira Neshat, Barnaby J. Scholefield, Ceri Robbins, Helen Winmill, Stéphane Paulus, Andrew J. Pollard, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Shrijana Shrestha, Meeru Gurung, Puja Amatya, Bhishma Pokhrel, Sanjeev Man Bijukchhe, Tim Lubinda, Sarah Kelly, Peter O’Reilly, Federico Martinón‐Torres, Antonio Salas, Fernando Álvez González, Xabier Bello, Mirian Ben García, Sandra Carnota, Miriam Cebey‐López, María José Currás-Tuala, Carlos Durán Suárez, Luisa García Vicente, Alberto Gómez‐Carballa, José Gómez Rial, Pilar Leboráns Iglesias, José María Martinón Sánchez, Belén Mosquera Pérez, Jacobo Pardo‐Seco, Lidia Piñeiro Rodríguez, Sara Pischedda, Sara Rey Vázquez, Irene Rivero‐Calle, Carmen Rodrı́guez-Tenreiro, Lorenzo Redondo-Collazo, Miguel Sadiki Ora, Sonia Serén Fernández, Cristina Serén Trasorras, Marisol Vilas Iglesias, Enitan D. Carrol, Elizabeth Cocklin, Aakash Khanijau, Rebecca Lenihan, Nadia Lewis-Burke, Karen Newal, Sam Romaine, Μαρία Τσολιά, Irini Eleftheriou, Νikos Spyridis, Maria Tambouratzi, Despoina Maritsi, Antonios Marmarinos, Marietta Xagorari, Lourida Panagiota, Pefanis Aggelos, Akinosoglou Karolina, Gogos Charalambos, Maragos Markos, Voulgarelis Michalis, Stergiou Ioanna, Marieke Emonts, Emma Lim, John T. Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabián, Evelyn Thomson, Caroline Miller, Ashley Bell, Fabian van der Velden, Geoff Shenton, David Price, Owen Treloar, Daisy Thomas, Pablo Rojo, Cristina Epalza, Serena Villaverde, Sonia Márquez, Manuel Gijón, Fátima Machín, Laura Cabello, Irene Hernández, Lourdes Gutiérrez, Ángela Manzanares, Taco W. Kuijpers, Martijn van de Kuip, A. Marceline van Furth, J. Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn van der Zee, Dasja Pajkrt, Michaël Boele van Hensbroek, D. Schonenberg, Mariken Gruppen, Sietse Q. Nagelkerke, Machiel H. Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiù, Martina Di Giuseppe, Clementien L. Vermont, Henriëtte A. Moll, Dorine Borensztajn, Nienke N. Hagedoorn, Chantal Tan, Joany M. Zachariasse, W. Dik, Ching‐Fen Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Bārzdiņa, Elza Barzdina, Monta Madelāne, Dagne Grãvele, Dace Svile, Romain Basmaci, Noémie Lachaume, Pauline Bories, Raja Ben Tkhayat, Laura Chériaux, Juraté Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sébastien Lê, Nathalie Vergnault, Hélène See, Laure Cohen, Alice de Tugny, Névéna Danékova, Marine Mommert-Tripon, Karen Brengel‐Pesce, Mojca Kolnik, Tadej Avčin, Tanja Avramoska, Natalija Bahovec, Petra Bogovič, Lidija Kitanovski, Mirijam Nahtigal, Lea Papst, Tina Plankar Srovin, Franc Strle, Anja Srpčič, Katarina Vincek, Michiel van der Flier, Wim J. E. Tissing, Roelie M. Wösten‐van Asperen, Sebastiaan J. Vastert, Daniel C. Vijlbrief, Louis Bont, Tom F.W. Wolfs, Coco R. Beudeker, Philipp Agyeman, Luregn J. Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schlüchter, Verena Wyss, Nina Schöbi, Elisa Zimmermann, Kathrin Weber, Éric Giannoni, Martin Stocker, Klara M. Posfay‐Barbe, Ulrich Heininger, Sara Bernhard‐Stirnemann, Anita Niederer-Loher, Christian R. Kahlert, Giancarlo Natalucci, Christa Relly, Thomas Riedel, Christoph Berger, Jennifer Holden, Leo Calvo‐Bado, B. J. K. Evans, Jake Stevens, Peter Matthews, Kyle Billing, Werner Zenz, Alexander Binder, Benno Kohlmaier, Daniela S. Kohlfürst, Nina A. Schweintzger, Christoph Zurl, Susanne Hösele, Manuel Leitner, Lena Pölz, Alexandra Rusu, Glorija Rajic, Bianca Stoiser, Martina Strempfl, Manfred G. Sagmeister, Sebastian Bauchinger, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallistl, Harald Haidl, Almuthe Hauer, Christa Hude, Andreas Kapper, Markus Keldorfer, Sabine Löffler, Tobias Niedrist, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Siegfried Rödl, Andrea Skrabl‐Baumgartner, Volker Strenger, Elmar Wallner, Dennie Tempel, Daniëlle van Keulen, Annelieke M. Strijbosch, Maike K. Tauchert, Ulrich von Both, Laura Kolberg, Patricia Schmied, Irene Alba‐Alejandre, Katharina Danhauser, Nikolaus Haas, Florian Hoffmann, Matthias Griese, Tobias Feuchtinger, Sabrina Juranek, Matthias Kappler, Eberhard Lurz, Esther M. Maier, Karl Reiter, Carola Schoen, Sebastian Schroepf, Shunmay Yeung, Manuel Dewez, David Bath, Elizabeth Fitchett, Fiona V Cresswell, Aubrey J. Cunnington, Jethro Herberg, Mysini Kaforou, Victoria Wright, Lucas Baumard, Clive Hoggart, Sara Hourmat, Ian Maconochie, Naomi Lin, Ivonne Pena Paz, Ladan Ali, Rikke Jørgensen, Salina Persand, Molly M. Stevens, Eunjung Kim, Benjamin C. Pierce, Julia Dudley, Emma Tavliavini, Hsiao‐Sheng Liu, Shih-Min Wang, Cristina Balo Farto, Ruth Barral‐Arca, Maria Barreiro Castro, Anda Balode, Dãrta Deksne, Ilze Grope, Anija Meiere, Ieva Nokalna, Jana Pavāre, Zanda Pučuka, Katrīna Selecka, Aleksandra Sidorova, Urzula Nora Urbāne, Effua Usuf, Kalifa Bojang, Syed M. A. Zaman, Fatou Secka, Suzanne P. Anderson, Anna RocaIsatou Sarr, Momodou Saidykhan, Saffiatou Darboe, Samba Ceesay, Umberto D’Alessandro, Rebecca Jennings, Joanne Johnston, Simon Leigh, Karen Newall, Kelly Syggelou, Hinrich Baumgart, Gunther Gores, Larissa Krenn, Gudrun Nordberg, Matthias Sperl, Laura Stampfer, Holger Till, Andreas Trobisch, Juan Emmanuel Dewez, Martin L. Hibberd, Alec Miners, Catherine J. Wedderburn, Anne Meierford, Baptiste Leurent, Ronald de Groot, Marien I. de Jonge, Koen van Aerde, Wynand Alkema, Bryan van den Broek, Jolein Gloerich, Alain J. van Gool, Stefanie Henriet, Martijn Huijnen, Ria Philipsen, Esther Willems, G. P. J. M. Gerrits, M. van Leur, J. Heidema, Lieuwe de Haan, C. J. Miedema, C. Neeleman, Charlie C. Obihara, Gerdien A. Tramper‐Stranders, Rama Kandasamy, Daniel O’Connor, Sagida Bibi, Dominic F. Kelly, Stephen Thorson, Imran Shafique Ansari, David R. Murdoch, Lucille Valentine, Karen E. Allen, Adora Chan, Kirsty Devine, Sharon King, Paul McAlinden, Sam McDonald, Anne McDonnell, Ailsa Pickering, Amanda Wood, Diane Wallia, Phil Woodsford, Frances Baxter, Mathew Rhodes, Rachel Agbeko, Christine Mackerness, Bryan Baas, Lieke Kloosterhuis, Wilma Oosthoek, Tasnim Arif, Joshua Bennet, Kalvin Collings, Ilona van der Giessen, Alex Martin, Aqeela Rashid, Emily Rowlands, Gabriella de Vries, Mike W. Martin, Ravi Mistry, Manuela Zwerenz, Judith Buschbeck, Christoph Bidlingmaier, Vera Binder, Julia Keil, Georg Muench, François Mallet, Alexandre Pachot, Marine Mommert, Petra Prunk, Veronika Osterman, Ilse Jongerius, J.M. van den Berg, Anouk M. Barendregt, Martijn van der Kuip, Evelien G. G. Sprenkeler, Judith Zandstra, Gerard van Mierlo, Judy Geissler, Gail Carson, Peter Openshaw, Jake Dunning, Laura Merson, Clark D Russell, David W. Dorward, Richard S. Tedder, Say Khoo, Lance Turtle, Tom Solomon, Samreen Ijaz, Tom Fletcher, Massimo Palmarini, Antonia Ho, Nicholas Price, Thushan I. de Silva, Chloe Donohue, Hayley Hardwick, Wilna Oosthuyzen, Lauren Obosi, Sara Clohisey, Andrew Law, Lucy Norris, Sarah Tait, Murray Wham, Richard E. Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Sarah E. McDonald, Victoria Shaw, J. A. Armstrong, Lauren Lett, Paul Henderson, Louisa Pollock, Shyla Kishore, Helen Brotherton, Lawrence E. Armstrong, Andrew Mita, Anna Dall, Kristýna Böhmová, Sheena Logan, Louise Gannon, Ken Agwuh, Srikanth Chukkambotla, Ingrid DuRand, Duncan Fullerton, Sanjeev Garg, Clive Graham, Stuart Hartshorn, Luke Hodgson, Paul Jennings, George Koshy, Tamás Leiner, James Limb, Jeff Little, Fiona McGill, Craig F. Morris, John A. Morrice, David Price, Henrik Reschreiter, Tim Reynolds, Paul Whittaker, Rachel Tayler, Clare Irving, Maxine Ramsay, Margaret Millar, Barry Milligan, Naomy Hickey, Maggie Connon, Catriona Ward, Laura Beveridge, Susan MacFarlane, Karen Leitch, Claire Bell, Lauren Finlayson, Joy Dawson, Janie Candlish, Laura McGenily, Tara Roome, Cynthia Diaba, Jasmine Player, Natassia Powell, Ruth Howman, Sara Burling, Sharon Floyd, Sarah Farmer, Susie Ferguson, Susan Hope, Lucy Rubick, Rachel Swingler, Emma Collins, Collette Spencer, Amaryl Jones, Barbara A. Wilson, Diane Armstrong, Mark Birt, Holly Dickinson, Rosemary Harper, Darran Martin, Amy Roff, Sarah Mills, Joanne E. Martin, Ines Ushiro‐Lumb, Mahdad Noursadeghi, Maesha Deheragoda, Nedim Hadžić, Tassos Grammatikopoulos, Rachel Brown, Chayarani Kelgeri, Konstantinos Thalassinos, Simon N. Waddington, Thomas S. Jacques, Emma C. Thomson, Michael Levin, Julianne R. Brown, Judith Breuer
Bibliographic record
VenueNature · 2023
Typearticle
Languageen
FieldMedicine
TopicViral gastroenteritis research and epidemiology
Canadian institutionsInstitute of Infection and Immunity
FundersInstitute of GeneticsNIHR Great Ormond Street Hospital Biomedical Research CentreNational Cheng Kung UniversityUniversität ZürichGreat Ormond Street Hospital for ChildrenNewcastle upon Tyne Hospitals NHS Foundation TrustPublic Health EnglandGreat Ormond Street Institute of Child HealthNewcastle UniversityUniversiteit van AmsterdamSheffield Teaching Hospitals NHS Foundation TrustEuropean CommissionRadboud UniversiteitNational Institute for Health Research Health Protection Research UnitUniversity of OxfordCancer Research UKWellcome TrustImperial College Healthcare NHS TrustUniversity College LondonCHILDREN with CANCER UKKing's College LondonMedizinische Universität GrazImperial College LondonNHS Blood and TransplantNational Institute for Health and Care ResearchSt. Antonius ZiekenhuisUK Research and InnovationNorthumbria UniversityUniversity of OtagoMedical Research CouncilUniverza v LjubljaniDepartment of Health and Social CareDeutsches Zentrum für InfektionsforschungKarl-Franzens-Universität GrazMcGill UniversityLondon School of Hygiene and Tropical Medicine
KeywordsAcute hepatitisMedicineGeneticsHepatitisBiologyVirologyComputational biology
Abstract
. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.033
Threshold uncertainty score0.389
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.013
GPT teacher head0.316
Teacher spread0.302 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations130
Published2023
Admission routes2
Has abstractyes