Difference in markers of microbial translocation and cell apoptosis in HIV monoinfected and HIV/HCV coinfected patients

Funding Information: The authors thank Valentina Sondore, MD. This study was supported by National Research Programme “Biomedicine for Public Health” (BIOMEDICINE) and by corporation “Latvijas Gâze”. Publisher Copyright: © 2019 Monta Madelane et al., published by Sciendo 2019.Immune activation in human immunodeficiency virus (HIV) infection is driven by microbial translocation and in HIV patients is one of the contributors to faster progression of liver disease along with increased cell apoptosis. The aim of the study was to compare microbial translocation and apoptosis markers in HIV monoinfected and HIV/hepatitis C virus (HCV) coinfected patients, depending on HIV immune status and antiretroviral treatment (ART). We analysed data for 78 HIV monoinfected and 105 HIV/HCV coinfected patients from the Rīga East University Hospital. Lipopolysaccharide (LPS), endotoxin core antibodies (EndoCAb), cytokeratin 18 (CK18) and cyto-chrome c (Cyt-c) levels were measured. No significant difference in LPS, EndoCAb, Cyt-c levels between HIV and HIV/HCV patients was found. The CK18 level was higher in the HIV/HCV group. Correlation between CD4+ cell count and EndoCAb antibodies was found in HCV positive patients. There was a significant effect of ART on markers for EndoCAb IgA and EndoCAb IgM antibodies in the HIV monoinfected group. Correlation between CD4+ cell count and EndoCAb antibodies and LPS was found in HIV/HCV patients on ART. Coinfection with HCV can lead to more pronounced response in EndoCAb antibody production and higher levels of cell apoptosis markers, despite similar LPS levels. ART has a positive effect on immune activation.publishersversionPeer reviewe

Association of non-invasive markers of liver fibrosis with HCV coinfection and antiretroviral therapy in patients with HIV

Publisher Copyright: © 2019 Oksana Koļesova et al., published by Sciendo 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.The aim of this study was to assess the main effects and interaction between viral hepatitis C (HCV) coinfection and antiretroviral therapy (ART) by using a nonparametric ANOVA on direct and indirect markers of liver fibrosis in HIV-infected patients. The sample included 178 HIV patients aged from 23 to 65 (36% females). The following parameters were determined in blood of patients: hyaluronic acid, pro-matrix metalloproteinase-1, alanine aminotransferase, aspartate aminotransferase, and platelet count. The FIB-4 index was also calculated. The nonparametric ANOVA revealed no significant interaction between HCV coinfection and ART. This provides evidence for an independent contribution of each factor on promotion of the pathology. The results also demonstrated that the direct and indirect indicators of liver fibrosis are associated differently with the studied factors. Therefore, a combination of markers should be used for monitoring of liver fibrosis in HIV-infected patients.Peer reviewe

Biobanking and consenting to research : a qualitative thematic analysis of young people’s perspectives in the North East of England

Funding Information: We would like to thank the Young Person’s Advisory Group North England and their connections to local secondary schools for making this project possible. DIAMONDS consortium Michael Levin7, Aubrey Cunnington7, Jethro Herberg7, Myrsini Kaforou7, Victoria Wright7, Evangelos Bellos7, Claire Broderick7, Samuel Channon-Wells7,Samantha Cooray7, Tisham De7, Giselle D’Souza7, Leire Estramiana Elorrieta7, Diego Estrada-Rivadeneyra7, Rachel Galassini7, Dominic Habgood-Coote7, Shea Hamilton7, Heather Jackson7, James Kavanagh7, Mahdi Moradi Marjaneh7, Samuel Nichols7, Ruud Nijman7, Harsita Patel7, Ivana Pennisi7, Oliver Powell7, Ruth Reid7, Priyen Shah7, Ortensia Vito7, Elizabeth Whittaker7, Clare Wilson7, Rebecca Womersley7, Amina Abdulla8, Sarah Darnell8, Sobia Mustafa8, Pantelis Georgiou9, Jesus-Rodriguez Manzano10, Nicolas Moser9, Michael Carter11, Shane Tibby11, Jonathan Cohen11, Francesca Davis11, Julia Kenny11, Paul Wellman11, Marie White11, Matthew Fish12, Aislinn Jennings13, Manu Shankar-Hari13, Katy Fidler14, Dan Agranoff15, Julia Dudley14, Vivien Richmond14, Matthew Seal15, Saul Faust16, Dan Owen16, Ruth Ensom16, Sarah McKay16, Diana Mondo17, Mariya Shaji17, Rachel Schranz17, Prita Rughnani18, Amutha Anpananthar19, Susan Liebeschuetz20, Anna Riddell18, Divya Divakaran19, Louise Han19, Nosheen Khalid18, Ivone Lancoma Malcolm19, Jessica Schofield19, Teresa Simagan19, Mark Peters21, Alasdair Bamford21, Lauran O’Neill21, Nazima Pathan22, Esther Daubney23, Debora White23, Melissa Heightman24, Sarah Eisen24, Terry Segal24, Lucy Wellings24, Simon B Drysdale25, Nicole Branch25, Lisa Hamzah25, Heather Jarman25, Maggie Nyirenda25, Lisa Capozzi26, Emma Gardiner26, Robert Moots27, Magda Nasher28, Anita Hanson28, Michelle Linforth27, Sean O’Riordan29, Donna Ellis29, Akash Deep30, Ivan Caro30, Fiona Shackley31, Arianna Bellini31, Stuart Gormley31, Samira Neshat32, Barnaby J Scholefield33, Ceri Robbins33, Helen Winmill33, Stéphane C Paulus34, Andrew J Pollard35, Mark Anthony36, Sarah Hopton36, Danielle Miller36, Zoe Oliver36, Sally Beer36, Bryony Ward36, Shrijana Shrestha37, Meeru Gurung37, Puja Amatya37, Bhishma Pokhrel37, Sanjeev Man Bijukchhe37, Madhav Chandra Gautam37, Peter O’Reilly35, Sonu Shrestha35, Federico Martinón-Torres38, Antonio Salas38, Fernando Álvez González38, Sonia Ares Gómez38, Xabier Bello38, Mirian Ben García38, Fernando Caamaño Viña38, Sandra Carnota38, María José Curras-Tuala38, Ana Dacosta Urbieta38, Carlos Durán Suárez38, Isabel Ferreiros Vidal38, Luisa García Vicente38, Alberto Gómez-Carballa38, Jose Gómez Rial38, Pilar Leboráns Iglesias38, Narmeen Mallah38, Nazareth Martinón-Torres38, José María Martinón Sánchez38, Belén Mosquera Perez38, Jacobo Pardo-Seco38, Sara Pischedda38, Sara Rey Vázquez38, Irene Rivero Calle38, Carmen Rodríguez-Tenreiro38, Lorenzo Redondo-Collazo38, Sonia Serén Fernández38, Marisol Vilas Iglesias38, Enital D Carrol39, Elizabeth Cocklin39, Abbey Bracken39, Ceri Evans40Aakash Khanijau39, Rebecca Lenihan39, Nadia Lewis-Burke39, Karen Newall41, Sam Romaine39, Jennifer Whitbread39, Maria Tsolia42, Irini Eleftheriou42, Nikos Spyridis42, Maria Tambouratzi42, Despoina Maritsi42, Antonios Marmarinos42, Marietta Xagorari42, Lourida Panagiota43, Pefanis Aggelos43, Akinosoglou Karolina44, Gogos Charalambos44, Maragos Markos44, Voulgarelis Michalis45, Stergiou Ioanna45, Marieke Emonts1,2, Emma Lim1,5,6, John Isaacs2, Kathryn Bell46, Stephen Crulley46, Daniel Fabian46, Evelyn Thomson46, Diane Walia46, Caroline Miller46, Ashley Bell46, Fabian JS van der Velden1,2, Geoff Shenton47, Ashley Price48, Owen Treloar2, Daisy Thomas1, Pablo Rojo49, Cristina Epalza49, Serena Villaverde49, Sonia Márquez49, Manuel Gijón49, Fátima Marchín49, Laura Cabello49, Irene Hernández49, Lourdes Gutiérrez49, Ángela Manzanares49, Taco W Kuijpers50, Martijn van de Kuip50, Marceline van Furth50, Merlijn van den Berg50, Giske Biesbroek50, Floris Verkuil50, Carlijn W van der Zee50, Dasja Pajkrt50, Michael Boele van Hensbroek50, Dieneke Schonenberg50, Mariken Gruppen50, Sietse Nagelkerke50, Machiel H Jansen50, Ines Goedschalckx51, Lorenza Romani52, Maia De Luca52, Sara Chiurchiù52, Constanza Tripiciano52, Stefania Mercadante52, Clementien L Vermont53, Henriëtte A Moll54, Dorine M Borensztajn54, Nienke N Hagedoorn54, Chantal Tan54, Joany Zachariasse54, Willem A Dik55, Shen Ching-Fen56, Dace Zavadska57, Sniedze Laivacuma58, Aleksandra Rudzate57, Diana Stoldere57, Arta Barzdina57, Elza Barzdina57, Monta Madelane59, Dagne Gravele59, Dace Svile59, Romain Basmaci60, Noémie Lachaume60, Pauline Bories60, Raja Ben Tkhayat60, Laura Chériaux60, Juraté Davoust60, Kim-Thanh Ong60, Marie Cotillon60, Thibault de Groc60, Sébastien Le60, Nathalie Vergnault60, Hélène Sée60, Laure Cohen60, Alice de Tugny60, Nevena Danekova60, Marine Mommert-Tripon61, Marko Pokorn62, Mojca Kolnik62, Tadej Avčin62, Tanja Avramoska62, Natalija Bahovec63, Petra Bogovič63, Lidija Kitanovski62, Mirijam Nahtigal63, Lea Papst63, Tina Plankar Srovin63, Franc Strle63, Katarina Vincek63, Michiel van der Flier64, Wim JE Tissing65, Roelie M Wösten-van Asperen66, Sebastiaan J Vastert67, Daniel C Vijlbrief68, Louis J Bont69, Tom FW Wolfs69, Coco R Beudeker69, Sanne C Hulsmann69, Philipp KA Agyeman70, Luregn Schlapbach71, Christoph Aebi70, Mariama Usman70, Stefanie Schlüchter70, Verena Wyss70, Nina Schöbi70, Elisa Zimmermann70, Marion Meier71, Kathrin Weber71, Eric Giannoni72, Martin Stocker73, Klara M Posfay-Barbe74, Ulrich Heininger75, Sara Bernhard-Stirnemann76, Anita Niederer-Loher77, Christian Kahlert78, Giancarlo Natalucci79, Christa Relly80, Thomas Riedel81, Christoph Berger81, Colin Fink82, Marie Voice82, Leo Calvo-Bado82, Michael Steele82, Jennifer Holden82, Andrew Taylor82, Ronan Calvez82, Catherine Davies82, Benjamin Evans82, Jake Stevens82, Peter Matthews82, Kyle Billing82, Werner Zenz83, Alexander Binder83, Benno Kohlmaier83, Daniel S Kohlfürst83, Nina A Schweintzger83, Christoph Zurl83, Susanne Hösele83, Manuel Leitner83, Lena Pölz83, Alexandra Rusu83, Glorija Rajic83, Bianca Stoiser83, Martina Strempfl83, Manfred G Sagmeister83, Sebastian Bauchinger83, Martin Benesch84, Astrid Ceolotto83, Ernst Eber83, Siegfried Gallistl83, Harald Haidl83, Almuthe Hauer83, Christa Hude83, Andreas Kapper85, Markus Keldorfer86, Sabine Löffler86, Tobias Niedrist87, Heidemarie Pilch86, Andreas Pfleger88, Klaus Pfurtscheller89, Siegfried Rödl89, Andrea Skrabl-Baumgartner83, Volker Strenger84, Elmar Wallner85, Maike K Tauchert90, Ulrich von Both91, Laura Kolberg91, Patricia Schmied91, Ioanna Mavridi91, Irene Alba-Alejandre92, Katharina Danhauser93, Niklaus Haas94, Florian Hoffmann95, Matthias Griese96, Tobias Feuchtinger97, Sabrina Juranek98, Matthias Kappler96, Eberhard Lurz99, Esther Maier98, Karl Reiter95, Carola Schoen95, Sebastian Schroepf100, Shunmay Yeung101, Manuel Dewez101, David Bath102, Elizabeth Fitchett101, Fiona Cresswell101, Effua Usuf103, Kalifa Bojang103, Anna Roca103, Isatou Sarr103, Momodou Ndure1038Children’s Clinical Research Unit, St Mary’s Hospital, Praed Street, London W2 1NY, UK9Imperial College London, Department of Electrical and Electronic Engineering, South Kensington Campus, London, SW7 2AZ, UK10Imperial College London, Department of Infectious Disease, Section of Adult Infectious Disease, Hammersmith Campus, London, W12 0NN, UK11Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK12Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK13Department of Intensive Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK14Royal Alexandra Children's Hospital, University Hospitals Sussex, Brighton, UK15Dept of Infectious Diseases, University Hospitals Sussex, Brighton, UK16NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust and University of Southampton, UK17Department of R&D, University Hospital Southampton NHS Foundation Trust, UK18Royal London Hospital, Whitechapel Rd, London E1 1FR, UK19Whipps Cross University Hospital, Whipps Cross Road, London, E11 1NR, UK20Newham University Hospital, Glen Rd, London E13 8SL, UK21Great Ormond Street Hospital, London, WC1N 3JH, UK22Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK23Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK24University College London Hospital, Euston Road, London NW1 2BU, UK25St George’s Hospital, Blackshaw Road, London SW17 0QT, UK26University Hospital Lewisham, London SE13 6LH, UK27Aintree University Hospital, Lower Lane, Liverpool L9 7AL, UK28Royal Liverpool Hospital, Prescot St, Liverpool L7 8XP, UK29Leeds Children’s Hospital, Leeds LS1 3EX, UK30Kings College Hospital, Denmark Hill, London SE5 9RS, UK31Sheffield Children’s Hospital, Broomhall, Sheffield S10 2TH, UK32Leicester General Hospital, Leicester LE1 5WW, UK33Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK34Department of Paediatrics, University of Oxford, UK35Oxford Vaccine Group, University of Oxford, UK36John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK37Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal38Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain39Institute of Infection, Veterinary and Ecoological Sciences, University of Liverpool, Liverpool, UK40Alder Hey Children’s Hospital, Department of Infectious Diseases, Eaton Road, Liverpool, L12 2AP, UK41Alder Hey Children’s Hospital, Clinical Research Business Unit, Eaton Road, Liverpool, L12 2AP, UK422nd Department of Pediatrics, National and Kapodistrian University of Athens (NKUA), Children’s Hospital “P, and A. Kyriakou”, Athens, Greece431st Department of Infectious Diseases, General Hospital “Sotiria”, Athens, Greece44Pathology Department, University of Patras, General Hospital “Panagia i Voithia”, Greece45Pathophysiology Department, Medical Faculty, National and Kapodistrian University of Athens (NKUA), General Hospital “Laiko”, Athens, Greece46Great North Children’s Hospital, Paediatric Research Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom47Great North Children’s Hospital, Paediatric Oncology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom48Department of Infection & Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom49Servicio Madrileño de Salud, Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain50Amsterdam UMC, Emma Children's Hospital, Dept of Pediatric Immunology, Rheumatology and Infectious Disease, University of Amsterdam, The Netherlands51Sanquin, Dept of Molecular Hematology, University Medical Center, Amsterdam, The Netherlands52Infectious Disease Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy53Erasmus MC-Sophia Children’s Hospital, Department of Paediatric Infectious Diseases & Immunology, Rotterdam, the Netherlands54Erasmus MC-Sophia Children’s Hospital, Department of General Paediatrics, Rotterdam, the Netherlands55Erasmus MC, Department of Immunology, Rotterdam, the Netherlands56Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan57Children’s Clinical University Hospital, Riga Stradins University, Riga, Latvia58Riga East Clinical Hospital, Riga Stradins University, Riga, Latvia59Children’s Clinical University Hospital, Riga, Latvia60Service de Pédiatrie-Urgences, AP-HP, Hôpital Louis-Mourier, F-92700 Colombes, France61bioMérieux—Open Innovation & Partnerships Department, Lyon, France62University Children's Hospital, University Medical Centre Ljubljana, Slovenia63Department of Infectious diseases, University Medical Centre Ljubljana, Slovenia64Pediatric Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands65Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands66Pediatric Intensive Care Unit, University Medical Center Utrecht, Utrecht, the Netherlands67Pediatric Rheumatology, University Medical Center Utrecht, Utrecht, the Netherlands68Pediatric Neonatal Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands69Pediatric Infectious Disease and Immunology, University Medical Center Utrecht, Utrecht, the Netherlands70Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland71Department of Intensive Care and Neonatology, and Children`s Research Center, University Children`s Hospital Zurich, Zurich, Switzerland72Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Switzerland73Department of Pediatrics, Children’s Hospital Lucerne, Lucerne, Switzerland74Pediatric Infectious Diseases Unit, Children’s Hospital of Geneva, University Hospitals of Geneva, Geneva, Switzerland75Infectious Diseases and Vaccinology, University of Basel Children’s Hospital, Basel, Switzerland76Children’s Hospital Aarau, Aarau, Switzerland77Division of Infectious Diseases and Hospital Epidemiology, Children’s Hospital of Eastern Switzerland St. Gallen, St. Gallen, Switzerland78Department of Neonatology, University Hospital Zurich, Zurich, Switzerland79Division of Infectious Diseases and Hospital Epidemiology, and Children’s Research Center, University Children’s Hospital Zurich, Switzerland80Children’s Hospital Chur, Chur, Switzerland81Division of Infectious Diseases and Hospital Epidemiology, and Children’s Research Center, University Children’s Hospital Zurich, Switzerland82Micropathology Ltd, The Venture Center, University of Warwick Science Park, Sir William Lyons Road, Coventry, CV4 7EZ, UK83Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria84Department of Pediatric Hematooncology, Medical University of Graz, Graz, Austria85Department of Internal Medicine, State Hospital Graz II, Location West, Graz, Austria86University Clinic of Pediatrics and Adolescent Medicine Graz, Medical University Graz, Graz, Austria87Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria88Department of Pediatric Pulmonology, Medical University of Graz, Graz, Austria89Paediatric Intensive Care Unit, Medical University of Graz, Graz, Austria90Biobanking and BioMolecular Resources Research Infrastructure—European Research Infrastructure Consortium (BBMRI-ERIC), Neue Stiftingtalstrasse 2/B/6, 8010, Graz, Austria91Division of Pediatric Infectious Diseases, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany92Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany93Division of Pediatric Rheumatology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany94Department of Pediatric Cardiology and Pediatric Intensive Care, University Hospital, LMU Munich, Germany95Paediatric Intensive Care Unit, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany96Division of Pediatric Pulmonology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany97Division of Pediatric Haematology & Oncology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany98Division of General Pediatrics, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany99Division of Pediatric Gastroenterology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany100Neonatal Intensive Care Unit, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany101Clinical Research Department, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK102Department of Global Health and Development, Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK103Medical Research Council at LSHTM, Fajara, the Gambia Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 848196. The funding body played no role in the design of the study and collection, analysis, interpretation of data, and in writing the manuscript. Publisher Copyright: © 2023, The Author(s).Background: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people’s (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. Methods: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person’s Advisory Group North England (YPAGne) and participating CYP’s secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. Results: One hundred two CYP completed the survey. Most were between 16–18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: ‘altruism’, ‘potential benefits outweigh individual risk’, 'frugality', and ‘(in)convenience’. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: ‘altruism’, ‘body integrity’ and ‘sample frugality’. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80). Conclusion: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible.Peer reviewe

Adeno-associated virus 2 infection in children with non-A–E hepatitis

Funding Information: We wish to acknowledge the contribution of the participating children and their parents who agreed to participate in the ISARIC CCP-UK and DIAMONDS studies, and the research teams who recruited the patients; S. Bennett-Slater from NHS Greater Glasgow and Clyde for assisting with sample location and testing; the histopathology team, Veterinary Diagnostic, University of Glasgow, for excellent technical assistance; P. Murcia for providing resources and advice; P. Olmo for administrative assistance; and E. J. Kremer from the Institut de Génétique Moléculaire de Montpellier, Université de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We wish to acknowledge the contribution of the participating children and their parents who agreed to participate in the ISARIC CCP-UK and DIAMONDS studies, and the research teams who recruited the patients; S. Bennett-Slater from NHS Greater Glasgow and Clyde for assisting with sample location and testing; the histopathology team, Veterinary Diagnostic, University of Glasgow, for excellent technical assistance; P. Murcia for providing resources and advice; P. Olmo for administrative assistance; and E. J. Kremer from the Institut de Génétique Moléculaire de Montpellier, Université de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status.Peer reviewe

Genomic investigations of unexplained acute hepatitis in children

Funding Information: UKHSA funded the metagenomics and HAdV sequencing. We thank A. Nathwani for helpful discussions. We acknowledge the considerable contribution from the GOSH microbiology laboratory. We thank the medical students who contributed to the DIAMOND consortium. All research at GOSH and UCL GOSH Institute of Child Health is made possible by the NIHR GOSH Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research (NIHR), the UKRI or the Department of Health and Social Care. The work was part funded by the NIHR Blood and Transplant Research Unit in Genomics to Enhance Microbiology Screening (GEMS), the National Institute for Health and Care Research (CO-CIN-01) or jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). S. Morfopoulou is funded by a W.T. Henry Wellcome fellowship (206478/Z/17/Z). S.B. and O.E.T.M. are funded by the NIHR Blood and Transplant Research Unit (GEMS). M.M.M. and M.L. are supported in part by the NIHR Biomedical Research Centre of Imperial College NHS Trust. J.B. receives NIHR Senior Investigator Funding. M.N. and J.B. are supported by the Wellcome Trust (207511/Z/17/Z and 203268/Z/16/Z). M.N., J.B. and G.P. are supported by the NIHR University College London Hospitals Biomedical Research Centre. P. Simmonds is supported by the NIHR (NIHR203338). T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, GOSH Children’s Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the NIHR. DIAMONDS is funded by the European Union (Horizon 2020; grant 848196). PERFORM was funded by the European Union (Horizon 2020; grant 668303). Publisher Copyright: © 2023, The Author(s).Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. 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.publishersversionPeer reviewe

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. 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

Association of Non-Invasive Markers of Liver Fibrosis with HCV Coinfection and Antiretroviral Therapy in Patients with HIV

Publisher Copyright: © 2019 Oksana Koļesova et al., published by Sciendo 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.The aim of this study was to assess the main effects and interaction between viral hepatitis C (HCV) coinfection and antiretroviral therapy (ART) by using a nonparametric ANOVA on direct and indirect markers of liver fibrosis in HIV-infected patients. The sample included 178 HIV patients aged from 23 to 65 (36% females). The following parameters were determined in blood of patients: hyaluronic acid, pro-matrix metalloproteinase-1, alanine aminotransferase, aspartate aminotransferase, and platelet count. The FIB-4 index was also calculated. The nonparametric ANOVA revealed no significant interaction between HCV coinfection and ART. This provides evidence for an independent contribution of each factor on promotion of the pathology. The results also demonstrated that the direct and indirect indicators of liver fibrosis are associated differently with the studied factors. Therefore, a combination of markers should be used for monitoring of liver fibrosis in HIV-infected patients.Peer reviewe