1,011 results on '"Royal Hospital for Sick Children [Edinburgh]"'
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2. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies
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Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Immunology ,Central nervous system ,Alpha interferon ,Aicardi-Goutières syndrome ,cerebrospinal fluid ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Medical microbiology ,Downregulation and upregulation ,systemic lupus erythematosus ,Interferon ,Humans ,Immunology and Allergy ,Medicine ,Child ,Retrospective Studies ,business.industry ,Infant ,Interferon-alpha ,medicine.disease ,3. Good health ,Hydrocephalus ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Organ Specificity ,Case-Control Studies ,Child, Preschool ,Interferon Type I ,Mutation ,Aicardi–Goutières syndrome ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Disease Susceptibility ,STING-associated vasculopathy with onset in infancy ,business ,030215 immunology ,medicine.drug - Abstract
International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
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- 2021
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3. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling
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Nicolas Manel, Siham Boulisfane-El Khalifi, Mary Brennan, Darragh Duffy, Nadia Nathan, Serge Amselem, Kathryn J. McKenzie, Maria José Martin-Niclos, Jonny Hertzog, Carolina Uggenti, Marie Legendre, Stéphanie Chhun, Caroline Thumerelle, Luis Seabra, Marie-Louise Frémond, Vincent Bondet, Bénédicte Neven, Joseph A. Marsh, Marie Wislez, Catherine McDougall, Marine Depp, Jan Rehwinkel, Gillian I. Rice, Aurore Coulomb L'Hermine, Yanick J. Crow, Lucienne Chatenoud, Melvin Le Bihan, Thierry Jo Molina, Karen J. Mackenzie, Alice Lepelley, Edwin Carter, Jonathan Marey, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Radcliffe Department of Medicine [Oxford], University of Oxford [Oxford], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Royal Hospital for Sick Children [Edinburgh], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de pathologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Infirmary of Edinburgh, Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (000427993) and acknowledges La Fondation Square. Y.J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs), and a state subsidy managed by the Agence Nationale de la Recherche under the 'Investments for the Future' program (ANR-10-IAHU-01). Y.J. Crow and D. Duffy acknowledge the Agence Nationale de la Recherche (grant CE17001002). J.A. Marsh is supported by a Medical Research Council Career Development Award (MR/M02122X/1) and is a Lister Institute of Preventive Medicine Research Prize Fellow. N. Manel was supported by LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR-17-CE15-0025-01, ANR-18-CE92-0022-01, Fondation BMS, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ71745), Sidaction (VIH2016126002), and Ile-de-France Emergence. M. Le Bihan received a doctoral fellowship from Ile-de-France ARDoc. The project was supported by MSDAVENIR (Devo-Decode Project)., We thank Immunoqure AG for provision of antibodies for the Simoa assay., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE15-0025,STINGCHECK,Mécanismes des points de contrôle du senseur de l'immunité innée STING(2017), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Mécanismes des points de contrôle du senseur de l'immunité innée STING - - STINGCHECK2017 - ANR-17-CE15-0025 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
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0301 basic medicine ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Protein subunit ,Immunology ,Mutant ,Biology ,medicine.disease_cause ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Interferon ,medicine ,Immunology and Allergy ,Gene silencing ,Mutation ,HEK 293 cells ,Golgi apparatus ,eye diseases ,3. Good health ,Cell biology ,Sting ,030104 developmental biology ,030220 oncology & carcinogenesis ,symbols ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,medicine.drug - Abstract
International audience; Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
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- 2020
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4. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
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Tadbir K. Bariana, William J. Astle, Paquita Nurden, Jonathan Stephens, Sandra Le Quellec, Suthesh Sivapalaratnam, Andreas Greinacher, Jose A. Guerrero, Karyn Megy, Laxmikanth Kollipara, Hanna Shalev, Rachel Reed, Marie-Christine Alessi, Ron Kerr, Anthony D. Whetton, Matthew C Sims, Nihr BioResource, Man-Chiu Poon, Kathleen Freson, Samantha Farrow, Orna Steinberg-Shemer, Wendy N. Erber, Diane J. Nugent, Harriet McKinney, Cécile Lavenu-Bombled, Robert Campbell Tait, Mallika Sekhar, Rutendo Mapeta, Eva Leinoe, Anne M. Kelly, Louisa Mayer, Janine Collins, Mattia Frontini, Thierry M Leblanc, Elizabeth Chalmers, Albert Sickmann, Willem H. Ouwehand, Barbara Zieger, Taco W. Kuijpers, Antonio Rodriguez-Romera, Gian Marco Podda, Daniel P. Hart, Paolo Gresele, Daniel Greene, Keith Gomez, Wadie F. Bahou, Soo J. Park, Erica De Candia, Dave Lee, Luigi Grassi, Alan D. Michelson, Sara Morais, Denis Seyres, Kate Downes, John Pasi, Sri V V Deevi, John K. Wu, Loredana Bury, Frances Burden, Rachael Da Silva, Sofia Papadia, Marie-Françoise Hurtaud, Ernest Turro, Rémi Favier, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Cambridge [UK] (CAM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Manchester [Manchester], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of Perugia, Royal Hospital for Sick Children [Edinburgh], Catholic University School of Medicine, Royal Free London NHS Foundation Trust, Universitätsmedizin Greifswald, Queen Mary University of London (QMUL), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Ninewells Hospital and Medical School [Dundee], Hospices Civils de Lyon (HCL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Harvard Medical School [Boston] (HMS), Centro Hospitalar Universitário do Porto, Children's Hospital of Orange County, University of California, Università degli Studi di Milano [Milano] (UNIMI), University of Calgary, Manchester Academic Health Science Centre (MAHSC), Ben-Gurion University of the Negev (BGU), Tel Aviv University [Tel Aviv], Glasgow Royal Infirmary, University of British Columbia (UBC), University of Freiburg [Freiburg], VU University Medical Center [Amsterdam], University of Aberdeen, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The University of Western Australia (UWA), Hôpital Xavier Arnozan, Università degli Studi di Perugia = University of Perugia (UNIPG), University of California (UC), Università degli Studi di Milano = University of Milan (UNIMI), Tel Aviv University (TAU), and Prémilleux, Annick
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Biopsy ,[SDV]Life Sciences [q-bio] ,030204 cardiovascular system & hematology ,medicine.disease_cause ,GUIDELINES ,NBEAL2 ,Biochemistry ,Cohort Studies ,0302 clinical medicine ,Megakaryocyte ,Gene Frequency ,Medicine ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,ABNORMALITIES ,Hematology ,Blood Proteins ,ASSOCIATION ,3. Good health ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Phenotype ,BEACH-DOMAIN ,Immune System Diseases ,medicine.symptom ,BLOOD Commentary ,Platelet disease ,NEUROBEACHIN-LIKE 2 ,PROTEINS ,Immunology ,education ,Inflammation ,Cytoplasmic Granules ,Gray Platelet Syndrome ,CLASSIFICATION ,Gray platelet syndrome ,Diagnosis, Differential ,03 medical and health sciences ,Genetic Heterogeneity ,Immune system ,Humans ,Genetic Association Studies ,030304 developmental biology ,Autoimmune disease ,business.industry ,Autoantibody ,Grey platelet syndrome ,Cell Biology ,Immune dysregulation ,medicine.disease ,Bleeding disease ,PROTEOME ,Settore MED/15 - MALATTIE DEL SANGUE ,Case-Control Studies ,Immune System ,Mutation ,Bone marrow ,business ,PATHOGENICITY ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. ispartof: BLOOD vol:136 issue:17 pages:1956-1967 ispartof: location:United States status: published
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- 2020
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5. OP0107 HETEROZYGOUS MUTATIONS IN COPA ARE ASSOCIATED WITH ENHANCED TYPE I INTERFERON SIGNALLING
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Yanick J. Crow, Serge Amselem, Gillian I. Rice, Darragh Duffy, Siham Boulisfane, Nadia Nathan, Caroline Thumerelle, Vincent Bondet, Maria José Martin-Niclos, Mary Brennan, Marie Legendre, Carolina Uggenti, Marine Depp, Thierry Jo Molina, Alice Lepelley, Marie-Louise Frémond, BONDET, Vincent, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Royal Hospital for Sick Children [Edinburgh], CHU Lille, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), RespiRare - Centre pédiatrique de pneumologie et de référence pour les maladies pulmonaires rares [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
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Gene knockdown ,biology ,business.industry ,[SDV]Life Sciences [q-bio] ,Wild type ,Context (language use) ,Molecular biology ,3. Good health ,[SDV] Life Sciences [q-bio] ,Small hairpin RNA ,Interferon ,medicine ,biology.protein ,STAT1 ,business ,IRF3 ,Gene ,ComputingMilieux_MISCELLANEOUS ,medicine.drug - Abstract
Background Heterozygous mutations in COPA, encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy (SAVI). Mutations were originally described to cause endoplasmic reticulum (ER) stress and priming of a T helper 17 response. More recently, increased transcription of interferon (IFN)-stimulated genes (ISGs) was reported in blood circulating cells of affected individuals. However, the precise pathophysiology of this disease remains unclear. Objectives To better decipher the mechanism of COPA syndrome. Methods We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in COPA. We assessed type I IFN status by IFNα ultra-sensitive digital quantification in plasma, STAT1 phosphorylation and RNA expression of ISGs in whole blood from patients. In vitro assays also were performed in HEK293T and THP-1 cells to study IFN signalling in the context of COPA mutations. Results We observed commonalities in the lung pathology between COPA and SAVI, as well as an IFN signature, raised levels of IFNα protein in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model of HEK293T, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids. In THP-1 cells, short hairpin RNA knockdown of COPA induced IFN signalling that was abrogated in the absence of STING. Conclusion Our data suggest that mutations in COPA lead to constitutive activation of type I IFN signalling through STING. Based on these results, one patient has been treated with the JAK1/2 inhibitor ruxolitinib for the last 12 months. How COPA interacts with ER-resident STING remains to be investigated. References [1] Watkin et al, Nat Genet2015;47:654-60. [2] Volpi et al, Clin Immunol2018;187:33-36. Disclosure of Interests None declared
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- 2019
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6. ERS statement on standardisation of cardiopulmonary exercise testing in chronic lung diseases
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Asterios Kampouras, Sarah Crook, Jana De Brandt, Richard Casaburi, Danilo C. Berton, Zafeiris Louvaris, Roberto A Rabinovich, Pierantonio Laveneziana, Martijn A. Spruit, Georgios Kaltsakas, Yvonne M J Goërtz, Helge Hebestreit, Ioannis Vogiatzis, Milo A. Puhan, Jeanette Boyd, Sauwaluk Dacha, J. Alberto Neder, Samuel Verges, Frits M.E. Franssen, Don S. Urquhart, Dimitris Kontopidis, Thomy Tonia, Ernst Eber, Thierry Troosters, Dionne C.W. Braeken, Chris Burtin, Thomas Radtke, Daniel Langer, Pulmonologie, RS: NUTRIM - R3 - Respiratory & Age-related Health, Afdeling Onderwijs FHML, University of Zurich, Hebestreit, Helge, Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Guy's and St Thomas' NHS Foundation Trust [London, UK], National and Kapodistrian University of Athens (NKUA), University Hospitals Leuven [Leuven], Technologie campus Gent - KU Leuven (KU Leuven), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Royal Hospital for Sick Children [Edinburgh], 424 General Military Training Hospital [Thessaloniki, Greece] (424 GMTH), University of Edinburgh, Royal Infirmary of Edinburgh, Hypoxie et PhysioPathologie (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Hellenic Cystic Fibrosis Association [Athens, Greece] (HCFA), The European Lung Foundation (ELF), University of Bern, Hasselt University (UHasselt), CIRO [Horn, The Netherlands], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Chiang Mai University (CMU), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Medical University of Graz, University Hospital Gasthuisberg [Leuven], Queen's University [Kingston, Canada], Harbor UCLA Medical Center [Torrance, Ca.], University of Northumbria at Newcastle [United Kingdom], University Hospital of Würzburg, and SALAS, Danielle
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Lung Diseases ,[SDV]Life Sciences [q-bio] ,Medical Physiology ,Respiratory System ,PULSE-OXIMETRY ,030204 cardiovascular system & hematology ,Cochrane Library ,0302 clinical medicine ,Clinical Protocols ,Medicine ,Treadmill ,610 Medicine & health ,Lung ,Cardiopulmonary exercise testing ,[SDV] Life Sciences [q-bio] ,Europe ,VISUAL ANALOG SCALES ,Respiratory ,NONINVASIVE ASSESSMENT ,360 Social problems & social services ,Recovery phase ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,MEDLINE ,RESPIRATORY GAS-EXCHANGE ,Work rate ,OBSTRUCTIVE PULMONARY-DISEASE ,03 medical and health sciences ,Clinical Research ,Humans ,lcsh:RC705-779 ,Task force ,business.industry ,10060 Epidemiology, Biostatistics and Prevention Institute (EBPI) ,lcsh:Diseases of the respiratory system ,HEART-RATE RECOVERY ,C600 ,PHYSIOLOGICAL-RESPONSES ,SCIENTIFIC STATEMENT ,030228 respiratory system ,2740 Pulmonary and Respiratory Medicine ,Chronic Disease ,Physical therapy ,Exercise Test ,Diagnostic assessment ,OXYGEN-UPTAKE ,business ,MAXIMAL VOLUNTARY VENTILATION - Abstract
The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data. Funding was received from the European Respiratory Society, grant number TF-2016-12. The research of Jana De Brandt is financially supported by FWO (grant #11B4718N) and the research of Chris Burtin is partially sponsored by Limburg Kankerfonds. Funding information for this article has been deposited with the Crossref Funder Registry. Hebestreit, H (reprint author), Univ Kinderklin, ERN LUNG, Josef Schneider Str 2, D-97080 Wurzburg, Germany. hebestreit@uni-wuerzburg.de
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- 2019
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7. Heterozygous mutations in COPA are associated with enhanced type I interferon signalling
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Frémond, Marie-Louise, Lepelley, Alice, Uggenti, Carolina, Martin-Niclos, Maria José, Depp, Marine, Bondet, Vincent, Duffy, Darragh, Rice, Gillian, Brennan, Mary, Thumerelle, Caroline, Boulisfane-El Khalifi, Siham, Legendre, Marie, Amselem, Serge, Jo Molina, Thierry, Nathan, Nadia, Crow, Yanick, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Royal Hospital for Sick Children [Edinburgh], CHU Lille, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and Couvet, Sandrine
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[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics - Abstract
International audience; Introduction: Heterozygous mutations in COPA, encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy (SAVI). Mutations were originally described to cause endoplasmic reticulum (ER) stress and priming of a T helper 17 response. More recently, increased transcription of interferon (IFN)-stimulated genes (ISGs) was reported in blood circulating cells of affected individuals. However, the precise pathophysiology of this disease remains unclear.Objectives: To better decipher the mechanism of COPA syndrome.Methods: We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in COPA. We assessed type I IFN status by IFNa ultra-sensitive digital quantification in plasma, STAT1 phosphorylation and RNA expression of ISGs in whole blood from patients. In vitro assays also were performed in HEK293T and THP-1 cells to study IFN signalling in the context of COPA mutations.Results: We observed commonalities in the lung pathology between COPA and SAVI, as well as an IFN signature, raised levels of IFNa protein in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model of HEK293T, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids. In THP-1 cells, short hairpin RNA knockdown of COPA induced IFN signalling that was abrogated in the absence of STING.Conclusion: Our data suggest that mutations in COPA lead to constitutive activation of type I IFN signalling through STING. Based on these results, one patient has been treated with the JAK1/2 inhibitor ruxolitinib for the last 12 months. How COPA interacts with ER-resident STING remains to be investigated.
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- 2019
8. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
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Richard H. Duerr, Dalin Li, Ming-Hsi Wang, Tariq Ahmad, John D. Rioux, Patrick Sulem, Daniel B. Graham, Steven R. Brant, Severine Vermeire, Mark Tremelling, James Lee, Leena Halme, K. de Lane, Miguel Regueiro, M Parkes, David C. Wilson, Alain Bitton, R. Milgrom, Daniel G. MacArthur, Marijn C. Visschedijk, Sören Mucha, Kenneth Croitoru, Alison Simmons, Mark S. Silverberg, Rinse K. Weersma, Jonas Halfvarson, Daniel L. Rice, J. M. Stempak, Christopher J. Hawkey, Mauro D'Amato, Christopher G. Mathew, Philippe Goyette, Frauke Degenhardt, Daniel F. Gudbjartsson, Mark J. Daly, Kari Stefansson, Beryl B. Cummings, Maarit Lappalainen, Päivi Saavalainen, Paulina Paavola-Sakki, P. Fleshner, Talin Haritunians, Joshua C. Randall, Elaine R. Nimmo, Taru Tukiainen, Christine Stevens, Subra Kugathasan, Monkol Lek, Andre Franke, Kimmo Kontula, Unnur Thorsteinsdottir, Andrew Hart, Martin O. Pollard, Gabrielle Boucher, Natalie J. Prescott, Benjamin M. Neale, Holm H. Uhlig, Carl A. Anderson, Ashwin N. Ananthakrishnan, Luke Jostins, C. Mowatt, Judy H. Cho, B. Newman, A. Nicole Desch, Yang Luo, Dermot P.B. McGovern, Clara Abraham, Ingileif Jonsdottir, Jeffrey C. Barrett, John C. Mansfield, Jean-Paul Achkar, Charlie W. Lees, Martti Färkkilä, Ramnik J. Xavier, S. R. Targan, Manuel A. Rivas, Deborah D. Proctor, Johan Van Limbergen, Nicholas A. Kennedy, Christopher A. Lamb, Jürgen Glas, Vito Annese, Yashoda Sharma, Phil Schumm, Graham A. Heap, Cathryn Edwards, Lotta L. E. Koskinen, Jack Satsangi, Mitja I. Kurki, Aarno Palotie, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8 School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden Department of Medicine, University of Helsinki, 00100 Helsinki, Finland Helsinki University Hospital, 00100 Helsinki, Finland Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK Graham A. Heap Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4 Department of Gastroenterology, Torbay Hospital, Devon, UK Department of Medicine, St. Mark’s Hospital, Middlesex, UK Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK Christ Church, University of Oxford, Oxford, UK Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK Newcastle University, Newcastle upon Tyne, UK Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge, UK Department of Medical and Molecular Genetics, Guy’s Hospital, London, UK Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK Child Life and Health, University of Edinburgh, Edinburgh, UK Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Immunobiology Research Program, Research Programs Unit, Department of Medical and Clinical Genetics, Medicum, II kirurgian klinikka, Department of Surgery, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Immunomics, Kimmo Kontula Research Group, and Genomics of Neurological and Neuropsychiatric Disorders
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0301 basic medicine ,AAI12 ,Chemistry(all) ,SUSCEPTIBILITY LOCI ,Science ,Population ,General Physics and Astronomy ,Physics and Astronomy(all) ,OF-FUNCTION VARIANTS ,Inflammatory bowel disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,NUMBER ,medicine ,Ring finger ,IMPUTATION ,Allele ,education ,POPULATION ,RISK ,education.field_of_study ,Multidisciplinary ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,MUTATIONS ,General Chemistry ,ASSOCIATION ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,digestive system diseases ,3. Good health ,Ubiquitin ligase ,Transport protein ,Transmembrane domain ,030104 developmental biology ,medicine.anatomical_structure ,RARE VARIANTS ,Immunology ,biology.protein ,Cancer research ,3111 Biomedicine ,INFLAMMATORY-BOWEL-DISEASE - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763
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- 2016
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9. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study
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H. Valette, Denis Servent, Eylert Brodtkorb, B. Steinborn, D. Roumenov, Sameer M. Zuberi, W. Saba, Michel Bottlaender, A. Hufnagel, Antonio Gambardella, Fabienne Picard, Carole Fruchart-Gaillard, D. Bruel, M.-A. Schöllhorn-Peyronneau, Department of Neurology [Genève], Hôpitaux Universitaires de Genève (HUG), Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Psychiatry [St. Olav's hospital, Trondheim], St. Olav's Hospital, Royal Hospital for Sick Children [Edinburgh], Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Poznan University of Medical Sciences [Poland] (PUMS), Department of Neurology [Duisburg-Essen], and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
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Adult ,Male ,Fluorine Radioisotopes ,medicine.medical_specialty ,Pyridines ,[SDV]Life Sciences [q-bio] ,Epilepsy, Frontal Lobe ,Autosomal dominant nocturnal frontal lobe epilepsy ,Receptors, Nicotinic ,Mesencephalon ,Cerebellum ,Internal medicine ,Image Processing, Computer-Assisted ,medicine ,Humans ,genetics ,Prefrontal cortex ,Cells, Cultured ,Geographic difference ,fluoro-A-85380 ,Brain ,medicine.disease ,PET ,medicine.anatomical_structure ,Endocrinology ,Nicotinic agonist ,nervous system ,Frontal lobe ,Cerebral cortex ,Positron-Emission Tomography ,Mutation ,ADNFLE ,Azetidines ,Female ,Orbitofrontal cortex ,Neurology (clinical) ,Brainstem ,nicotinic receptor ,Psychology ,Neuroscience - Abstract
International audience; Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR $\alpha$4 or $\beta$2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since $\alpha$4$\beta$2 nAChRs are known to be widely distributed within the entire brain. PET study using [18F]-F-A-85380, a high affinity agonist at the $\alpha$4$\beta$2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [$^{18}$F]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. In five patients who underwent an additional [18F]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal.
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- 2006
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10. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
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Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
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Netherlands Twin Register (NTR) ,Medizin ,Inheritance Patterns ,Social Sciences ,AUTISM SPECTRUM DISORDERS ,nosology ,heritability ,COMMON SNPS ,0302 clinical medicine ,Crohn Disease ,SCHIZOPHRENIA ,Child ,Psychiatric genetics ,Genetics & Heredity ,MAJOR DEPRESSIVE DISORDER ,RISK ,0303 health sciences ,ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ,120 000 Neuronal Coherence ,Mental Disorders ,Variants ,BIPOLAR DISORDER ,ASSOCIATION ,Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3] ,Psychiatric Disorders ,CROHNS-DISEASE ,3. Good health ,Schizophrenia ,genetic association study ,Medical genetics ,Major depressive disorder ,SNPs ,Adult ,medicine.medical_specialty ,genetic etiology ,medical genetics ,DEFICIT HYPERACTIVITY DISORDER ,Biology ,Polymorphism, Single Nucleotide ,behavioral disciplines and activities ,Article ,Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] ,Heritability ,Genetic Heterogeneity ,03 medical and health sciences ,Prevalence of mental disorders ,mental disorders ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,medicine ,ddc:61 ,Humans ,Attention deficit hyperactivity disorder ,Genetic Predisposition to Disease ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,DCN PAC - Perception action and control NCEBP 9 - Mental health ,ddc:610 ,Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters ,Bipolar disorder ,Psychiatry ,030304 developmental biology ,Depressive Disorder, Major ,Genome, Human ,Genetic heterogeneity ,medicine.disease ,schizophrenia ,Attention Deficit Disorder with Hyperactivity ,Child Development Disorders, Pervasive ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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- 2013
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11. Evaluation of pituitary function after traumatic brain injury in childhood
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Khadr, Sophie N, Crofton, Patricia M, Jones, Patricia, Wardhaugh, Barbara, Roach, Jennifer, Drake, Amanda, Minns, Robert, Kelnar, Christopher J H, General & Adolescent Paediatrics, UCL Institute of Child Health, Paediatric Biochemistry, Royal Hospital for Sick Children [Edinburgh], Section of Child Life and Health, University of Edinburgh, and Paediatric Endocrinology
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Medicine - Abstract
International audience; Objectives: Post-traumatic hypopituitarism is well described among adult traumatic brain injury survivors. We aimed to determine the prevalence and clinical significance of pituitary dysfunction after head injury in childhood. Design: Retrospective exploratory study. Patients: 33 survivors of accidental head injury (27 males). Mean (range) age at study was 13.4y (5.4-21.7y) and median (range) interval since injury, 4.3y (1.4-7.8y). Functional outcome at study: 15 good recovery, 16 moderate disability, two severe disability. Measurements: Early morning urine osmolality and basal hormone evaluation were followed by the GnRH and insulin tolerance (n=25) or glucagon tests (if previous seizures, n=8). Subjects were not primed. Head injury details were extracted from patient records. Results: No subject had short stature (mean height SD score +0.50, range -1.57 to +3.00). Sub-optimal GH responses (Conclusions: No clinically significant endocrinopathy was identified amongst survivors of accidental childhood TBI, although minor pituitary hormone abnormalities were observed.
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- 2010
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12. An inter-observer and intra-observer study of a classification of RetCam images of retinal haemorrhages in children
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Robert A. Minns, Alan O. Mulvihill, Anamika Tandon, Brian W Fleck, Patricia A. Jones, Princess Alexandra Eye Pavilion, Edinburgh, and Royal Hospital for Sick Children [Edinburgh]
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Male ,medicine.medical_specialty ,Eye disease ,Nerve fibre layer ,Diagnostic Techniques, Ophthalmological ,Trauma ,Retina ,Diagnosis, Differential ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Ophthalmology ,medicine ,Craniocerebral Trauma ,Humans ,Child ,Observer Variation ,business.industry ,Head injury ,Infant ,Retinal Hemorrhage ,Retinal ,medicine.disease ,Intra observer ,Sensory Systems ,Craniocerebral trauma ,chemistry ,Child, Preschool ,030221 ophthalmology & optometry ,Female ,Child health (paediatrics) ,business ,Retinopathy ,Retinal haemorrhage - Abstract
International audience; Background: There is currently no universally accepted classification of childhood retinal haemorrhages. Aim: To measure the inter- and intra-observer agreement of clinical classifications of retinal haemorrhages in children. Methods: Four examiners (2 consultant ophthalmologists and 2 other clinicians) were shown 142 retinal haemorrhages on 31 RetCam photographs. The retinal haemorrhages were from children with accidental or abusive head injury, or other encephalopathies, and included retinal haemorrhages of different ages. Specified haemorrhages were initially classified by each examiner according to their clinical understanding. Twenty-six haemorrhages were re-presented to test intra-observer consistency. Examiners then agreed a common description for each haemorrhage type and five categories were described (vitreous, pre-retinal, nerve fibre layer, intra-retinal/sub-retinal, or indeterminate), and the study repeated. Results: There was ‘fair agreement' initially (Fleiss' unweighted kappa = 0.219), and with the agreed classification, slight improvement (0.356). Intra-observer agreement marginally improved on re-test. The 2 consultant ophthalmologists showed ‘fair' agreement on both occasions (paired kappa statistic). The other rater pair improved from ‘fair' to ‘substantial' agreement with the new classification. Conclusions: The classification of retinal haemorrhage in children by appearance alone shows only fair agreement between examiners. Clinicians who are not consultant ophthalmologists appear to benefit from the new succinct classification. (200 words)
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- 2010
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13. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data
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Pm, Thompson, Jl, Stein, Se, Medland, Dp, Hibar, Aa, Vasquez, Me, Renteria, Toro R, Jahanshad N, Schumann G, Franke B, Mj, Wright, Ng, Martin, Agartz I, Alda M, Alhusaini S, Almasy L, Almeida J, Alpert K, Nc, Andreasen, Oa, Andreassen, Lg, Apostolova, Appel K, Nj, Armstrong, Aribisala B, Me, Bastin, Bauer M, Ce, Bearden, Bergmann O, Eb, Binder, Blangero J, Hj, Bockholt, Bøen E, Bois C, Di, Boomsma, Booth T, Ij, Bowman, Bralten J, Rm, Brouwer, Hg, Brunner, Dg, Brohawn, Rl, Buckner, Buitelaar J, Bulayeva K, Jr, Bustillo, Vd, Calhoun, Dm, Cannon, Rm, Cantor, Ma, Carless, Caseras X, Gl, Cavalleri, Mm, Chakravarty, Kd, Chang, Cr, Ching, Christoforou A, Cichon S, Vp, Clark, Conrod P, Coppola G, Crespo-Facorro B, Je, Curran, Czisch M, Ij, Deary, Ej, Geus, den Braber A, Delvecchio G, Depondt C, de Haan L, Gi, Zubicaray, Dima D, Dimitrova R, Djurovic S, Dong H, Donohoe G, Duggirala R, Td, Dyer, Ehrlich S, Cj, Ekman, Elvsåshagen T, Emsell L, Erk S, Espeseth T, Fagerness J, Fears S, Fedko I, Fernández G, Se, Fisher, Foroud T, Pt, Fox, Francks C, Frangou S, Em, Frey, Frodl T, Frouin V, Garavan H, Giddaluru S, Dc, Glahn, Godlewska B, Rz, Goldstein, Rl, Gollub, Hj, Grabe, Grimm O, Gruber O, Guadalupe T, Re, Gur, Rc, Gur, Hh, Göring, Hagenaars S, Hajek T, Gb, Hall, Hall J, Hardy J, Ca, Hartman, Hass J, Sn, Hatton, Uk, Haukvik, Hegenscheid K, Heinz A, Ib, Hickie, Bc, Ho, Hoehn D, Pj, Hoekstra, Hollinshead M, Aj, Holmes, Homuth G, Martine Hoogman, Le, Hong, Hosten N, Jj, Hottenga, He, Hulshoff Pol, Ks, Hwang, Cr, Jack Jr, Jenkinson M, Johnston C, Eg, Jönsson, Rs, Kahn, Kasperaviciute D, Kelly S, Kim S, Kochunov P, Koenders L, Krämer B, Jb, Kwok, Lagopoulos J, Laje G, Landen M, Ba, Landman, Lauriello J, Sm, Lawrie, Ph, Lee, Le Hellard S, Lemaître H, Cd, Leonardo, Cs, Li, Liberg B, Dc, Liewald, Liu X, Lm, Lopez, Loth E, Lourdusamy A, Luciano M, Macciardi F, Mw, Machielsen, Gm, Macqueen, Uf, Malt, Mandl R, Ds, Manoach, Jl, Martinot, Matarin M, Ka, Mather, Mattheisen M, Mattingsdal M, Meyer-Lindenberg A, McDonald C, Am, Mcintosh, Fj, Mcmahon, Kl, Mcmahon, Meisenzahl E, Melle I, Milaneschi Y, Mohnke S, Gw, Montgomery, Dw, Morris, Ek, Moses, Ba, Mueller, Muñoz Maniega S, Tw, Mühleisen, Müller-Myhsok B, Mwangi B, Nauck M, Nho K, Te, Nichols, Lg, Nilsson, Ac, Nugent, Nyberg L, Rl, Olvera, Oosterlaan J, Ra, Ophoff, Pandolfo M, Papalampropoulou-Tsiridou M, Papmeyer M, Paus T, Pausova Z, Gd, Pearlson, Bw, Penninx, Cp, Peterson, Pfennig A, Phillips M, Gb, Pike, Jb, Poline, Sg, Potkin, Pütz B, Ramasamy A, Rasmussen J, Rietschel M, Rijpkema M, Sl, Risacher, Jl, Roffman, Roiz-Santiañez R, Romanczuk-Seiferth N, Ej, Rose, Na, Royle, Rujescu D, Ryten M, Ps, Sachdev, Salami A, Td, Satterthwaite, Savitz J, Aj, Saykin, Scanlon C, Schmaal L, Hg, Schnack, Aj, Schork, Sc, Schulz, Schür R, Seidman L, Shen L, Jm, Shoemaker, Simmons A, Sm, Sisodiya, Smith C, Jw, Smoller, Jc, Soares, Sr, Sponheim, Sprooten E, Jm, Starr, Vm, Steen, Strakowski S, Strike L, Sussmann J, Pg, Sämann, Teumer A, Aw, Toga, Tordesillas-Gutierrez D, Trabzuni D, Trost S, Turner J, Van den Heuvel M, Nj, Wee, van Eijk K, Tg, Erp, Ne, Haren, van 't Ent D, Mj, Tol, Mc, Valdés Hernández, Dj, Veltman, Versace A, Völzke H, Walker R, Walter H, Wang L, Jm, Wardlaw, Me, Weale, Mw, Weiner, Wen W, Lt, Westlye, Hc, Whalley, Cd, Whelan, White T, Am, Winkler, Wittfeld K, Woldehawariat G, Wolf C, Zilles D, Mp, Zwiers, Thalamuthu A, Pr, Schofield, Nb, Freimer, Ns, Lawrence, Drevets W, The Alzheimer’s Disease Neuroimaging Initiative, Epigen Consortium, Laboratory of Neuro Imaging [Los Angeles] (LONI), University of California [Los Angeles] (UCLA), University of California-University of California, David Geffen School of Medicine [Los Angeles], Medstar Research Institute, Keck School of Medicine [Los Angeles], University of Southern California (USC), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Department of Psychiatry, Donders Centre for Neuroscience, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Genetic Epidemiology Lab [Brisbane], Queensland Institute of Medical Research, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Dalhousie University [Halifax], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Department of Genetics, Southwest Foundation for Biomedical Research, Departamento de Matemática Pura, Faculdade de Ciências (UNIVERSIDADE DO PORTO), Universidade do Porto = University of Porto, Department of Psychiatry and Psychotherapy, University of Edinburgh, Center for Sepsis Control & Care, Jena University Hospital, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Texas Biomedical Research Institute [San Antonio, TX], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Radboud University Medical Center [Nijmegen], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Department of Genomics, Douglas Mental Health University Institute, McGill University = Université McGill [Montréal, Canada], sans affiliation, Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), School of Psychology, University of Queensland, University of Queensland [Brisbane], Department of Hematology, 'Ion Chiricuta' Cancer Institute, University of Oslo (UiO), The University of Texas Health Science Center at Houston (UTHealth), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Department of Psychiatry, Division of Medical Psychology, Champalimaud Neuroscience Programme, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Division of Hemato-Oncology, Saint Anna Children's Hospital [Vienne] = St Anna Kinderspital (St. Anna Children's Hospital), Psychiatry and Psychotherapy, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Vermont [Burlington], Haukeland University Hospital, University of Bergen (UiB), Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Laboratory of Molecular Neuropsychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg], International Max Planck Research School for Language Sciences (IMPRS ), Lancaster University, Georgia Institute of Technology [Atlanta], Greifswald University Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, University Medical Center Groningen [Groningen] (UMCG), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Mental Health Sciences Unit, University College of London [London] (UCL), University Medical Center [Utrecht], Department of Radiology [Rochester], Mayo Clinic [Rochester], Department of Clinical Neurology [Oxford], University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], Centre for the Cellular Basis of Behavior, Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine, Imperial College London, MetaCase [Jyväskylä], Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, University of Maryland System, Sahlgrenska Academy at University of Gothenburg [Göteborg], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Université de Cergy Pontoise (UCP), Université Paris-Seine, National Institutes of Health [Bethesda] (NIH), Department of Forensic and Neurodevelopmental Sciences, University of California [Irvine] (UCI), University of California, Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], VU University Medical Center [Amsterdam], Metacohorts Consortium, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Indiana Alzheimer Disease Center, Department of Statistics [Warwick], University of Warwick [Coventry], Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, University of Pennsylvania [Philadelphia], Department of Cognitive Sciences [San Diego], University of California [San Diego] (UC San Diego), Indiana University System, Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of psychiatry-King‘s College London, Institute of Neurology [London], Laboratoire des symbioses tropicales et méditerranéennes (UMR LSTM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], King Faisal Specialist Hospital and Research Centre, Georgia State University, University System of Georgia (USG), Department of Psychiatry and Human Behavior [Irvine], Leiden University Medical Center (LUMC), Institute for Community Medicine, School of Music and Music Education (UNSW), Science & Technology Information Institute, Shandong Academy of Agricultural Science, University of California [San Francisco] (UCSF), Department of Physics [Hong Kong University of Science and Technology], Hong Kong University of Science and Technology (HKUST), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Research Laboratory for Archaeology & the History of Art, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dundee Technopole, CXR Biosciences Ltd, Georg-August-University [Göttingen], Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Prince of Wales Medical Research Institute, Center for Neurobehavioral Genetics, Wales Institute of Cognitive Neuroscience, Cardiff University, Complutense University of Madrid (UCM), Universidade do Porto [Porto], Texas Biomedical Research Institute [San Antonio, Texas], Karakter Child and Adolescent Psychiatry University Centre, McGill University, Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), St. Anna Children's Hospital, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Bergen (UIB), Yale University School of Medicine, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), McGill University-McGill University, Technische Universität Dresden (TUD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Inria Saclay - Ile de France, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Physics [Kowloon], University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Neurosciences, Neurology Division, Karolinska Institutet, Karolinska University Hospital [Stockholm], Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University [Chicago, Ill. USA], Norwegian Centre for Mental Disorders Research [Oslo] (NORMENT), University of Oslo (UiO)-Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB)-Oslo University Hospital [Oslo], Ernst-Moritz-Arndt-Universität Greifswald, School of Mathematics and Statistics, Brain Research Imaging Centre, Imaging Sciences, University Hospital Carl Gustav Carus [Dresden, Germany], Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Royal Hospital for Sick Children [Edinburgh], Department of General Practice/EMGO Institute, Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), University of Edinburgh-Medical Research Council (MRC), Radboud University [Nijmegen], Brain Centre Rudolf Magnus [Utrecht], Department of Human Genetics [Nijmegen], Psychiatric and Neurodevelopmental Genetics Unit, Harvard University, Russian Academy of Sciences [Moscow] (RAS), The University of New Mexico [Albuquerque], The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), National University of Ireland [Galway] (NUI Galway), University of California (UC), Institute of Psychological Medicine and Clinical Neurosciences, Centre for Addiction and Mental Health [Toronto] (CAMH), Institute of Biomaterials and Biomedical Engineering [Toronto, ON, Canada] (IBBME), University of Toronto, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Universität Bonn = University of Bonn, Jülich Research Centre, University of Basel (Unibas), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Fundación Marqués de Valdecilla-Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Centre for Cognitive Ageing and Cognitive Epidemiology, Trinity College Dublin, Department of Psychiatry Massachusetts General Hospital (MGH), South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, University Hospital Regensburg, Hartford Hospital, University of Oxford, HELIOS Klinikum Stralsund Hanseatic, University of Heidelberg, Medical Faculty, Georg-August-University = Georg-August-Universität Göttingen, University of Pennsylvania, McMaster University [Hamilton, Ontario], UCL, Institute of Neurology [London], Brain and Mind Research Institute, University of Technology Sydney (UTS), Diakonhjemmet Hospital, University of Maryland School of Medicine, Oakland University, University of Rochester School of Medicine, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), South London and Maudsley NHS Foundation Trust, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Maryland [Baltimore], Neuroscience Research Australia (NeuRA), University of Gothenburg (GU), Karolinska Institutet [Stockholm], Vanderbilt University [Nashville], University of Missouri [Columbia] (Mizzou), University of Missouri System, Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neuroscience, Yale University School of Medicine, Columbia University Medical Center (CUMC), Columbia University [New York], University of Nottingham, UK (UON), University of California [Irvine] (UC Irvine), Università degli Studi di Milano = University of Milan (UNIMI), Hotchkiss Brain Institute, University of Calgary, Oslo and Akershus University College of Applied Sciences [Oslo] (HiOA), Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Aarhus University [Aarhus], Sorlandet Hospital HF, University Hospital Mannheim | Universitätsmedizin Mannheim, Centre for Advanced Imaging [Brisbane] (CAI), Ludwig Maximilian University [Munich] (LMU), Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, The University of Western Australia (UWA), University of Minnesota [Morris], University of Minnesota System, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), The University of Texas Medical School at Houston, Indiana State University, Stockholm Brain Institute [Stockholm, Sweden], Stockholm University, Umeå University, University of Texas Health Science Center, Department of Clinical Neuropsychology, University of Amsterdam [Amsterdam] (UvA), Rotman Research Institute at the Baycrest Centre (RRI), The Hospital for sick children [Toronto] (SickKids), University of Pittsburgh (PITT), University of California [Berkeley] (UC Berkeley), King's College, Reta Lila Weston Institute, UCL Institute of Neurology, Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, University of Cantabria, Santander, Research Triangle Institute International (RTI International), Martin-Luther-Universität Halle Wittenberg (MLU), Prince of Wales Hospital, Karolinska Institute, Laureate institute for brain research, Tulsa, University of Tulsa, Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), University of Minnesota Medical School, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Maudsley NHS Foundation Trust and Institute of Psychiatry, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Edinburgh Dementia Prevention & Centre for Clinical Brain Sciences, Center for Human Genetic Research, VA NY Harbor Health Care System, Alzheimer Scotland Dementia Research Centre, Department of Psychiatry and Behavioral Neuroscience [UC, Cincinnati], University of Cincinnati (UC), University of Cincinnati College of Medicine, Marqués de Valdecilla University Hospital [Santander], King Faisal Specialist Hospital and Resarch Centre [Riyadh, Saudi Arabia] (KFSHRC), Psychiatry and Leiden Institute for Brain and Cognition, Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), The Centre for Regenerative Medicine, Berlin School of Mind and Brain [Berlin], Humboldt University Of Berlin, University of California [San Francisco] (UC San Francisco), School of Chemistry, University of Edinburgh, Department of Public Health, Erasmus University Medical Centre, Rotterdam, Erasmus University Medical Centre, Rotterdam, Department of Psychiatry and Biobehavioral Sciences, University of Exeter, Janssen Research & Development, A complete listing of ADNI investigators is available at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf The work reviewed here was funded by a large number of federal and private agencies worldwide, listed in Stein et al. (2012), the funding for listed consortia is also itemized in Stein et al. (2012)., Medical Oncology, Epidemiology, Clinical Chemistry, Cardiology, Neurosciences, Child and Adolescent Psychiatry / Psychology, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Universidade do Porto, FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Université de Lorraine (UL)-Université de Strasbourg (UNISTRA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Service NEUROSPIN (NEUROSPIN), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Smoller, Jordan, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
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endocrine system ,Multi-site ,Cognitive Neuroscience ,[SDV]Life Sciences [q-bio] ,body-mass index ,Clinical Neurology ,multivariate parallel ica ,Neuroimaging ,methods [Genome-Wide Association Study] ,human brain structure ,methods [Brain Mapping] ,Behavioral Neuroscience ,Cellular and Molecular Neuroscience ,ddc:150 ,Meta-Analysis as Topic ,cortical surface-area ,Genetics ,voxel-based morphometry ,GWAS ,Humans ,Cooperative Behavior ,disease risk variant ,Brain Mapping ,MRI ,Consortium ,Meta-analysis ,white-matter microstructure ,SI: Genetic Neuroimaging in Aging and Age-Related Diseases ,Psychiatry and Mental health ,Neurology ,Radiology Nuclear Medicine and imaging ,quantitative trait loci ,RC0321 ,genome-wide association ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,tensor-based morphometry ,methods [Neuroimaging] ,Genome-Wide Association Study - Abstract
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
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14. Semen analysis and reproductive hormones in boys with classical Hodgkin lymphoma treated according to the EuroNet-PHL-C2 protocol.
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Drechsel KCE, Broer SL, van Breda HMK, Stoutjesdijk FS, van Dulmen-den Broeder E, Beishuizen A, Wallace WH, Körholz D, Mauz-Körholz C, Hasenclever D, Cepelova M, Uyttebroeck A, Ronceray L, Twisk JWR, Kaspers GJL, and Veening MA
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- Humans, Male, Child, Adolescent, Semen Analysis, Azoospermia drug therapy, Etoposide therapeutic use, Etoposide administration & dosage, Vincristine therapeutic use, Follicle Stimulating Hormone blood, Doxorubicin therapeutic use, Doxorubicin adverse effects, Prednisone therapeutic use, Prednisone administration & dosage, Sperm Count, Inhibins blood, Oligospermia drug therapy, Prospective Studies, Dacarbazine therapeutic use, Child, Preschool, Sperm Motility drug effects, Hodgkin Disease drug therapy, Cyclophosphamide therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects
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Study Question: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters?, Summary Answer: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility., What Is Known Already: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years., Study Design, Size, Duration: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021., Participants/materials, Setting, Methods: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21)., Main Results and the Role of Chance: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy., Limitations, Reasons for Caution: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited., Wider Implications of the Findings: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment., Study Funding/competing Interest(s): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
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- 2024
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15. Contributors to Organ Damage in Childhood Lupus: Corticosteroid Use and Disease Activity.
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Hanif M, Sarker C, Al-Abadi E, Armon K, Bailey K, Bohm M, Brennan M, Ciurtin C, Gardner-Medwin J, Hawley DP, Kinder A, Leahy A, Malik G, McLaren Z, Moraitis E, Mosley E, Ramanan AV, Rangaraj S, Ratcliffe A, Riley P, Rostron H, Sen E, Beresford MW, and Smith EMD
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Background: Awareness of paediatric-specific predictors of damage in Childhood-lupus is needed to inform mitigation measures., Objectives: To ascertain how clinical and demographic variables correlate with damage accrual and identify predictors of damage., Methods: Analysis included UK JSLE Cohort Study participants. Univariable and multivariable Prentice-Williams-Peterson models investigated how demographic and clinical factors influenced hazards of new damage. Analyses were performed across the entire cohort, in patients with minimal disease activity marked by a time-adjusted average SLEDAI-2K score (AMS)≤2, low activity (AMS ≤ 4), moderate-high activity (AMS > 4) and those with no corticosteroids., Results: Within the entire cohort (n = 430), factors associated with damage included: any methylprednisolone (Hazard Ratio, HR 2.20, [CI 1.33-3.62]), time-adjusted mean Physicians Global Assessment (PGA) (HR 2.87, [CI 1.48-5.56]) and AMS score (HR 1.13, [CI 1.03-1.24], all p< 0.05). Within the low activity subgroup, any methylprednisolone (HR 2.61, [CI 1.04-6.53]) and time-adjusted mean PGA (HR 3.41, [CI 1.52-7.76]) were associated with damage (both p< 0.05). Within the moderate-high activity subgroup, any methylprednisolone (HR 2.29, [CI 1.31-4.00]), time-adjusted mean PGA (HR 2.66, [CI 1.20-5.87]) and AMS score (HR 1.15, [CI 1.03-1.29]), were predictive of damage (all p< 0.05). Baseline organ damage was predictive of subsequent damage accrual in the minimal activity (HR 1.33, CI [1.78-8.08]) and no corticosteroids subgroups (HR 3.64, CI [1.83-7.24], both p< 0.005)., Conclusion: Disease activity levels (AMS/PGA) and proxy indicators (methylprednisolone exposure, baseline damage) were found to be key predictors of damage accrual. This highlights the importance of practical strategies, to reduce disease activity and long-term treatment toxicity, such as treat-to-target., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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16. Closed-Loop Therapy and Sleep in Young People Newly Diagnosed With T1D and Their Parents.
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Madrid-Valero JJ, Scott EM, Boughton CK, Allen JM, Ware J, Wilinska ME, Hartnell S, Thankamony A, Randell T, Ghatak A, Besser REJ, Elleri D, Trevelyan N, Campbell FM, Hovorka R, and Gregory AM
- Abstract
Background: A diagnosis of type 1 diabetes in a young person can create vulnerability for sleep. Historically it has been rare for young people to be offered a closed-loop system soon after diagnosis meaning that studies examining sleep under these circumstances in comparison with standard treatment have not been possible. In this study, we examine sleep in young people (and their parents) who were provided with hybrid closed-loop therapy at diagnosis of type 1 diabetes versus those who receive standard treatment over a 2-year period., Methods: The sample comprised 97 participants (mean age = 12.0 years; SD = 1.7) from a multicenter, open-label, randomized, parallel trial, where young people were randomized to either hybrid closed-loop insulin delivery or standard care at diagnosis. Sleep was measured using actigraphy and the Pittsburgh Sleep Quality Index (PSQI) in the young people, and using the PSQI in parents., Results: Sleep in young people using hybrid closed-loop insulin delivery did not differ significantly compared with those receiving standard care (although there were nonsignificant trends for better sleep in the closed-loop group for 4 of the 5 sleep actigraphy measures and PSQI). Similarly, there were nonsignificant differences for sleep between the groups at 24 months (with mixed direction of effects)., Conclusions: This study assessed for the first time sleep in young people using a closed-loop system soon after diagnosis. Although sleep was not significantly different for young people using closed-loop insulin delivery as compared with those receiving standard care, the direction of effects of the nonsignificant results indicates a possible tendency for better sleep quality in the hybrid closed-loop insulin delivery group at the beginning of the treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EMS has received research support from Medical Research Council, Diabetes UK, National Institute for Health Research (NIHR), Abbott Diabetes Care and speaker honoraria: from Abbott Diabetes Care, Ypsomed, and Lilly Diabetes Care. CKB has received consulting fees from CamDiab and speaker honoraria from Ypsomed. JW has received speaker honoraria from Ypsomed and Novo Nordisk. MEW reports patents related to closed-loop and being a consultant at CamDiab. SH serves as a member of Medtronic advisory board, is a director of Ask Diabetes Ltd providing training and research support in health care settings, and reports having received training honoraria from Medtronic and Sanofi and consulting fees for CamDiab. TR receives consultancy fees from Abbott Diabetes care and has received honoraria from NovoNordisk for delivering educational meetings. REJB reports receiving speaker honoraria from Eli Lilly and Springer Healthcare, and reports sitting on the NovoNordisk UK Foundation Research Selection Committee on a voluntary basis. She acted as an independent advisor for Provent Bio, and received speaking honoraria from Sanofi and Medcape, which were donated to an education research fund. RH reports receiving speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license and/or consultancy fees from BBraun and Abbott Diabetes Care; patents related to closed-loop, and being director at CamDiab. AMG is an advisor for a project initially sponsored by Johnson’s Baby. She was a consultant for Perrigo (2021+). She receives royalties for two books Nodding Off (Bloomsbury Sigma, 2018) and The Sleepy Pebble (Flying Eye, 2019) and a sleep gift (The Gift of Sleep, Laurence King Publishers, 2023). She was previously a CEO of Sleep Universal LTD (2022). She is a regular contributor to BBC Focus Magazine and has contributed to other outlets (such as The Conversation, The Guardian, and Balance Magazine). She occasionally receives sample products related to sleep (eg, blue light–blocking glasses) and has given a paid talk to a business (Investec). She is a specialist subject editor at JCPP (sleep) for which she receives a small honorarium. She has contributed a paid article to Neurodiem.JJM-V, JMA, AT, AG, DE, NT, and FMC declare no competing financial interests.
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- 2024
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17. Real-world use of venetoclax in the treatment of paediatric and teenage/young adult haematological malignancies.
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Wilson A, Moussa A, Trinquand A, Malone A, Tewari S, Calvert R, Patrick K, Nicholson E, Smith K, Grandage V, Baird S, George L, Qureshi A, Borg A, Gibson B, Patel P, Bartram J, Samrin L, and O'Connor D
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Early-phase trials of venetoclax in children and teenagers/young adults with leukaemia have yielded promising results, but there remains a paucity of real-world data. To address this, we report a cohort of 41 children treated with venetoclax for a range of haematological malignancies, demonstrating complete remission in 43.6%, with most achieving minimal residual disease (MRD) negativity. Venetoclax was particularly effective as a bridge to transplant, with bridging successful in 75% of patients. Patients with MRD <1% at initiation of venetoclax were more likely to achieve MRD negativity (81.8% vs. 34.5%, p = 0.007) and had improved overall survival (54.5% vs. 17.9%, p = 0.004)., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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18. Treating severe paediatric asthma with mepolizumab or omalizumab: a protocol for the TREAT randomised non-inferiority trial.
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Cornelius V, Babalis D, Carroll WD, Cunningham S, Fleming L, Gaillard E, Gupta A, Janani L, Kennington E, Murray C, Nagakumar P, Roberts G, Seddon P, Sinha I, Streatfield C, Weir E, and Saglani S
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- Humans, Child, Adolescent, Quality of Life, Male, Female, Equivalence Trials as Topic, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Treatment Outcome, Severity of Illness Index, Asthma drug therapy, Omalizumab therapeutic use, Anti-Asthmatic Agents therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use
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Introduction: A minority of school-aged children with asthma have persistent poor control and experience frequent asthma attacks despite maximal prescribed maintenance therapy. These children have higher morbidity and risk of death. The first add-on biologic therapy, omalizumab, a monoclonal antibody that blocks immunoglobulin (Ig)E, was licensed for children with severe asthma in 2005. While omalizumab is an effective treatment, non-response is common. A second biologic, mepolizumab which blocks interleukin 5 and targets eosinophilic inflammation, was licensed in 2018, but the licence was granted by extrapolation of adult clinical trial data to children. This non-inferiority (NI) trial will determine whether mepolizumab is as efficacious as omalizumab in reducing asthma attacks in children with severe therapy resistant asthma (STRA) and refractory difficult asthma (DA)., Methods and Analysis: This is an ongoing multicentre 1:1 randomised NI open-label trial of mepolizumab and omalizumab. Up to 150 children and young people (CYP) aged 6-17 years with severe asthma will be recruited from specialist paediatric severe asthma centres in the UK. Prior to randomisation, children will be monitored for medication adherence for up to 16 weeks to determine STRA and refractory DA diagnoses. Current prescribing recommendations of serum IgE and blood eosinophils will not influence eligibility or enrolment. The primary outcome is the 52-week asthma attack rate. Bayesian analysis using clinician-elicited prior distributions will be used to calculate the posterior probability that mepolizumab is not inferior to omalizumab. Secondary outcomes include Composite Asthma Severity Index, Paediatric Asthma Quality of Life Questionnaire, lung function measures (forced expiratory volume in one second (FEV1), bronchodilator reversibility), fractional exhaled nitric oxide, Asthma Control Test (ACT), health outcomes EuroQol 5 Dimension (EQ-5D) and optimal serum IgE and blood eosinophil levels that may predict a response to therapy. These outcomes will be analysed in a frequentist framework using longitudinal models., Ethics and Dissemination: The study has been approved by the South Central-Berkshire Research Ethics Committee REC Number 19/SC/0634 and had Clinical Trials Authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2019-004085-17). All parents/legal guardians will give informed consent for their child to participate in the trial, and CYP will give assent to participate. The results will be published in peer-reviewed journals, presented at international conferences and disseminated via our patient and public involvement partners., Trial Registration Number: ISRCTN12109108; EudraCT Number: 2019-004085-17., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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19. Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.
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Black HA, de Proce SM, Campos JL, Meynert A, Halachev M, Marsh JA, Hirst RA, O'Callaghan C, Shoemark A, Toddie-Moore D, Santoyo-Lopez J, Murray J, Macleod K, Urquhart DS, Unger S, Aitman TJ, and Mill P
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Background: Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. Given overlapping clinical features and genetic heterogeneity, diagnosis can be difficult and often occurs late. Of those tested an estimated 30% of genetically screened PCD patients still lack a molecular diagnosis. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes., Methods: WGS was used to screen for pathogenic variants in eight patients with PCD., Results: 7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B., Conclusion: Here, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)
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- 2024
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20. The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.
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Drechsel KCE, Broer SL, Stoutjesdijk FS, van Dulmen-den Broeder E, Beishuizen A, Wallace WH, Körholz D, Mauz-Körholz C, Hasenclever D, Cepelova M, Uyttebroeck A, Ronceray L, Twisk JWR, Kaspers GJL, and Veening MA
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- Humans, Female, Child, Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Prospective Studies, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Anti-Mullerian Hormone blood, Hodgkin Disease blood, Hodgkin Disease drug therapy
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Study Question: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)?, Summary Answer: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL., What Is Known Already: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol., Study Design, Size, Duration: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021., Participants/materials, Setting, Methods: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses., Main Results and the Role of Chance: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years., Limitations, Reasons for Caution: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis., Wider Implications of the Findings: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol., Study Funding/competing Interest(s): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
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- 2024
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21. Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth With Type 1 Diabetes: A Randomized Trial.
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Ware J, Boughton CK, Allen JM, Wilinska ME, Hartnell S, Thankamony A, Randell T, Ghatak A, Besser REJ, Elleri D, Trevelyan N, Campbell FM, Sibayan J, Bailey R, Calhoun P, Dunseath G, and Hovorka R
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- Humans, Adolescent, Male, Child, Female, Glycemic Control methods, Hypoglycemic Agents therapeutic use, Hypoglycemic Agents administration & dosage, Glycated Hemoglobin metabolism, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 metabolism, C-Peptide blood, Insulin therapeutic use, Insulin administration & dosage, Blood Glucose metabolism, Blood Glucose drug effects, Insulin Infusion Systems
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Objective: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months., Research Design and Methods: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat., Results: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase., Conclusions: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion., (© 2024 by the American Diabetes Association.)
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- 2024
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22. Safety of User-Initiated Intensification of Insulin Delivery Using Cambridge Hybrid Closed-Loop Algorithm.
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Ware J, Wilinska ME, Ruan Y, Allen JM, Boughton CK, Hartnell S, Bally L, de Beaufort C, Besser REJ, Campbell FM, Draxlbauer K, Elleri D, Evans ML, Fröhlich-Reiterer E, Ghatak A, Hofer SE, Kapellen TM, Leelarathna L, Mader JK, Mubita WM, Narendran P, Poettler T, Rami-Merhar B, Tauschmann M, Randell T, Thabit H, Thankamony A, Trevelyan N, and Hovorka R
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- Humans, Adolescent, Child, Retrospective Studies, Male, Female, Adult, Middle Aged, Child, Preschool, Infant, Young Adult, Aged, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 blood, Algorithms, Insulin Infusion Systems adverse effects, Insulin administration & dosage, Insulin adverse effects, Hypoglycemic Agents administration & dosage, Hypoglycemic Agents adverse effects, Blood Glucose analysis, Blood Glucose drug effects, Hypoglycemia chemically induced, Hypoglycemia epidemiology
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Objective: Many hybrid closed-loop (HCL) systems struggle to manage unusually high glucose levels as experienced with intercurrent illness or pre-menstrually. Manual correction boluses may be needed, increasing hypoglycemia risk with overcorrection. The Cambridge HCL system includes a user-initiated algorithm intensification mode ("Boost"), activation of which increases automated insulin delivery by approximately 35%, while remaining glucose-responsive. In this analysis, we assessed the safety of "Boost" mode., Methods: We retrospectively analyzed data from closed-loop studies involving young children (1-7 years, n = 24), children and adolescents (10-17 years, n = 19), adults (≥24 years, n = 13), and older adults (≥60 years, n = 20) with type 1 diabetes. Outcomes were calculated per participant for days with ≥30 minutes of "Boost" use versus days with no "Boost" use. Participants with <10 "Boost" days were excluded. The main outcome was time spent in hypoglycemia <70 and <54 mg/dL., Results: Eight weeks of data for 76 participants were analyzed. There was no difference in time spent <70 and <54 mg/dL between "Boost" days and "non-Boost" days; mean difference: -0.10% (95% confidence interval [CI] -0.28 to 0.07; P = .249) time <70 mg/dL, and 0.03 (-0.04 to 0.09; P = .416) time < 54 mg/dL. Time in significant hyperglycemia >300 mg/dL was 1.39 percentage points (1.01 to 1.77; P < .001) higher on "Boost" days, with higher mean glucose and lower time in target range ( P < .001)., Conclusions: Use of an algorithm intensification mode in HCL therapy is safe across all age groups with type 1 diabetes. The higher time in hyperglycemia observed on "Boost" days suggests that users are more likely to use algorithm intensification on days with extreme hyperglycemic excursions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RH reports having received speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk; receiving license fees from BBraun; patents related to closed-loop; and being director at CamDiab. JW reports receiving speaker honoraria from Ypsomed. YR is a consultant at CamDiab. MEW is a consultant at CamDiab and reports patents related to closed-loop. CKB reports receiving consultancy fees from CamDiab and speaker honoraria from Ypsomed. SH reports speaker and advisory board fees from Dexcom, Medtronic, Sanofi, and Ypsomed; being director at ASK Diabetes Ltd; and receiving consulting/training fees from CamDiab. LB reports receiving research support from Dexcom and CamDiab. REJB reports receiving speaking honoraria from Eli Lilly and Springer Healthcare, and sitting as a voluntary unpaid member of the NovoNordisk UK Foundation Research Selection committee. FMC reports receiving speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk and Insulet, and consultancy fees from Abbott Diabetes Care. EF-R reports having received speaker honoraria from Eli Lilly and Novo Nordisk, serving on advisory boards for Eli Lilly and Sanofi. MLE is a clinical triallist with or has served on advisory boards or received speakers or writers fees from Medtronic, Dexcom, Abbott Diabetes Care, Roche, AstraZeneca, Novo Nordisk, Eli Lilly, Zucara, Pila Pharma, and Imcyse Pharma. SEH has received speaker honoraria by Eli Lilly, Vertex, Minimed Medtronic, Insulet, Ypsomed, and Sanofi. TMK reports having received speaker honoraria from Eli Lilly and Novo. LL has received personal fees from Abbott Diabetes Care, Dexcom, Insulet, Medtronic, Novo Nordisk, Sanofi, and Diabetes Care. JKM is a member on the advisory board of Boehringer Ingelheim, Becton-Dickinson, Eli Lilly, Medtronic, Prediktor A/S, Roche Diabetes Care, and Sanofi-Aventis, and received speaker honoraria from Abbott Diabetes Care, AstraZeneca, Becton-Dickinson, Dexcom, Eli Lilly, Mercke Sharp & Dohme, NovoNordisk, Roche Diabetes Care, Sanofi, Servier, and Ypsomed. TR reports receiving speaker honoraria from Novo Nordisk and consultancy fees from Abbott Diabetes Care. HT reports receiving research support from Dexcom and speaker honoraria from Eli Lilly. MT reports having received speaker honoraria from Eli Lilly, Novo Nordisk, and Medtronic and advisory board fees from Abbott Diabetes Care. BR-M has received speaker honoraria from Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi, and Menarini and has been on the advisory boards of Eli Lilly, Roche Diabetes Care, and Abbott Diabetes Care. CdB has received speaker honoraria from Minimed Medtronic, and has been member of their European Psychology and e-learning Advisory Board. JMA reports training fees from CamDiab. DE, WMM, PN, TP, AG, AT, KD, and NT have no disclosures.
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- 2024
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23. Fertility-Preserving Treatments and Patient- and Parental Satisfaction on Fertility Counseling in a Cohort of Newly Diagnosed Boys and Girls with Childhood Hodgkin Lymphoma.
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Drechsel KCE, IJgosse IM, Slaats S, Raasen L, Stoutjesdijk FS, van Dulmen-den Broeder E, Wallace WH, Beishuizen A, Körholz D, Mauz-Körholz C, Cepelova M, Uyttebroeck A, Ronceray L, Kaspers GJL, Broer SL, and Veening MA
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Purpose: The purpose of this study is to evaluate the use of fertility-preserving (FP) treatments and fertility counseling that was offered in a cohort of newly diagnosed children with classical Hodgkin lymphoma (cHL)., Methods: In this observational study, boys and girls with cHL aged ≤ 18 years with scheduled treatment according to the EuroNet-PHL-C2 protocol were recruited from 18 sites (5 countries), between January 2017 and September 2021. In 2023, a subset of Dutch participants (aged ≥ 12 years at time of diagnosis) and parents/guardians were surveyed regarding fertility counseling., Results: A total of 101 boys and 104 girls were included. Most post-pubertal boys opted for semen cryopreservation pre-treatment (85% of expected). Invasive FP treatments were occasionally chosen for patients at a relatively low risk of fertility based on scheduled alkylating agent exposure (4/5 testicular biopsy, 4/4 oocyte, and 11/11 ovarian tissue cryopreservation). A total of 17 post-menarchal girls (20%) received GnRH-analogue co-treatment. Furthermore, 33/84 parents and 26/63 patients responded to the questionnaire. Most reported receiving fertility counseling (97%/89%). Statements regarding the timing and content of counseling were generally positive. Parents and patients considered fertility counseling important (94%/87% (strongly agreed) and most expressed concerns about (their child's) fertility (at diagnosis 69%/46%, at present: 59%/42%)., Conclusion: Systematic fertility counseling is crucial for all pediatric cHL patients and their families. FP treatment should be considered depending on the anticipated risk and patient factors. We encourage the development of a decision aid for FP in pediatric oncology.
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- 2024
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24. Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL.
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Hodder A, Mishra AK, Enshaei A, Baird S, Elbeshlawi I, Bonney D, Clesham K, Cummins M, Vedi A, Gibson B, George L, Ingham D, Jigoulina G, Lancaster D, Lindsay K, Madni M, Malone A, Mitchell B, Moppett J, Motwani J, Moorman AV, Patrick K, Samrin L, Tewari S, Thakur I, O'Connor D, Samarasinghe S, and Vora A
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- Child, Humans, Infant, Child, Preschool, Adolescent, Young Adult, Adult, Philadelphia Chromosome, Neoplasm Recurrence, Local drug therapy, Antibodies, Bispecific adverse effects, Leukemia, Myeloid, Acute drug therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Purpose: We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant., Methods: Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer., Results: From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed., Conclusion: Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.
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- 2024
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25. Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Glycemic Outcomes with Closed-Loop Insulin Delivery.
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Lakshman R, Najami M, Allen JM, Ware J, Wilinska ME, Hartnell S, Thankamony A, Randell T, Ghatak A, Besser REJ, Elleri D, Trevelyan N, Campbell FM, Hovorka R, and Boughton CK
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- Adolescent, Humans, Insulin therapeutic use, Blood Glucose, Insulin Infusion Systems, Insulin, Regular, Human, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 drug therapy, Diabetic Ketoacidosis etiology
- Abstract
The presence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) is associated with higher glycated hemoglobin levels over time. We evaluated whether hybrid-closed loop (HCL) therapy from onset of T1D could prevent the adverse impact of DKA at diagnosis on long-term glycemic outcomes. This was a posthoc analysis from 51 adolescents using HCL from diagnosis of T1D as part of the CLOuD trial (NCT02871089). We compared glycemic and insulin metrics between adolescents with ( n = 17) and without ( n = 34) DKA at diagnosis. Participants with and without DKA at diagnosis had similar time in target glucose range 3.9-10.0 mmol/L (70-180 mg/dL), time below range (<3.9 mmol/L, <70 mg/dL) and HbA1c at 6, 12, and 24 months. While insulin requirements at 6 months were higher in those with DKA at diagnosis, this was not statistically significant after adjusting for bodyweight. Residual C-peptide secretion was similar between groups. We conclude that HCL therapy may mitigate against the negative glycemic effects of DKA at T1D diagnosis.
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- 2024
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26. Identifying the Optimum Strategy for Identifying Adults and Children With Celiac Disease: A Cost-Effectiveness and Value of Information Analysis.
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Keeney E, Elwenspoek MMC, Jackson J, Roadevin C, Jones HE, O'Donnell R, Sheppard AL, Dawson S, Lane D, Stubbs J, Everitt H, Watson JC, Hay AD, Gillett P, Robins G, Mallett S, Whiting PF, and Thom H
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- Child, Male, Adult, Humans, Female, Cost-Benefit Analysis, Transglutaminases, Immunoglobulin A, HLA Antigens, Celiac Disease diagnosis
- Abstract
Objectives: Celiac disease (CD) is thought to affect around 1% of people in the United Kingdom, but only approximately 30% are diagnosed. The aim of this work was to assess the cost-effectiveness of strategies for identifying adults and children with CD in terms of who to test and which tests to use., Methods: A decision tree and Markov model were used to describe testing strategies and model long-term consequences of CD. The analysis compared a selection of pre-test probabilities of CD above which patients should be screened, as well as the use of different serological tests, with or without genetic testing. Value of information analysis was used to prioritize parameters for future research., Results: Using serological testing alone in adults, immunoglobulin A (IgA) tissue transglutaminase (tTG) at a 1% pre-test probability (equivalent to population screening) was most cost-effective. If combining serological testing with genetic testing, human leukocyte antigen combined with IgA tTG at a 5% pre-test probability was most cost-effective. In children, the most cost-effective strategy was a 10% pre-test probability with human leukocyte antigen plus IgA tTG. Value of information analysis highlighted the probability of late diagnosis of CD and the accuracy of serological tests as important parameters. The analysis also suggested prioritizing research in adult women over adult men or children., Conclusions: For adults, these cost-effectiveness results suggest UK National Screening Committee Criteria for population-based screening for CD should be explored. Substantial uncertainty in the results indicate a high value in conducting further research., Competing Interests: Author Disclosures Links to the disclosure forms provided by the authors are available here., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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27. Treatments for Morton's neuroma.
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Matthews BG, Thomson CE, Harding MP, McKinley JC, and Ware RS
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- Humans, Anesthetics, Local, Quality of Life, Pain, Atrophy, Morton Neuroma therapy
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Background: Morton's neuroma (MN) is a painful neuropathy resulting from a benign enlargement of the common plantar digital nerve that occurs commonly in the third webspace and, less often, in the second webspace of the foot. Symptoms include burning or shooting pain in the webspace that extends to the toes, or the sensation of walking on a pebble. These impact on weight-bearing activities and quality of life., Objectives: To assess the benefits and harms of interventions for MN., Search Methods: On 11 July 2022, we searched CENTRAL, CINAHL Plus EBSCOhost, ClinicalTrials.gov, Cochrane Neuromuscular Specialised Register, Embase Ovid, MEDLINE Ovid, and WHO ICTRP. We checked the bibliographies of identified randomised trials and systematic reviews and contacted trial authors as needed., Selection Criteria: We included all randomised, parallel-group trials (RCTs) of any intervention compared with placebo, control, or another intervention for MN. We included trials where allocation occurred at the level of the individual or the foot (clustered data). We included trials that confirmed MN through symptoms, a clinical test, and an ultrasound scan (USS) or magnetic resonance imaging (MRI)., Data Collection and Analysis: We used standard Cochrane methodological procedures. We assessed bias using Cochrane's risk of bias 2 tool (RoB 2) and assessed the certainty of the evidence using the GRADE framework., Main Results: We included six RCTs involving 373 participants with MN. We judged risk of bias as having 'some concerns' across most outcomes. No studies had a low risk of bias across all domains. Post-intervention time points reported were: three months to less than 12 months from baseline (nonsurgical outcomes), and 12 months or longer from baseline (surgical outcomes). The primary outcome was pain, and secondary outcomes were function, satisfaction or health-related quality of life (HRQoL), and adverse events (AE). Nonsurgical treatments Corticosteroid and local anaesthetic injection (CS+LA) versus local anaesthetic injection (LA) Two RCTs compared CS+LA versus LA. At three to six months: • CS+LA may result in little to no difference in pain (mean difference (MD) -6.31 mm, 95% confidence interval (CI) -14.23 to 1.61; P = 0.12, I
2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Assessed via a pain visual analogue scale (VAS; 0 to 100 mm); a lower score indicated less pain.) • CS+LA may result in little to no difference in function when compared with LA (standardised mean difference (SMD) -0.30, 95% CI -0.61 to 0.02; P = 0.06, I2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Function was measured using: the American Orthopaedic Foot and Ankle Society Lesser Toe Metatarsophalangeal-lnterphalangeal Scale (AOFAS; 0 to 100 points) - we transformed the scale so that a lower score indicated improved function - and the Manchester Foot Pain and Disability Schedule (MFPDS; 0 to 100 points), where a lower score indicated improved function.) • CS+LA probably results in little to no difference in HRQoL when compared to LA (MD 0.07, 95% CI -0.03 to 0.17; P = 0.19; 1 study, 122 participants; moderate-certainty evidence), and CS+LA may not increase satisfaction (risk ratio (RR) 1.08, 95% CI 0.63 to 1.85; P = 0.78; 1 study, 35 participants; low-certainty evidence). (Assessed using the EuroQol five dimension instrument (EQ-5D; 0-1 point); a higher score indicated improved HRQoL.) • The evidence is very uncertain about the effects of CS+LA on AE when compared with LA (RR 9.84, 95% CI 1.28 to 75.56; P = 0.03, I2 = 0%; 2 studies, 157 participants; very low-certainty evidence). Adverse events for CS+LA included mild skin atrophy (3.9%), hypopigmentation of the skin (3.9%) and plantar fat pad atrophy (2.6%); no adverse events were observed with LA. Ultrasound-guided (UG) CS+LA versus non-ultrasound-guided (NUG) CS+LA Two RCTs compared UG CS+LA versus NUG CS+LA. At six months: • UG CS+LA probably reduces pain when compared with NUG CS+LA (MD -15.01 mm, 95% CI -27.88 to -2.14; P = 0.02, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). (Assessed with a pain VAS.) • UG CS+LA probably increases function when compared with NUG CS+LA (SMD -0.47, 95% CI -0.84 to -0.10; P = 0.01, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). We do not know of any established minimum clinical important difference (MCID) for the scales that assessed function, specifically, the MFPDS and the Manchester-Oxford Foot Questionnaire (MOXFQ; 0 to 100 points; a lower score indicated improved function.) • UG CS+LA may increase satisfaction compared with NUG CS+LA (risk ratio (RR) 1.71, 95% CI 1.19 to 2.44; P = 0.003, I2 = 15%; 2 studies, 114 feet; low-certainty evidence). • HRQoL was not measured. • UG CS+LA may result in little to no difference in AE when compared with NUG CS+LA (RR 0.42, 95% CI 0.12 to 1.39; P = 0.15, I2 = 0%; 2 studies, 116 feet; low-certainty evidence). AE included depigmentation or fat atrophy for UG CS+LA (4.9%) and NUG CS+LA (12.7%). Surgical treatments Plantar incision neurectomy (PN) versus dorsal incision neurectomy (DN) One study compared PN versus DN. At 34 months (mean; range 28 to 42 months), PN may result in little to no difference for satisfaction (RR 1.06, 95% CI 0.87 to 1.28; P = 0.58; 1 study, 73 participants; low-certainty evidence), or for AE (RR 0.95, 95% CI 0.32 to 2.85; P = 0.93; 1 study, 75 participants; low-certainty evidence) compared with DN. AE for PN included hypertrophic scaring (11.4%), foreign body reaction (2.9%); AE for DN included missed nerve (2.5%), artery resected (2.5%), wound infection (2.5%), postoperative dehiscence (2.5%), deep vein thrombosis (2.5%) and reoperation with plantar incision due to intolerable pain (5%). The data reported for pain and function were not suitable for analysis. HRQoL was not measured., Authors' Conclusions: Although there are many interventions for MN, few have been assessed in RCTs. There is low-certainty evidence that CS+LA may result in little to no difference in pain or function, and moderate-certainty evidence that UG CS+LA probably reduces pain and increases function for people with MN. Future trials should improve methodology to increase certainty of the evidence, and use optimal sample sizes to decrease imprecision., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)- Published
- 2024
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28. The evolution of nutritional care in children and young people with acute lymphoblastic leukaemia: a narrative review.
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Lovell AL, Gardiner B, Henry L, Bate JM, Brougham MFH, and Iniesta RR
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Background: Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy in the world. Advances in treatment protocols have resulted in survival rates of >80% in most high-income countries (HIC); however, children and young people (CYP) with ALL continue to face significant nutrition-related challenges during treatment., Methods: This narrative review outlines the changing landscape of treatment and survivorship for CYP with ALL and the advances in nutrition knowledge that call for changes to clinical nutrition practice., Results: The incidence of ALL has remained stable in HIC; however, there have been significant advances in survival over the past 30 years. Overweight and obesity are increasingly prevalent in CYP with ALL at diagnosis, during treatment and in survivorship. Coupled with poor diet quality, high-energy and saturated fat intakes, altered eating behaviours and inactivity, this necessitates the need for a shift in nutrition intervention. Undernutrition remains a concern for CYP with high-risk treatment protocols where oral or enteral nutrition support remains a cornerstone of maintaining nutrition status., Conclusions: With improved treatment protocols and high survival rates, a shift to focusing on diet quality, prevention of excessive weight gain and obesity during treatment and survivorship is necessary., (© 2024 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)
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- 2024
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29. Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.
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Salpietro V, Maroofian R, Zaki MS, Wangen J, Ciolfi A, Barresi S, Efthymiou S, Lamaze A, Aughey GN, Al Mutairi F, Rad A, Rocca C, Calì E, Accogli A, Zara F, Striano P, Mojarrad M, Tariq H, Giacopuzzi E, Taylor JC, Oprea G, Skrahina V, Rehman KU, Abd Elmaksoud M, Bassiony M, El Said HG, Abdel-Hamid MS, Al Shalan M, Seo G, Kim S, Lee H, Khang R, Issa MY, Elbendary HM, Rafat K, Marinakis NM, Traeger-Synodinos J, Ververi A, Sourmpi M, Eslahi A, Khadivi Zand F, Beiraghi Toosi M, Babaei M, Jackson A, Bertoli-Avella A, Pagnamenta AT, Niceta M, Battini R, Corsello A, Leoni C, Chiarelli F, Dallapiccola B, Faqeih EA, Tallur KK, Alfadhel M, Alobeid E, Maddirevula S, Mankad K, Banka S, Ghayoor-Karimiani E, Tartaglia M, Chung WK, Green R, Alkuraya FS, Jepson JEC, and Houlden H
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- Animals, Humans, Drosophila melanogaster genetics, GTP Phosphohydrolases genetics, Phenotype, Drosophila Proteins genetics, GTP-Binding Proteins genetics, Microcephaly, Nervous System Malformations, Neurodevelopmental Disorders genetics
- Abstract
The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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30. Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.
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Schoeler NE, Marston L, Lyons L, Halsall S, Jain R, Titre-Johnson S, Balogun M, Heales SJR, Eaton S, Orford M, Neal E, Reilly C, Eltze C, Stephen E, Mallick AA, O'Callaghan F, Agrawal S, Parker A, Kirkpatrick M, Brunklaus A, McLellan A, McCullagh H, Samanta R, Kneen R, Tan HJ, Devlin A, Prasad M, Rattihalli R, Basu H, Desurkar A, Williams R, Fallon P, Nazareth I, Freemantle N, and Cross JH
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- Child, Adult, Humans, Male, Infant, Female, Child, Preschool, Seizures drug therapy, United Kingdom, Treatment Outcome, Diet, Ketogenic adverse effects, Drug Resistant Epilepsy drug therapy, Epilepsy
- Abstract
Background: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy., Methods: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding., Findings: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee., Interpretation: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests NES was supported for a research post by Vitaflo (International) and received grants from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Matthew's Friends charity, and honoraria from Nutricia Advanced Medical Nutrition, Vitaflo (International), and Dr Schaer. SE, SJRH, and JHC report receiving grants from Vitaflo (International) and having a patent nutritional product (WO2013186570) and a patent anticonvulsant compound (WO2016038379A1) issued. JHC reports receiving honoraria from Nutricia and grants from GW Pharmaceuticals, Zogenix, Marinius, and Ovid. SJRH reports receiving consultancy fees and PhD studentship funding from Vitaflo (International). CE reports receiving honorarium from GW Pharmaceuticals/JAZZ Pharmaceuticals. HJT reports receiving honoraria from UCB Pharma, Nutricia, and GW Pharmaceuticals. SA reports receiving honorarium from Nutricia. AP reports receiving honorarium from Biomarin. EN reports receiving honorarium from Vitaflo (International). AD reports receiving consultancy fees from Nutricia and honoraria from Nutricia, GW Pharmaceuticals, and Zogenix. AAM reports receiving honoraria from LivaNova and Danone. NF reports receiving grants from the National Institute for Health and Care Research, the Medical Research Council, Cure Parkinson's Trust, and the European Union, consultancy fees from ALK, Sanofi Aventis, Gedeon Richter, Abbott, Galderma, AstraZeneca, Ipsen, Vertex, Thea, Novo Nordisk, Aimmune, and Ipsen, and honorarium from Abbott Singapore. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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31. Reproductive ability in survivors of childhood, adolescent, and young adult Hodgkin lymphoma: a review.
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Drechsel KCE, Pilon MCF, Stoutjesdijk F, Meivis S, Schoonmade LJ, Wallace WHB, van Dulmen-den Broeder E, Beishuizen A, Kaspers GJL, Broer SL, and Veening MA
- Subjects
- Adolescent, Female, Humans, Male, Pregnancy, Young Adult, Anti-Mullerian Hormone, Follicle Stimulating Hormone, Quality of Life, Testosterone, Azoospermia complications, Hodgkin Disease complications, Hodgkin Disease drug therapy, Primary Ovarian Insufficiency etiology, Cancer Survivors
- Abstract
Background: Owing to a growing number of young and adolescent Hodgkin lymphoma (HL) survivors, awareness of (long-term) adverse effects of anticancer treatment increases. The risk of impaired reproductive ability is of great concern given its impact on quality of life. There is currently no review available on fertility after childhood HL treatment., Objective and Rationale: The aim of this narrative review was to summarize existing literature on different aspects of reproductive function in male and female childhood, adolescent, and young adult HL survivors., Search Methods: PubMed and EMBASE were searched for articles evaluating fertility in both male and female HL survivors aged <25 years at diagnosis. In females, anti-Müllerian hormone (AMH), antral follicle count, premature ovarian insufficiency (POI), acute ovarian failure, menstrual cycle, FSH, and pregnancy/live births were evaluated. In males, semen-analysis, serum FSH, inhibin B, LH, testosterone, and reports on pregnancy/live births were included. There was profound heterogeneity among studies and a lack of control groups; therefore, no meta-analyses could be performed. Results were presented descriptively and the quality of studies was not assessed individually., Outcomes: After screening, 75 articles reporting on reproductive markers in childhood or adolescent HL survivors were included. Forty-one papers reported on 5057 female HL survivors. The incidence of POI was 6-34% (median 9%; seven studies). Signs of diminished ovarian reserve or impaired ovarian function were frequently seen (low AMH 55-59%; median 57%; two studies. elevated FSH 17-100%; median 53%; seven studies). Most survivors had regular menstrual cycles. Fifty-one studies assessed fertility in 1903 male HL survivors. Post-treatment azoospermia was highly prevalent (33-100%; median 75%; 29 studies). Long-term follow-up data were limited, but reports on recovery of semen up to 12 years post-treatment exist. FSH levels were often elevated with low inhibin B (elevated FSH 0-100%; median 51.5%; 26 studies. low inhibin B 19-50%; median 45%; three studies). LH and testosterone levels were less evidently affected (elevated LH 0-57%, median 17%; 21 studies and low testosterone 0-43%; median 6%; 15 studies). In both sexes, impaired reproductive ability was associated with a higher dose of cumulative chemotherapeutic agents and pelvic radiotherapy. The presence of abnormal markers before treatment indicated that the disease itself may also negatively affect reproductive function (Females: AMH
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- 2023
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32. Ankle-foot orthoses among children with cerebral palsy: a cross-sectional population-based register study of 8,928 children living in Northern Europe.
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Stockman J, Eggertsdóttir G, Gaston MS, Jeglinsky-Kankainen I, Hollung SJ, Nordbye-Nielsen K, von Rosen P, and Alriksson-Schmidt AI
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- Adolescent, Child, Humans, Ankle, Gait physiology, Cross-Sectional Studies, Europe epidemiology, Foot Orthoses, Cerebral Palsy diagnosis, Cerebral Palsy epidemiology, Cerebral Palsy therapy
- Abstract
Background: Cerebral palsy (CP) is an umbrella term where an injury to the immature brain affects muscle tone and motor control, posture, and at times, the ability to walk and stand. Orthoses can be used to improve or maintain function. Ankle-foot orthoses (AFOs) are the most frequently used orthoses in children with CP. However, how commonly AFOs are used by children and adolescents with CP is still unknown. The aims of this study were to investigate and describe the use of AFOs in children with CP in Sweden, Norway, Finland, Iceland, Scotland, and Denmark, and compare AFO use between countries and by gross motor function classification system (GMFCS) level, CP subtype, sex, and age., Method: Aggregated data on 8,928 participants in the national follow-up programs for CP for the respective countries were used. Finland does not have a national follow-up program for individuals with CP and therefore a study cohort was used instead. Use of AFOs were presented as percentages. Logistic regression models were used to compare the use of AFOs among countries adjusted for age, CP subtype, GMFCS level, and sex., Results: The proportion of AFO use was highest in Scotland (57%; CI 54-59%) and lowest in Denmark (35%; CI 33-38%). After adjusting for GMFCS level, children in Denmark, Finland, and Iceland had statistically significantly lower odds of using AFOs whereas children in Norway and Scotland reported statistically significantly higher usage than Sweden., Conclusion: In this study, the use of AFOs in children with CP in countries with relatively similar healthcare systems, differed between countries, age, GMFCS level, and CP subtype. This indicates a lack of consensus as to which individuals benefit from using AFOs. Our findings present an important baseline for the future research and development of practical guidelines in terms of who stands to benefit from using AFOs., (© 2023. The Author(s).)
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- 2023
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33. Sedation and Analgesia for Reduction of Pediatric Ileocolic Intussusception.
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Poonai N, Cohen DM, MacDowell D, Mistry RD, Mintegi S, Craig S, Roland D, Miller M, Shavit I, Wang Y, Nager A, Heyming T, Burns R, Trehan I, Lipshaw M, Sulton C, Li J, Ojo A, Kelly S, Thornton M, Caperell K, Amoni I, Abrams A, Duong M, Wassem M, Davis A, Gravel J, Doyon Trottier E, Bar Am N, Thompson G, Sabhaney V, Meckler G, Jain R, Ali S, Bressan S, Zangardi T, Villa G, Giacalone M, Seiler M, Sahyoun C, Romano F, Bognar Z, Hajosi-Kalcakosz S, Amir L, Hachimi-Idrissi S, Pucuka Z, Zviedre A, Zeltina E, Phillips N, Borland M, O'Brien S, Marchant J, Kochar A, George S, Pennington V, Lyttle M, Browning J, McLoughlin A, Hartshorn S, Urooj C, Johnston L, Walton E, Subrahmanyam Puthucode D, Peacock P, Conroy J, Marañon R, Garcia S, Cahís N, Cámara-Otegui A, Gomez A, Carbonero M, Angelats-Romero C, Yock-Corrales A, Hualde G, Spigariol F, Donas A, Gübeli Linné C, Rocchi A, Pedrazzini A, Cozzi G, Barbi D, Baggio L, La Fauci G, Mauro A, Steimle M, Buonsenso D, Ugalde I, Nieva G, Harper C, Sforzi I, and Jain S
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- Male, Child, Humans, Adolescent, Female, Analgesics, Opioid therapeutic use, Cross-Sectional Studies, Intussusception complications, Intestinal Perforation etiology, Analgesia adverse effects
- Abstract
Importance: Ileocolic intussusception is an important cause of intestinal obstruction in children. Reduction of ileocolic intussusception using air or fluid enema is the standard of care. This likely distressing procedure is usually performed without sedation or analgesia, but practice variation exists., Objective: To characterize the prevalence of opioid analgesia and sedation and assess their association with intestinal perforation and failed reduction., Design, Setting, and Participants: This cross-sectional study reviewed medical records of children aged 4 to 48 months with attempted reduction of ileocolic intussusception at 86 pediatric tertiary care institutions in 14 countries from January 2017 to December 2019. Of 3555 eligible medical records, 352 were excluded, and 3203 medical records were eligible. Data were analyzed in August 2022., Exposures: Reduction of ileocolic intussusception., Main Outcomes and Measures: The primary outcomes were opioid analgesia within 120 minutes of reduction based on the therapeutic window of IV morphine and sedation immediately before reduction of intussusception., Results: We included 3203 patients (median [IQR] age, 17 [9-27] months; 2054 of 3203 [64.1%] males). Opioid use was documented in 395 of 3134 patients (12.6%), sedation 334 of 3161 patients (10.6%), and opioids plus sedation in 178 of 3134 patients (5.7%). Perforation was uncommon and occurred in 13 of 3203 patients (0.4%). In the unadjusted analysis, opioids plus sedation (odds ratio [OR], 5.92; 95% CI, 1.28-27.42; P = .02) and a greater number of reduction attempts (OR, 1.48; 95% CI, 1.03-2.11; P = .03) were significantly associated with perforation. In the adjusted analysis, neither of these covariates remained significant. Reductions were successful in 2700 of 3184 attempts (84.8%). In the unadjusted analysis, younger age, no pain assessment at triage, opioids, longer duration of symptoms, hydrostatic enema, and gastrointestinal anomaly were significantly associated with failed reduction. In the adjusted analysis, only younger age (OR, 1.05 per month; 95% CI, 1.03-1.06 per month; P < .001), shorter duration of symptoms (OR, 0.96 per hour; 95% CI, 0.94-0.99 per hour; P = .002), and gastrointestinal anomaly (OR, 6.50; 95% CI, 2.04-20.64; P = .002) remained significant., Conclusions and Relevance: This cross-sectional study of pediatric ileocolic intussusception found that more than two-thirds of patients received neither analgesia nor sedation. Neither was associated with intestinal perforation or failed reduction, challenging the widespread practice of withholding analgesia and sedation for reduction of ileocolic intussusception in children.
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- 2023
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34. Klinefelter syndrome: going beyond the diagnosis.
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Butler G, Srirangalingam U, Faithfull J, Sangster P, Senniappan S, and Mitchell R
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- Female, Pregnancy, Adult, Adolescent, Infant, Newborn, Humans, Male, Child, Prospective Studies, Semen, Testis, Testosterone therapeutic use, Klinefelter Syndrome complications, Klinefelter Syndrome diagnosis, Klinefelter Syndrome drug therapy, Hypogonadism drug therapy
- Abstract
Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes being identified with speech or developmental delay or incidental antenatal diagnosis. The only regular feature is testicular dysfunction. Postnatal gonadotropin surge (mini-puberty) may be lower, but treatment with testosterone needs prospective studies. The onset of puberty is at the normal age and biochemical hypogonadism does not typically occur until late puberty. Testosterone supplementation can be considered then or earlier for clinical hypogonadism. The size at birth is normal, but growth acceleration is more rapid in early and mid-childhood, with adult height greater than mid-parental height. Extreme tall stature is unusual. The incidence of adolescent gynaecomastia (35.6%) is not increased compared with typically developing boys and can be reduced or resolved by testosterone supplementation, potentially preventing the need for surgery. Around two-thirds require speech and language therapy or developmental support and early institution of therapy is important. Provision of psychological support may be helpful in ameliorating these experiences and provide opportunities to develop strategies to recognise, process and express feelings and thoughts. Boys with KS are at increased risk of impairment in social cognition and less accurate perceptions of social emotional cues. The concept of likely fertility problems needs introduction alongside regular reviews of puberty and sexual function in adolescents. Although there is now greater success in harvesting sperm through techniques such as testicular sperm extraction, it is more successful in later than in early adolescence. In vitro maturation of germ cells is still experimental., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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35. A rare presentation of a bilateral intracranial parameningeal embryonal rhabdomyosarcoma mimicking vestibular schwannoma in a two-year-old child: a case report.
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Salloum NL, Sokol D, Kandasamy J, Torgerson A, Wallace HB, and Kaliaperumal C
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- Male, Humans, Child, Child, Preschool, Combined Modality Therapy, Rhabdomyosarcoma, Embryonal diagnostic imaging, Rhabdomyosarcoma, Embryonal therapy, Neuroma, Acoustic diagnostic imaging, Rhabdomyosarcoma therapy, Facial Paralysis
- Abstract
Intracranial parameningeal rhabdomyosarcomas are rare, aggressive, rapidly progressive paediatric malignancies that carry a poor prognosis. The authors report a case of a 2-year-old boy who initially presented with a left facial palsy, ataxia and, shortly after, bloody otorrhoea. MRI imaging was initially suggestive of a vestibular schwannoma. However, there was rapid progression of symptoms and further MRI imaging showed very rapid increase in tumour size with mass effect and development of a similar tumour on the contralateral side. A histological diagnosis of bilateral parameningeal embryonal rhabdomyosarcoma was made. Despite treatment, progression led to hydrocephalus and diffuse leptomeningeal disease, from which the patient did not survive. Few intracranial parameningeal rhabdomyosarcomas have previously been reported and these report similar presenting symptoms and rapid disease progression. However, this is the first reported case of a bilateral intracranial parameningeal embryonal rhabdomyosarcoma which, on initial presentation and imaging, appeared to mimic a vestibular schwannoma., (© 2022. The Author(s).)
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- 2023
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36. UK Dietary Practices for Tyrosinaemias: Time for Change.
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Daly A, Adam S, Allen H, Ash J, Dale C, Dixon M, Dunlop C, Ellerton C, Evans S, Firman S, Ford S, Freedman F, Gribben J, Howe S, Khan F, McDonald J, McStravick N, Nguyen P, Oxley N, Skeath R, Simpson E, Terry A, Woodall A, White L, and MacDonald A
- Subjects
- Diet, Vegetables, Fruit, Phenylalanine, United Kingdom, Tyrosinemias
- Abstract
In the UK, different dietary systems are used to calculate protein or tyrosine/phenylalanine intake in the dietary management of hereditary tyrosinaemia, HTI, II and III (HT), with no systematic evidence comparing the merits and inadequacies of each. This study aimed to examine the current UK dietary practices in all HTs and, using Delphi methodology, to reach consensus agreement about the best dietary management system. Over 12 months, five meetings were held with UK paediatric and adult dietitians working in inherited metabolic disorders (IMDs) managing HTs. Eleven statements on the dietary system for calculating protein or tyrosine/phenylalanine intake were discussed. Dietitians from 12 of 14 IMD centres caring for HT patients participated, and 7/11 statements were agreed with one Delphi round. Nine centres (three abstentions) supported a 1 g protein exchange system for all foods except fruit and vegetables. The same definitions used in the UK for phenylketonuria (PKU) were adopted to define when to calculate foods as part of a protein exchange system or permit them without measurement. Fruit and vegetables contain a lower amount of tyrosine/phenylalanine per 1 g of protein than animal and cereal foods. The correlation of tyrosine vs. phenylalanine (mg/100 g) for vegetables and fruits was high (r = 0.9). In Delphi round 2, agreement was reached to use the tyrosine/phenylalanine analyses of fruits/vegetables, for their allocation within the HT diet. This allowed larger portion sizes of measured fruits and vegetables and increased the variety of fruit and vegetables that could be eaten without measurement. In HTs, a combined dietary management system will be used: 1 g protein exchanges for cereal and milk protein sources and tyrosine/phenylalanine exchanges for fruit and vegetables. Intensive, systematic communication with IMD dietitians and reappraisal of the evidence has redefined and harmonised HT dietary practice across the UK.
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- 2022
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37. Near-infrared spectroscopy (NIRS) measured tissue oxygenation in neonates with gastroschisis: a pilot study.
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Stienstra RM and McHoney M
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- Infant, Newborn, Humans, Spectroscopy, Near-Infrared methods, Pilot Projects, Prospective Studies, Ischemia, Gastroschisis complications
- Abstract
Background: Management of gastroschisis involves either primary or staged closure. Bowel ischemia and abdominal compartment syndrome (ACS) are possible complications that can be related to a method of treatment. NIRS monitoring has never been applied in this group of patients and may allow for earlier detection of complications., Objective: To assess near-infrared spectroscopy (NIRS) monitoring in neonates with gastroschisis for detecting changes in tissue oxygenation (rSO
2 ) related to bowel reductions or height of bowel in the silo and for detecting tissue ischemia., Methods: Patients with gastroschisis and controls underwent continuous multi-channel assessment of oxygenation of the brain (CrSO2 ), kidney (RrSO2 ) and bowel (GrSO2 ) in a prospective pilot study., Results: Fifteen neonates were treated with primary closure ( n = 3) or staged closure ( n = 12); two had confirmed bowel ischemia, none developed ACS.There was no significant correlation between height of the bowel and GrSO2 at apex ( p = .72) or base ( p = .54) within the silo. During staged reductions there was a clinically non-significant change in RrSO2 (Δ-2.5%, p = .04), but no significant changes in CrSO2 ( p = .11), and GrSO2 of apex ( p = .97) and base ( p = .31). Patients with confirmed ischemia had GrSO2 that were lower than controls., Conclusions: Measuring GrSO2 through a silo is feasible. Staged reduction seems safe based on NIRS measurements, with minimal effect of hydrostatic pressure on bowel oxygenation. NIRS was able to detect subtle changes in intra-abdominal renal perfusion during reduction and could differentiate healthy and ischemic bowel.- Published
- 2022
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38. Delayed versus early repair of inguinal hernia in preterm infants: A systematic review and meta-analysis.
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Choo CS, Chen Y, and McHoney M
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- Herniorrhaphy methods, Humans, Infant, Infant, Newborn, Infant, Premature, Postoperative Complications epidemiology, Postoperative Complications etiology, Postoperative Complications surgery, Hernia, Inguinal etiology, Infant, Premature, Diseases epidemiology, Infant, Premature, Diseases etiology, Infant, Premature, Diseases surgery
- Abstract
Objectives: To evaluate the clinical outcomes of herniotomy in preterm infants undergoing early versus delayed repair, the risk factors for complications, and to identify best timing of surgery., Methods: Medline, Embase and Central databases were searched from inception until 25 Jan 2021 to identify publications comparing the timing of neonatal inguinal hernia repair between early intervention (before discharge from first hospitalization) and delayed (after first hospitalisation discharge) intervention. Inclusion criteria was preterm infants diagnosed with inguinal hernia during neonatal intensive care unit admission. Results were analyzed using fixed and random effects meta-analysis (RevManv5.4)., Results: Out of 721 articles found, six studies were included in the meta-analysis. Patients in the early group had lower odds of developing incarceration [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.34-0.55, I
2 = 0%, p < 0.001]; but higher risk of post-operative respiratory complications (OR 4.36, 95% CI 2.13-8.94, I2 = 40%, p < 0.001). No significant differences were reported in recurrence rate (OR 3.10, 95% CI 0.90-10.64, I2 = 0%, p = 0.07) and surgical complication rate (OR 0.94, 95% CI 0.18-4.83, I2 = 0%, p = 0.94) between early and delayed groups., Conclusion: While early inguinal hernia repair in preterm infants reduces the risk of incarceration, it increases the risk of post-operative respiratory complications compared to delayed repair. Surgeons should discuss the risks and benefits of delaying inguinal hernia repair with the caregivers to make an informed decision best suited to the patient physiology and circumstances., Level of Evidence: Treatment study, level 3., Competing Interests: Declaration of Competing Interest The study has been submitted as a dissertation course work for a master degree to the University of Edinburgh. The authors declare that there is no conflict of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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39. Efficacy and Safety of "Sleeper Plate" in Temporary Hemiepiphysiodesis and the Observation of "Tethering".
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Messner J and Cooper A
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- Humans, Bone Plates, Epiphyses
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- 2022
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40. Features of the transposed seasonality of the 2021 RSV epidemic in the UK and Ireland: analysis of the first 10 000 patients.
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Roland D, Williams T, Lyttle MD, Marlow R, Hardelid P, Sinha I, Swann O, Maxwell-Hodkinson A, and Cunningham S
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- Humans, Ireland epidemiology, United Kingdom epidemiology, Epidemics
- Abstract
Competing Interests: Competing interests: None declared.
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- 2022
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41. Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.
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Elwenspoek MM, Thom H, Sheppard AL, Keeney E, O'Donnell R, Jackson J, Roadevin C, Dawson S, Lane D, Stubbs J, Everitt H, Watson JC, Hay AD, Gillett P, Robins G, Jones HE, Mallett S, and Whiting PF
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- United States, Adult, Child, Male, Humans, Female, Longitudinal Studies, Prospective Studies, Immunoglobulin A, Randomized Controlled Trials as Topic, Celiac Disease, Skin Neoplasms, Osteoporosis
- Abstract
Background: Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma., Objectives: The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care., Design: (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives., Data Sources: For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE
® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used., Review Methods: For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed., Results: People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents ( n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research., Limitations: The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet., Conclusions: Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia)., Future Work: Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed., Study Registration: This study is registered as PROSPERO CRD42019115506 and CRD42020170766., Funding: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.- Published
- 2022
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42. Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.
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Chanchlani N, Lin S, Auth MK, Lee CL, Robbins H, Looi S, Murugesan SV, Riley T, Preston C, Stephenson S, Cardozo W, Sonwalkar SA, Allah-Ditta M, Mansfield L, Durai D, Baker M, London I, London E, Gupta S, Di Mambro A, Murphy A, Gaynor E, Jones KDJ, Claridge A, Sebastian S, Ramachandran S, Selinger CP, Borg-Bartolo SP, Knight P, Sprakes MB, Burton J, Kane P, Lupton S, Fletcher A, Gaya DR, Colbert R, Seenan JP, MacDonald J, Lynch L, McLachlan I, Shields S, Hansen R, Gervais L, Jere M, Akhtar M, Black K, Henderson P, Russell RK, Lees CW, Derikx LAAP, Lockett M, Betteridge F, De Silva A, Hussenbux A, Beckly J, Bendall O, Hart JW, Thomas A, Hamilton B, Gordon C, Chee D, McDonald TJ, Nice R, Parkinson M, Gardner-Thorpe H, Butterworth JR, Javed A, Al-Shakhshir S, Yadagiri R, Maher S, Pollok RCG, Ng T, Appiahene P, Donovan F, Lok J, Chandy R, Jagdish R, Baig D, Mahmood Z, Marsh L, Moss A, Abdulgader A, Kitchin A, Walker GJ, George B, Lim YH, Gulliver J, Bloom S, Theaker H, Carlson S, Cummings JRF, Livingstone R, Beale A, Carter JO, Bell A, Coulter A, Snook J, Stone H, Kennedy NA, Goodhand JR, and Ahmad T
- Subjects
- Adalimumab therapeutic use, Antibodies, Biological Therapy, Drug Monitoring, Humans, Immunologic Factors therapeutic use, Infliximab therapeutic use, Retrospective Studies, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases drug therapy, Tumor Necrosis Factor Inhibitors therapeutic use
- Abstract
Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD)., Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab., Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure., Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)
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- 2022
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43. Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.
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van Iersel L, Mulder RL, Denzer C, Cohen LE, Spoudeas HA, Meacham LR, Sugden E, Schouten-van Meeteren AYN, Hoving EW, Packer RJ, Armstrong GT, Mostoufi-Moab S, Stades AM, van Vuurden D, Janssens GO, Thomas-Teinturier C, Murray RD, Di Iorgi N, Neggers SJCMM, Thompson J, Toogood AA, Gleeson H, Follin C, Bardi E, Torno L, Patterson B, Morsellino V, Sommer G, Clement SC, Srivastava D, Kiserud CE, Fernandez A, Scheinemann K, Raman S, Yuen KCJ, Wallace WH, Constine LS, Skinner R, Hudson MM, Kremer LCM, Chemaitilly W, and van Santen HM
- Subjects
- Adolescent, Child, Female, Humans, Male, Survivors, Young Adult, Cancer Survivors, Endocrine System Diseases diagnosis, Endocrine System Diseases epidemiology, Hypothalamic Diseases, Neoplasms epidemiology, Pituitary Diseases, Thyroid Neoplasms
- Abstract
Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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44. Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes.
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Boughton CK, Allen JM, Ware J, Wilinska ME, Hartnell S, Thankamony A, Randell T, Ghatak A, Besser REJ, Elleri D, Trevelyan N, Campbell FM, Sibayan J, Calhoun P, Bailey R, Dunseath G, and Hovorka R
- Subjects
- Adolescent, Blood Glucose analysis, Child, Humans, Insulin Infusion Systems, C-Peptide metabolism, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 metabolism, Hypoglycemic Agents therapeutic use, Insulin therapeutic use
- Abstract
Background: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear., Methods: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis., Results: A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group., Conclusions: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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45. Rituximab in juvenile myasthenia gravis-an international cohort study and literature review.
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Ramdas S, Della Marina A, Ryan MM, McWilliam K, Klein A, Jacquier D, Alabaf S, Childs AM, Parasuraman D, Beeson D, Palace J, and Jungbluth H
- Subjects
- Adult, Child, Cohort Studies, Humans, Retrospective Studies, Rituximab adverse effects, Treatment Outcome, Myasthenia Gravis drug therapy
- Abstract
Juvenile myasthenia gravis (JMG) is a rare, antibody-mediated disorder of the neuromuscular junction. Treatment strategies in JMG are largely informed by adult MG treatments as the pathophysiology is similar. Rituximab is increasingly considered as a treatment option in refractory JMG but has not yet been systematically investigated in this patient group We conducted a retrospective study from five international centres with expertise in paediatric myasthenia. 10 JMG patients treated with rituximab were identified. Following rituximab treatment all patients had a reduction in JMG-related hospital admissions. At 24 month follow up, 6 patients (60%) had achieved complete stable remission or pharmacological remission and 7 patients were able to reduce immunomodulatory treatment(s). The main side-effect was infusion-related reactions (30%) which resolved in all patients with symptomatic treatment. We compared our cohort to previously reported JMG cases treated with rituximab and noted similar response rates but a slightly higher side-effect profile. Rituximab is a safe and effective treatment option in moderate to severe JMG and most patients have an improvement in MG symptoms post treatment., Competing Interests: Declaration of competing interest The authors do not have any competing interest to declare., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2022
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46. Prematurity, Delivery Method, and Infant Feeding Type Are Not Associated with Paediatric-onset Inflammatory Bowel Disease Risk: A Scottish Retrospective Birth Cohort Study.
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Burgess CJ, Schnier C, Wood R, Henderson P, and Wilson DC
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- Adolescent, Birth Cohort, Cesarean Section, Child, Chronic Disease, Cohort Studies, Female, Humans, Incidence, Infant, Infant, Newborn, Pregnancy, Retrospective Studies, Colitis, Ulcerative epidemiology, Crohn Disease epidemiology, Inflammatory Bowel Diseases epidemiology, Inflammatory Bowel Diseases etiology
- Abstract
Background and Aims: The incidence of paediatric-onset inflammatory bowel disease [PIBD] continues to rise globally. We aimed to determine whether mode of delivery, gestational age at birth, or type of infant feeding contribute to the development of PIBD in a nationwide cohort of Scottish children., Methods: All children born in Scotland between 1981 and 2017 were identified using linked health administrative data to determine mode of delivery, gestational age at birth, and type of infant feeding. PIBD cases were defined as onset of Crohn's disease [CD], ulcerative colitis [UC], or IBD-unclassified [IBDU] before age 16 years. Validation was performed within an entire Scottish health board [16% of total population] via individual case-note verification. Hazard ratios [HR] were calculated for each exposure using Cox proportional hazards models., Results: A study population of 2 013 851 children was identified including 1721 PIBD cases. Validation of 261 PIBD patients coded as CD and/or UC identified 242 [93%] as true positive. Children delivered vaginally did not have an altered risk of developing PIBD compared with those delivered by caesarean section, adjusted HR 0.95 [95% CI 0.84-1.08] [p = 0.46]. Compared with children born at term [≥37 weeks], children born prematurely did not have an altered risk of developing PIBD, i.e., at 24-31 weeks of gestation, HR 0.99 [95% CI 0.57-1.71] [p = 0.97] and at 32-36 weeks of gestation, HR 0.96 [95% CI 0.76-1.20] [p = 0.71]. Compared with children exclusively breastfed at age 6 weeks, children exclusively formula fed did not have an altered risk of developing PIBD: adjusted HR 0.97 [95% CI 0.81-1.15] [p = 0.69]., Conclusions: This population-based study demonstrates no association between mode of delivery, gestational age, or exclusive formula feeding at 6 weeks, and the development of PIBD., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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47. Attainment of low disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus.
- Author
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Smith EMD, Tharmaratnam K, Al-Abadi E, Armon K, Bailey K, Brennan M, Ciurtin C, Gardner-Medwin J, Haslam KE, Hawley D, Leahy A, Leone V, Malik G, McLaren Z, Pilkington C, Ramanan AV, Rangaraj S, Ratcliffe A, Riley P, Sen E, Sridhar A, Wilkinson N, Hedrich CM, Jorgensen A, and Beresford MW
- Subjects
- Adult, Cohort Studies, Disease Progression, Humans, Remission Induction, Severity of Illness Index, Lupus Erythematosus, Systemic drug therapy
- Abstract
Objectives: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE)., Methods: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage., Results: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P < 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (P < 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (P > 0.05). Attainment of all targets reduced the hazards of new damage (P < 0.05)., Conclusions: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2022
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48. Efficacy and Safety of "Sleeper Plate" in Temporary Hemiepiphysiodesis and the Observation of "Tethering".
- Author
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Gerges M, Messner J, Lim B, Chhina H, and Cooper A
- Subjects
- Bone Screws adverse effects, Humans, Retrospective Studies, Steel, Bone Plates adverse effects, Titanium
- Abstract
Background: Guided growth is commonly performed by placing an extraperiosteal 2-hole plate across the growth plate with one epiphyseal and one metaphyseal screw. Recent studies investigated the efficacy of the removal of the metaphyseal screw only (sleeper plate) after correction. They concluded the practice to be unnecessary as only 19% of patients showed recurrence of deformity. This study aims to examine the incidence of rebound and undesired bony in-growth of the plate (tethering) after metaphyseal screw removal only., Methods: In this retrospective case series, patient data on 144 plates inserted around the knee were obtained. Plates still in situ (n=69) at the time of study and full hardware removal (n=50) were excluded. The remaining 25 plates had only the metaphyseal screw removed after completed deformity correction. We analyzed the rate of tethering, rebound, and maintenance of correction in 2 age groups at latest follow (mean of 3.5 y). The Fisher exact test with Freeman-Halton extension was used to analyze categorical data and the Student t test for descriptive variables., Results: Twenty-five plates were identified as "sleeper plates" in our series. Thirteen plates (52%) maintained the achieved correction after a mean of 21 months (range: 4 to 39 mo), 9 plates (36%) required screw reinsertion due to rebound after a mean of 22 months (range: 12 to 48 mo) from screw removal, and 4 plates (16%) showed tethering with undesired continuation of guided growth after a mean of 14 months (range: 7 to 22 mo) from screw removal. Younger patients (<8 y at time of plate insertion) had higher rates of rebound and tethering ( P =0.0112, Fisher exact test). All tethering occurred in titanium plates, none occurred in steel plates., Conclusions: The sleeper plate is an acceptable treatment strategy for coronal deformities around the knee, however, tethering and rebound may occur, especially in younger patients. Titanium plates may increase the risk of tethering, however, further long-term follow-up is needed as there were only 6 steel plates versus 19 titanium in this study. We stress the importance of close postoperative follow-up to identify signs of tethering and rebound early to prevent over-correction., Level of Evidence: Level IV-retrospective case study., Competing Interests: A.C. has received an unrestricted research grant from Vilex and OrthoPediatrics. He is a consultant for OrthoPediatrics. He has been on the advisory board for Cerapedics and has done a consultancy work with IPSEN. J.M. is a speaker for OrthoPediatrics. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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49. Personalised 3D printed respirators for healthcare workers during the COVID-19 pandemic.
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Roche AD, McConnell AC, Donaldson K, Lawson A, Tan S, Toft K, Cairns G, Colle A, Coleman AA, Stewart K, Digard P, Norrie J, and Stokes AA
- Abstract
Widespread issues in respirator availability and fit have been rendered acutely apparent by the COVID-19 pandemic. This study sought to determine whether personalized 3D printed respirators provide adequate filtration and function for healthcare workers through a Randomized Controlled Trial (RCT). Fifty healthcare workers recruited within NHS Lothian, Scotland, underwent 3D facial scanning or 3D photographic reconstruction to produce 3D printed personalized respirators. The primary outcome measure was quantitative fit-testing to FFP3 standard. Secondary measures included respirator comfort, wearing experience, and function instrument (R-COMFI) for tolerability, Modified Rhyme Test (MRT) for intelligibility, and viral decontamination on respirator material. Of the 50 participants, 44 passed the fit test with the customized respirator, not significantly different from the 38 with the control ( p = 0.21). The customized respirator had significantly improved comfort over the control respirator in both simulated clinical conditions ( p < 0.0001) and during longer wear ( p < 0.0001). For speech intelligibility, both respirators performed equally. Standard NHS decontamination agents were able to eradicate 99.9% of viral infectivity from the 3D printed plastics tested. Personalized 3D printed respirators performed to the same level as control disposable FFP3 respirators, with clear communication and with increased comfort, wearing experience, and function. The materials used were easily decontaminated of viral infectivity and would be applicable for sustainable and reusable respirators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roche, McConnell, Donaldson, Lawson, Tan, Toft, Cairns, Colle, Coleman, Stewart, Digard, Norrie and Stokes.)
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- 2022
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50. Language function following preterm birth: prediction using machine learning.
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Valavani E, Blesa M, Galdi P, Sullivan G, Dean B, Cruickshank H, Sitko-Rudnicka M, Bastin ME, Chin RFM, MacIntyre DJ, Fletcher-Watson S, Boardman JP, and Tsanas A
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- Child, Child, Preschool, Diffusion Tensor Imaging, Female, Gestational Age, Humans, Infant, Infant, Newborn, Infant, Premature, Machine Learning, Pregnancy, Quality of Life, Language Development Disorders, Premature Birth
- Abstract
Background: Preterm birth can lead to impaired language development. This study aimed to predict language outcomes at 2 years corrected gestational age (CGA) for children born preterm., Methods: We analysed data from 89 preterm neonates (median GA 29 weeks) who underwent diffusion MRI (dMRI) at term-equivalent age and language assessment at 2 years CGA using the Bayley-III. Feature selection and a random forests classifier were used to differentiate typical versus delayed (Bayley-III language composite score <85) language development., Results: The model achieved balanced accuracy: 91%, sensitivity: 86%, and specificity: 96%. The probability of language delay at 2 years CGA is increased with: increasing values of peak width of skeletonized fractional anisotropy (PSFA), radial diffusivity (PSRD), and axial diffusivity (PSAD) derived from dMRI; among twins; and after an incomplete course of, or no exposure to, antenatal corticosteroids. Female sex and breastfeeding during the neonatal period reduced the risk of language delay., Conclusions: The combination of perinatal clinical information and MRI features leads to accurate prediction of preterm infants who are likely to develop language deficits in early childhood. This model could potentially enable stratification of preterm children at risk of language dysfunction who may benefit from targeted early interventions., Impact: A combination of clinical perinatal factors and neonatal DTI measures of white matter microstructure leads to accurate prediction of language outcome at 2 years corrected gestational age following preterm birth. A model that comprises clinical and MRI features that has potential to be scalable across centres. It offers a basis for enhancing the power and generalizability of diagnostic and prognostic studies of neurodevelopmental disorders associated with language impairment. Early identification of infants who are at risk of language delay, facilitating targeted early interventions and support services, which could improve the quality of life for children born preterm., (© 2021. Crown.)
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- 2022
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