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1. Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia

Author: Heba Morsy, Mehdi Benkirane, Elisa Cali, Clarissa Rocca, Kristina Zhelcheska, Valentina Cipriani, Evangelia Galanaki, Reza Maroofian, Stephanie Efthymiou, David Murphy, Mary O’Driscoll, Mohnish Suri, Siddharth Banka, Jill Clayton-Smith, Thomas Wright, Melody Redman, Jennifer A. Bassetti, Mathilde Nizon, Benjamin Cogne, Rami Abu Jamra, Tobias Bartolomaeus, Marion Heruth, Ilona Krey, Janina Gburek-Augustat, Dagmar Wieczorek, Felix Gattermann, Meriel Mcentagart, Alice Goldenberg, Lucie Guyant-Marechal, Hector Garcia-Moreno, Paola Giunti, Brigitte Chabrol, Severine Bacrot, Roger Buissonnière, Virginie Magry, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Béla Melegh, András Szabó, Katalin Sümegi, Mireille Cossée, Monica Ziff, Russell Butterfield, David Hunt, Georgina Bird-Lieberman, Michael Hanna, Michel Koenig, Michael Stankewich, Jana Vandrovcova, Henry Houlden, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, C. Patch, D. Perez-Gil, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, UCL, Institute of Neurology [London], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), William Harvey Research Institute, Barts and the London Medical School, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Weill Cornell Medicine [New York], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University Hospital Leipzig, University Hospital Düsseldorf, St George’s University Hospitals, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), Centre Hospitalier de Versailles André Mignot (CHV), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Auteur indépendant, University of Pécs Medical School (UP MS), University of Pecs, Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University of Utah School of Medicine [Salt Lake City], Princess Anne Hospital [Southampton, UK] (PAH), University of Southampton, University Hospital Southampton NHS Foundation Trust, Department of Pathology [Yale], Yale School of Medicine [New Haven, Connecticut] (YSM), H.M., J.V., and H.H. are supported by an Medical Research Council strategic award, MR/S005021/1, to establish International Centre for Genomic Medicine in Neuromuscular Diseases. H.M. is supported by Wellcome Trust grant 220906/Z/20/Z. H.H. is funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), NIHR University College London Hospitals Biomedical Research Centre, Rosetree Trust UK, Ataxia UK, Multiple System Atrophy Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK, and Multiple System Atrophy Trust. R.But. is supported by the Penelope Rare and Undiagnosed Disease Program at the University of Utah with funding from the Center for Genomic Medicine and with support from Matt Velinder (Department of Human Genetics, University of Utah) and Rong Mao and Pinar Bayrak-Toydemir (ARUP Laboratories). B.M. is supported by NKFIH K138669. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health and Care Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded the research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) community. A full list of centers which contributed to the generation of the data is available at https://deciphergenomics.org/about/stats and via email from contact@deciphergenomics.org. Funding for the DECIPHER project was provided by Wellcome. We are thankful to the Deciphering Developmental Disorders Study for the invaluable collaboration. The Deciphering Developmental Disorders Study (Cambridge South Research Ethics Committee approval 10/H0305/83 and the Republic of Ireland Research Ethics Committee GEN/284/12) presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and Department of Health and the Wellcome Trust Sanger Institute (grant number WT098051), MORNET, Dominique, Nottingham University Hospitals NHS Trust (NUH), Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: [SDV] Life Sciences [q-bio], Developmental delay, [SDV]Life Sciences [q-bio], Hereditary spastic paraplegia, Genetics (clinical), Hereditary ataxia, SPTAN1, Developmental epileptic encephalopathy
Abstract: On behalf of Queen Square Genomics On behalf of Genomics England Research Consortium; International audience; Purpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.
Published: 2022
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2. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Author: Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.
Subjects: Male, Models, Molecular, Hypertrichosis, [SDV]Life Sciences [q-bio], Mesomelic Dysplasia, Transcriptome, Mice, Gene Frequency, Missense mutation, Child, Zebrafish, Genetics (clinical), Genetics, Brain Diseases, 0303 health sciences, biology, Protein Stability, 030305 genetics & heredity, AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia, Nuclear Proteins, Syndrome, Phenotype, Ubiquitin ligase, [SDV] Life Sciences [q-bio], Child, Preschool, Female, Transcriptional Elongation Factors, Adolescent, Mutation, Missense, Osteochondrodysplasias, Article, Evolution, Molecular, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Fused Kidney, 030304 developmental biology, Epilepsy, Infant, Horseshoe kidney, biology.organism_classification, medicine.disease, biology.protein
Abstract: International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
Published: 2021
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3. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author: Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, 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), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), 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 de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract: Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
Published: 2020
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4. Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Author: Arn M. J. M. van den Maagdenberg, Stewart Wiseman, David Hunt, Gisela M. Terwindt, Isabelle Melki, Sarah McGlasson, Tracy A Briggs, Darragh Duffy, Alexandre Belot, Marie-Alexandra Alyanakian, Mathieu P Rodero, Flore Rozenberg, Pierre Quartier, Christina Hertel, Vincent Bondet, Isabelle Meyts, N. Bellon, Benedicte Neven, Adrian Hayday, Frédéric Rieux-Laucat, Nadine Pelzer, Jérémie Decalf, Matthew L. Albert, Lucile Musset, Joanna M. Wardlaw, Marie Hully, Gillian I. Rice, Marie-Louise Frémond, Scott W Werneke, Brigitte Bader-Meunier, Christine Barnerias, Christine Bodemer, Yanick J. Crow, Yoann Rose, Isabelle Desguerre, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre For Clinical Brain Sciences - Neuroimaging Sciences [Edinburgh, U.K.] (CCBS), University of Edinburgh, Medical Research Council (MRC) Human Genetics Unit [Edinburgh], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council-University of Edinburgh-Medical Research Council, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, 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), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Division of Evolution and Genomic Science [Manchester], School of Biological Sciences [Manchester]-Faculty of Biology, Medicine and Health [Manchester], Department of Neurology, Leiden University Medical Center (LUMC), Departments of Human Genetics & Neurology, General Paediatrics, Infectious Disease and Internal Medicine Department [Robert-Debré], Hôpital Robert Debré, Department of Microbiology and Immunology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Pediatric Immunodeficiencies, University Hospitals Leuven [Leuven], Service d'Immunologie [CHU Pitié-Salpétrière], 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), ImmunoQure AG, Peter Gorer Department of Immunobiology, King‘s College London, The Francis Crick Institute [London], Université Paris Descartes - Paris 5 (UPD5), Service de Virologie [CHU Cochin], Hôpital Cochin [AP-HP], Service de Génétique Médicale [CHU Necker], Y.J. Crow acknowledges support from the European Research Council (fellowshipGA 309449, fellowship), the European Leukodystrophy Association (ELA 2012-008I1), and a state subsidy managed by the Agence Nationale de la Recherche (ANR, France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y.J. Crow and D. Duffy acknowledge support from the ANR (CE17001002).Y.L. Crow and A.M.J.M. van den Maagdenberg acknowledge the EU FP7 project NIM BL(241779). D. Duffy acknowledges funding from a PasteurInnov grant and the EU FP7project PoC-HCV (261365) for development of Simoa assays. S. Wiseman andJ. Wardlaw acknowledge funding from Lupus UK. A. Hayday acknowledges supportfrom the Wellcome Trust (grant 106292/Z/14/Z). F. Rieux-Laucat and Y.J. Crow acknowledgethe ANR (ANR-14-CE14-0026-01 'Lumugene'). D. Hunt is supported bythe Wellcome Trust., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0026,Lumugene,Etude de familles multiplex de lupus pour l'identification de nouveaux gènes à fort impact phénotypique : de la découvertes des gènes à leurs fonctions(2014), European Project: 241779,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,NIMBL(2010), European Project: 261365,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SPHINX(2010), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Academic Unit of Medical Genetic, University of Manchester [Manchester], Medical Research Council Institute of Genetics and Molecular Medicine [Edinburgh, UK], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh-MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council-Medical Research Council, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - Etude de familles multiplex de lupus pour l'identification de nouveaux gènes à fort impact phénotypique : de la découvertes des gènes à leurs fonctions - - Lumugene2014 - ANR-14-CE14-0026 - Appel à projets générique - VALID, Nuclease Immune Mediated Brain and Lupus-like conditions (NIMBL): natural history, pathophysiology, diagnostic and therapeutic modalities with application to other disorders of autoimmunity - NIMBL - - EC:FP7:HEALTH2010-06-01 - 2013-11-30 - 241779 - VALID, Spontaneous clearance in Patients acutely infected with HCV - Immune profiling, Novel biomarkers and X-omics approaches - SPHINX - - EC:FP7:HEALTH2010-11-01 - 2014-04-30 - 261365 - VALID, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden-Universiteit Leiden, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Technical Advances, [SDV]Life Sciences [q-bio], T-Lymphocytes, medicine.medical_treatment, Immunology, Alpha interferon, Enzyme-Linked Immunosorbent Assay, Disease, Biology, medicine.disease_cause, Sensitivity and Specificity, Severity of Illness Index, Autoimmunity, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Research Articles, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, Lupus erythematosus, Autoantibody, Interferon-alpha, medicine.disease, 3. Good health, 030104 developmental biology, Cytokine, Interferon Regulatory Factors, [SDV.IMM]Life Sciences [q-bio]/Immunology, Vesicular Stomatitis, Interferon regulatory factors
Abstract: Rodero et al. report the direct quantification of IFNα protein in monogenic interferonopathies, autoimmunity, and infectious disease states, made possible by the combination of digital ELISA and high-affinity autoantibodies isolated from APECED patients, revealing differential levels and cellular sources dependent on underlying pathology., Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.
Published: 2017
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5. Type I interferon in patients with systemic autoimmune rheumatic disease is associated with haematological abnormalities and specific autoantibody profiles

Author: John A. Reynolds, Tracy A Briggs, Vincent Bondet, Ben Parker, Ariane L. Herrick, Sahena Haque, Hector Chinoy, Leo A. H. Zeef, Eoghan M. McCarthy, Gillian I. Rice, Sathya Darmalinggam, Ian N. Bruce, Andrew Hayes, Darragh Duffy, Ellen Bruce, Mumtaz Khan, University of Manchester [Manchester], Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Salford Royal NHS Foundation Trust [Salford, UK], This research was funded by the NIHR Manchester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This work was also supported by the Centre for Epidemiology Versus Arthritis (grant number 21755). Professor Bruce is an NIHR Senior Investigator and is funded by Versus Arthritis, the National Institute for Health Research Manchester Biomedical Research Centre and the NIHR Manchester Clinical Research Facility. Funding is also acknowledged from the National Institute for Health Research (NIHR) (NIHR Transitional Research Fellowship, Dr. Tracy Briggs, TRF-2016-09-002). This study was also supported by the Medical Research Council (MR/N003322/1). DD acknowledges support from the ANR (CE17001002) and Immunoqure for provision of mAbs for Simoa., Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, interferon-alpha, autoantibodies, Mucocutaneous zone, Alpha interferon, Autoimmune Diseases, Serology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rheumatic Diseases, Internal medicine, Humans, Medicine, Whole blood, Autoantibodies, 030203 arthritis & rheumatology, business.industry, Autoantibody, Interferon-alpha, virus diseases, Middle Aged, Systemic autoimmune rheumatic disease, Rheumatology, 3. Good health, 030104 developmental biology, Interferon alpha, Interferon Type I, Cohort, Immunology, Absolute neutrophil count, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:RC925-935, Transcriptome, business, Biomarkers, Research Article
Abstract: Objectives To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. Methods We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. Results Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p
Published: 2019
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6. Dyskalemia in people at increased risk for heart failure

Author: Luca Monzo, João Pedro Ferreira, John G.F. Cleland, Pierpaolo Pellicori, Beatrice Mariottoni, Job A.J. Verdonschot, Mark R. Hazebroek, Tim J. Collier, Joe J. Cuthbert, Burkert Pieske, Frank Edelmann, Johannes Petutschnigg, Javed Khan, Fozia Z. Ahmed, Nicolas Girerd, Erwan Bozec, Javier Díez, Arantxa González, Andrew L. Clark, Franco Cosmi, Jan A. Staessen, Stephane Heymans, Patrick Rossignol, Faiez Zannad, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universidade do Porto = University of Porto, University of Glasgow, Department of Cardiology, Cortona Hospital, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], London School of Hygiene and Tropical Medicine (LSHTM), Castle Hill Hospital, University of Hull [United Kingdom], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), Manchester University NHS Foundation Trust (MFT), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Netherlands Heart Institute, European Project: 305507, BOZEC, Erwan, HOMAGE (Heart Omics in Ageing consortium) - 305507 - INCOMING, MUMC+: MA Med Staf Artsass Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, and MUMC+: MA Med Staf Spec Cardiologie (9)
Subjects: Hyperkalaemia, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, heart failure prevention, hyperkalaemia, hypokalaemia, steroidal mineralocorticoid receptor antagonist, Heart failure prevention, Cardiology and Cardiovascular Medicine, Hypokalaemia, Steroidal mineralocorticoid receptor antagonist, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: AIMS: In people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. METHODS AND RESULTS: The HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25-75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at 5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration
Published: 2022
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7. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma

Author: Dominique Bron, Catherine Thieblemont, Umberto Vitolo, M Neves, Kim Linton, Martin Dreyling, Igor Gorbatchevsky, Pier Luigi Zinzani, J. Garcia-Vargas, David Cunningham, Li Liu, Carol Peña, Karl Koechert, M. Giurescu, Barrett H. Childs, Sarit Assouline, Krimo Bouabdallah, Gregor Verhoef, Florian Hiemeyer, Franck Morschhauser, Dreyling, M, Morschhauser, F, Bouabdallah, K, Bron, D, Cunningham, D, Assouline, S. E, Verhoef, G, Linton, K, Thieblemont, C, Vitolo, U, Hiemeyer, F, Giurescu, M, Garcia-Vargas, J, Gorbatchevsky, I, Liu, L, Koechert, K, Peña, C, Neves, M, Childs, B. H, Zinzani, P. L., Klinikum der Universität [München], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Ecole de Santé Publique [Université Libre de Bruxelles], Université libre de Bruxelles (ULB), IBM Thomas J. Watson Research Center, IBM, Jewish General Hospital, University Hospitals Leuven [Leuven], Manchester University NHS Foundation Trust (MFT), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Torino (UNITO), Bayer Pharma AG [Berlin], Bayer HealthCare Pharmaceuticals Inc [Whippany], University of Bologna, Università degli studi di Torino = University of Turin (UNITO), University of Bologna/Università di Bologna, Université de Lille, CHU Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Manchester University NHS Foundation Trust [MFT], Hopital Saint-Louis [AP-HP] [AP-HP], and Università degli studi di Torino = University of Turin [UNITO]
Subjects: Male, 0301 basic medicine, Pathology, copanlisib, Lymphoma, [SDV]Life Sciences [q-bio], Follicular lymphoma, Phases of clinical research, Aggressive lymphoma, Gastroenterology, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Phosphoinositide-3 Kinase Inhibitors, Aged, 80 and over, Haematologic Malignancies, Manchester Cancer Research Centre, treatment, Lymphoma, Non-Hodgkin, Malignant lymphoma, Hematology, Middle Aged, Hodgkin Disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, Rituximab, malignant lymphoma, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, PI3K inhibitor, Neutropenia, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Survival analysis, Aged, Copanlisib, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, PTEN Phosphohydrolase, Original Articles, medicine.disease, Isoflavones, Survival Analysis, Treatment, Editor's Choice, Pyrimidines, 030104 developmental biology, chemistry, Quinazolines, business, Hématologie
Abstract: Background: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. Patients and methods: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Conclusion: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017
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8. Protein Kinase Cδ Deficiency Causes Mendelian Systemic Lupus Erythematosus With B Cell-Defective Apoptosis and Hyperproliferation

Author: Belot, Alexandre, Kasher, Paul R., Trotter, Eleanor W., Foray, Anne-Perrine, Debaud, Anne-Laure, Rice, Gillian I., Szynkiewicz, Marcin, Zabot, Marie-Therese, Rouvet, Isabelle, Bhaskar, Sanjeev S., Daly, Sarah B., Dickerson, Jonathan E., Mayer, Josephine, O'Sullivan, James, Juillard, Laurent, Urquhart, Jill E., Fawdar, Shameem, Marusiak, Anna A., Stephenson, Natalie, Waszkowycz, Bohdan, W Beresford, Michael, Biesecker, Leslie G., C M Black, Graeme, René, Céline, Eliaou, Jean-François, Fabien, Nicole, Ranchin, Bruno, Cochat, Pierre, Gaffney, Patrick M., Rozenberg, Flore, Lebon, Pierre, Malcus, Christophe, Crow, Yanick J., Brognard, John, Bonnefoy, Nathalie, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Medicine, University of Manchester [Manchester]-Faculty of Human and Medical Sciences, Paterson Institute for Cancer Research, University of Manchester [Manchester]-Cancer Research UK, Manchester Centre for Genomic Medicine, St Mary's Hospital-Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Sciences Centre, Centre de Biotechnologie cellulaire, Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], University of Liverpool, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Référence des Maladies Rénales Rares, Hospices Civil de Lyon, Oklahoma Medical Research Foundation (OMRF), Université Paris Descartes - Paris 5 (UPD5), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], and University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester
Subjects: Male, Adult, Adolescent, Mutation, Missense, Apoptosis, Polymorphism, Single Nucleotide, Article, Young Adult, Immune Tolerance, Lupus Erythematosus, Systemic, Humans, Polymorphism, Child, Cell Proliferation, B-Lymphocytes, Hyperplasia, Lupus Erythematosus, Systemic, Homozygote, Genetic Variation, Single Nucleotide, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Kinase C-delta, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Missense
Abstract: International audience; OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS: We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.
Published: 2013
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9. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173 -activating mutations in 3 children

Author: Frédéric Rieux-Laucat, Didier Bessis, Bruno Charbit, Anne Hulin, Guilhem Cros, Philippe Reix, Darragh Duffy, Thierry Walzer, Muriel Le Bourgeois, Eric Jeziorski, Alexandre Belot, Mathieu P Rodero, Monique Fabre, Christine Bodemer, Yanick J. Crow, Stéphane Blanche, Nihel Khoudour, Nadia Jeremiah, Laureline Berteloot, Bénédicte Neven, Consuelo Modesto Caballero, Gillian I. Rice, Despina Moshous, Alain Fischer, Brigitte Bader-Meunier, Marie-Louise Frémond, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie, rhumatologie et dermatologie pédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), University of Manchester [Manchester], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Nephrology-Rheumatology-Dermatology Pediatric, Bron, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de dermatologie [CHU de Montpellier], Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], CHU Henri Mondor [Créteil], Vall d'Hebron University Hospital [Barcelona], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, CHU Henri Mondor, Chaire Médecine expérimentale (A. Fischer), and Davoine, Laure-Hélène
Subjects: 0301 basic medicine, Male, Ruxolitinib, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Pharmacology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Immunology and Allergy, Medicine, Humans, Child, Preschool, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030203 arthritis & rheumatology, Mutation, Janus kinase 2, biology, Janus kinase 1, business.industry, Membrane Proteins, Janus Kinase 1, Janus Kinase 2, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 030104 developmental biology, Membrane protein, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Pyrazoles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, medicine.drug
Abstract: International audience
Published: 2016
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10. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

Author: Daphne Heijsman, Rachel Schot, Grazia M.S. Mancini, Scott D. Speer, Frans W. Verheijen, Leontine van Unen, Rob Willemsen, Zhi Li, Johan M. Kros, Femke A.T. de Vries, Grétel Oudesluijs, Aida Bertoli Avella, Dusan Bogunovic, Marije E.C. Meuwissen, Marta Martín-Fernández, Rutger W W Brouwer, Maarten H. Lequin, Irenaeus F.M. de Coo, Yanick J. Crow, Sigrid Tinschert, Wilfred F. J. van IJcken, Jeroen Dudink, Tobias Goldmann, Mark Hermann, Sofija Buta, Wendy Stam, Marco Prinz, Sandra Pellegrini, Li, Zhi, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Medical Faculty Carl Gustav Carus, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Signalisation des Cytokines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), institute of neuropathology, University of Freiburg [Freiburg], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Financial support was obtained by NutsOhra Funds project 1203-030 to G.M.S. Mancini. D. Bogunovic is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02. Z. Li and S. Pellegrini acknowledge institutional support from Institut Pasteur, Centre National de la Recherche Scientifique, and Institut National de la Santé et de la Recherche Médicale. Y.J. Crow acknowledges the European Research Council (GA 309449)., Innsbruck Medical University [Austria] (IMU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Clinical Genetics, Pathology, Radiology & Nuclear Medicine, Cell biology, Neurology, and Pediatrics
Subjects: Male, 0301 basic medicine, MESH: Signal Transduction, MESH: Interferon Type I, Microcephaly, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Calcinosis, Torch syndrome, Polymicrogyria, Immunology and Allergy, MESH: Endopeptidases, Research Articles, Genetic disorder, Brain, Calcinosis, 3. Good health, MESH: Microglia, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, Microglia, medicine.symptom, Ubiquitin Thiolesterase, Signal Transduction, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Inflammation, Biology, Nervous System Malformations, MESH: Nervous System Malformations, 03 medical and health sciences, MESH: Brain, Autoimmune Diseases of the Nervous System, Endopeptidases, medicine, Journal Article, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, MESH: Humans, Brief Definitive Report, medicine.disease, Immunity, Innate, MESH: Male, MESH: Autoimmune Diseases of the Nervous System, 030104 developmental biology, Human medicine, MESH: Female, Interferon type I, Calcification
Abstract: Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy., Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.
Published: 2016
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11. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Author: Marie Therese Zabot, Jolan E. Walter, Anne Laure Mathieu, Marie Chansel, Gillian I. Rice, Jean-Pierre de Villartay, Luigi D. Notarangelo, Christine Ménétrier-Caux, François Plenat, Nicole Fabien, Brigitte Balme, Kari C. Nadeau, Chantal Rigal, E. Helen Kemp, Annick Lim, Christophe Malcus, Yves Bertrand, Sébastien Viel, Mirjam van der Burg, Despina Moshous, Jacques Bienvenu, A. Phan, Christine Bardin, Catharina Schuetz, Thierry Walzer, Christophe Caux, Capucine Picard, Ana Delgado, David J. Chen, Manish J. Butte, Krisztian Csomos, Isabelle Rouvet, Karin Chen, Jean François Meritet, Alexandre Belot, Héloïse Reumaux, Fanny Fouyssac, Pierre Cochat, Yanick J. Crow, Estelle Verronese, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Service d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Immunology and Inflammatory Diseases [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Department of Microbiology and Immunology [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Texas Southwestern Medical Center, University of Utah School of Medicine [Salt Lake City], Department of Pediatrics and Adolescent Medicine, Universität Ulm - Ulm University [Ulm, Allemagne], Unité Pédiatrique [Jeanne de Flandre], Hôpital Jeanne de Flandre [Lille], Service de Pathologie [CHRU Nancy], Epidémiologie, Pharmacologie, Investigation Clinique, Information médicale, Mère-Enfant (EPICIME), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Sheffield [Sheffield], Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France, parent, Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Institut Pasteur [Paris] (IP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine, St Mary's Hospital-Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Sciences Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology and Immunology, Stanford University School of Medicine [CA, USA], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], and Immunology
Subjects: Male, DNA End-Joining Repair, Skin Neoplasms, DCLRE1C, Autoimmunity, DNA-Activated Protein Kinase, medicine.disease_cause, DNA-Dependent Protein Kinase Catalytic Subunit, Immune tolerance, Mice, Immunology and Allergy, DNA-PKcs, B-Lymphocytes, Granuloma, tolerance, PRKDC, recombination-activating gene, V(D)J recombination, Nuclear Proteins, severe combined immunodeficiency, Autoimmune regulator, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adolescent, Immunology, Biology, Article, Young Adult, Th2 Cells, SDG 3 - Good Health and Well-being, medicine, Immune Tolerance, Animals, Humans, Autoantibodies, Severe combined immunodeficiency, Immunologic Deficiency Syndromes, Th1 Cells, VDJ recombination, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, V(D)J Recombination, Gene Expression Regulation, DNA-dependent protein kinase catalytic subunit, Mutation, Cancer research, Transcription Factors
Abstract: International audience; BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T~cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in~vitro. The latter defect correlated in~vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1~had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
Published: 2015
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12. Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

Author: Yanick J. Crow, Catherine Morrissey, Leo A. H. Zeef, Emma M. Jenkinson, Gillian I. Rice, Valérie Briolat, Jean-Pierre Levraud, David Gent, Paul R. Kasher, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Macrophages et Développement de l'Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Faculty of Life Sciences [Manchester], University of Manchester [Manchester], 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 de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), This work was supported by the Newlife Foundation, the Natalie Kate Moss Trust, the European Research Council (GA 309449: fellowship to Y.J.C.), and state subsidies managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01 and the 'Zebraflam' program bearing the reference ANR-10-MIDI-009., We thank Dr. Adam Hurlstone and Dr. Shane Herbert for sharing zebrafish strains and equipment and Mike Jackson at the University of Manchester Flow Cytometry Facility for technical support., ANR-10-MIDI-0009,ZebraFlam,Signaux et cellules de la réponse inflammatoire: suivi en temps réel chez un vertébré entier, le danio zébré(2010), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), 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), Briolat, Valérie, and MECANISMES INTEGRES DE L'INFLAMMATION - Signaux et cellules de la réponse inflammatoire: suivi en temps réel chez un vertébré entier, le danio zébré - - ZebraFlam2010 - ANR-10-MIDI-0009 - MI2 - VALID
Subjects: MESH: Interferon Type I, Adenosine Deaminase, MESH: Sequence Homology, Amino Acid, [SDV]Life Sciences [q-bio], ved/biology.organism_classification_rank.species, MESH: Microscopy, Fluorescence, MESH: Amino Acid Sequence, MESH: Acid Anhydride Hydrolases, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Cerebral Ventricles, Animals, Genetically Modified, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Developmental, Immunology and Allergy, MESH: Animals, MESH: Interferons, Zebrafish, MESH: Adenosine Deaminase, Gene knockdown, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, MESH: Rhombencephalon, MESH: SAM Domain and HD Domain-Containing Protein 1, Acid Anhydride Hydrolases, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Gene Knockdown Techniques, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, Intracranial Hemorrhages, MESH: Intracranial Hemorrhages, [SDV.IMM] Life Sciences [q-bio]/Immunology, Blotting, Western, Molecular Sequence Data, Immunology, MESH: Zebrafish Proteins, Biology, Nervous System Malformations, MESH: Nervous System Malformations, SAM Domain and HD Domain-Containing Protein 1, MESH: Animals, Genetically Modified, Autoimmune Diseases of the Nervous System, Immune system, medicine, Animals, Humans, MESH: Blotting, Western, Amino Acid Sequence, Model organism, MESH: Zebrafish, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Loss function, Innate immune system, MESH: Humans, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, ved/biology, Morphant, Zebrafish Proteins, medicine.disease, biology.organism_classification, MESH: Gene Knockdown Techniques, Immunity, Innate, MESH: Autoimmune Diseases of the Nervous System, Rhombencephalon, Disease Models, Animal, Microscopy, Fluorescence, Aicardi–Goutières syndrome, MESH: Cerebral Ventricles, Interferons, MESH: Disease Models, Animal
Abstract: In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism.
Published: 2015
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13. Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study

Author: Lee, S. I., Azcoaga-Lorenzo, A., Agrawal, U., Kennedy, J. I., Fagbamigbe, A. F., Hope, H., Subramanian, A., Anand, A., Taylor, B., Nelson-Piercy, C., Damase-Michel, C., Yau, C., Crowe, F., Santorelli, G., Eastwood, K-A., Vowles, Z., Loane, M., Moss, N., Brocklehurst, P., Plachcinski, R., Thangaratinam, S., Black, M., O'Reilly, D., Abel, K. M., Brophy, S., Nirantharakumar, K., McCowan, C., MuM-PreDiCT Group, University of St Andrews. Population and Behavioural Science Division, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of Birmingham [Birmingham], University of St Andrews [Scotland], Swansea University, University of Ibadan, University of Manchester [Manchester], Guy's and St Thomas NHS Foundation Trust [London], Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bradford Institute for Health Research [Bradford, UK], Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), Queen's University [Belfast] (QUB), University Hospitals Bristol, University of Ulster, Patient and Public Representative [London, UK] (P&PR), Birmingham Women's and Children's NHS Foundation Trust, University of Aberdeen, Manchester University NHS Foundation Trust (MFT), MuM-PreDiCT Group, and Malbec, Odile
Subjects: Adult, Adolescent, Epidemiology, [SDV]Life Sciences [q-bio], Maternity, Datasets as Topic, E-DAS, RT, Young Adult, SDG 3 - Good Health and Well-being, RA0421, Pregnancy, RA0421 Public health. Hygiene. Preventive Medicine, Prevalence, Humans, MCC, Multiple long-term conditions, United Kingdom/epidemiology, Obstetrics and Gynecology, Multimorbidity, Gynecology and obstetrics, Middle Aged, United Kingdom, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, Multiple chronic conditions, RG Gynecology and obstetrics, RG1-991, Female, Pregnant Women, RG, Routinely Collected Health Data
Abstract: Background Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). Study design Pregnant women aged 15–49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. Results The prevalence of multimorbidity was 44.2% (95% CI 43.7–44.7%), 46.2% (45.6–46.8%) and 19.8% (18.8–20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8–24.6%], 23.5% [23.0–24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8–31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04–3.17] 45–49 years vs 15–19 years), multigravid (1.68 [1.50–1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44–1.76], body mass index 30+ vs body mass index 18.5–24.9) and smoked preconception (1.61 [1.46–1.77) vs non-smoker). Conclusion Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.
Published: 2022
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14. An overview of using fungal DNA for the diagnosis of invasive mycoses

Author: P. Lewis White, Alexandre Alanio, Lottie Brown, Mario Cruciani, Ferry Hagen, Rebecca Gorton, Michaela Lackner, Laurence Millon, C. Oliver Morton, Riina Rautemaa-Richardson, Rosemary A. Barnes, J Peter Donnelly, Juergen Loffler, Public Health Wales [Cardiff, Royaume uni], Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Manchester University NHS Foundation Trust (MFT), Fungal PCR Initiative (FPCRI), University Medical Center [Utrecht], National Health Laboratory Services, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Western Sydney University, Cardiff University, and University Hospital Wuerzburg / Universitätsklinikum Würzburg
Subjects: MESH: Fungi, mucorales PCR, MESH: Molecular Diagnostic Techniques, Polymerase Chain Reaction, Pathology and Forensic Medicine, Genetics, Humans, candida PCR, Fungi/genetics, DNA, Fungal, Molecular Biology, aspergillus PCR, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Fungal/genetics, PCP PCR, Fungi, MESH: Polymerase Chain Reaction, DNA, fungal PCR, MESH: DNA, Fungal, Molecular Diagnostic Techniques, Molecular Medicine, Invasive fungal disease, Invasive Fungal Infections/diagnosis, Invasive Fungal Infections, MESH: Invasive Fungal Infections
Abstract: Introduction: Fungal PCR has undergone considerable standardization and together with the availability of commercial assays, external quality assessment schemes and extensive performance validation data, is ready for widespread use for the screening and diagnosis of invasive fungal disease (IFD).Areas Covered: Drawing on the experience and knowledge of the leads of the various working parties of the Fungal PCR initiative, this review will address general considerations concerning the use of molecular tests for the diagnosis of IFD, before focussing specifically on the technical and clinical aspects of molecular testing for the main causes of IFD and recent technological developments.Expert Opinion: For infections caused by Aspergillus, Candida and Pneumocystis jirovecii, PCR testing is recommended, combination with serological testing will likely enhance the diagnosis of these diseases. For other IFD (e.g. Mucormycosis) molecular diagnostics, represent the only non-classical mycological approach towards diagnoses and continued performance validation and standardization has improved confidence in such testing. The emergence of antifungal resistance can be diagnosed, in part, through molecular testing. Next-generation sequencing has the potential to significantly improve our understanding of fungal phylogeny, epidemiology, pathogenesis, mycobiome/microbiome and interactions with the host, while identifying novel and existing mechanisms of antifungal resistance and novel diagnostic/therapeutic targets.
Published: 2022
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15. Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

Author: Lien Van Eyck, Isabelle Melki, Carolina Uggenti, Frédéric Rieux-Laucat, Yanick J. Crow, Eric Legius, Isabelle Meyts, Petra De Haes, Marie-Louise Frémond, Stefano Volpi, Marie-Anne Morren, Mathieu P Rodero, Harm A.W.M. Tiddens, Yoann Rose, Carine Wouters, Christine Bodemer, Nadia Jeremiah, Anniek Corveleyn, Gillian I. Rice, Marco Gattorno, Suzanne W J Terheggen-Lagro, Anais Boulai, Emma M. Jenkinson, Isabelle Callebaut, Naoki Kitabayashi, Olivero Sacco, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Academic Unit of Medical Genetic, University of Manchester [Manchester], Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pediatrics, Radiology & Nuclear Medicine, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], and Rodero, Mathieu
Subjects: Adult, Male, 0301 basic medicine, Cellular pathology, Adolescent, [SDV]Life Sciences [q-bio], Immunology, Biology, medicine.disease_cause, TMEM173, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Interferon, medicine, Humans, Immunology and Allergy, Child, ComputingMilieux_MISCELLANEOUS, Inflammation, Mutation, Janus kinase 1, Membrane Proteins, type I interferonopathy, interferon, Stimulator of interferon genes (STING), 3. Good health, [SDV] Life Sciences [q-bio], Sting, HEK293 Cells, STAT1 Transcription Factor, 030104 developmental biology, Amino Acid Substitution, 030220 oncology & carcinogenesis, Stimulator of interferon genes, Interferon Type I, Cancer research, Female, STING-associated vasculopathy with onset in infancy, IRF3, Signal Transduction, Interferon type I, medicine.drug
Abstract: BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
Published: 2017
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16. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Author: Ahmad S. Halwani, Carlos Panizo, Iris Isufi, Alex F. Herrera, Craig Y. Okada, Elizabeth H. Cull, Bela Kis, Jorge M. Chaves, Nancy L. Bartlett, Weiyun Ai, Luis de la Cruz-Merino, Locke J. Bryan, Roch Houot, Kim Linton, Javier Briones, Ian Chau, Gottfried R. von Keudell, Hailing Lu, Adam Yakovich, Michael Chen, ter Meulen JH, Sergey Yurasov, Frank J. Hsu, Christopher R. Flowers, University of Utah, Clínica Universidad de Navarra [Pamplona], Universidad de Navarra [Pamplona] (UNAV), Yale University School of Medicine, H. Lee Moffitt Cancer Center and Research Institute, North-West University [Potchefstroom] (NWU), University of California [San Francisco] (UCSF), University of California, University of Sevilla, Augusta University, University System of Georgia (USG), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Manchester University NHS Foundation Trust (MFT), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], Immune Design Corp., Yale School of Medicine [New Haven, Connecticut] (YSM), University of California [San Francisco] (UC San Francisco), University of California (UC), Universidad de Sevilla / University of Sevilla, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0303 health sciences, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Antibodies, Monoclonal, Humanized, 3. Good health, Toll-Like Receptor 4, 03 medical and health sciences, 0302 clinical medicine, follicular lymphoma, Oncology, glucopyranosyl lipid A, 030220 oncology & carcinogenesis, Antineoplastic Combined Chemotherapy Protocols, Humans, TLR4, immunotherapy, pembrolizumab, Lymphoma, Follicular, 030304 developmental biology
Abstract: International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
Published: 2021
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17. Novel DNM1L variants impair mitochondrial dynamics through divergent mechanisms

Author: Kelsey A Nolden, John M Egner, Jack J Collier, Oliver M Russell, Charlotte L Alston, Megan C Harwig, Michael E Widlansky, Souphatta Sasorith, Inês A Barbosa, Andrew GL Douglas, Julia Baptista, Mark Walker, Deirdre E Donnelly, Andrew A Morris, Hui Jeen Tan, Manju A Kurian, Kathleen Gorman, Santosh Mordekar, Charu Deshpande, Rajib Samanta, Robert McFarland, R Blake Hill, Robert W Taylor, Monika Oláhová, Medical College of Wisconsin [Milwaukee] (MCW), Newcastle University [Newcastle], McGill University = Université McGill [Montréal, Canada], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), King‘s College London, University Hospital Southampton NHS Foundation Trust, University of Southampton, Plymouth University, Belfast City Hospital, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Central Manchester University Hospitals [Manchester, U.K.], University College of London [London] (UCL), Children's Health Ireland [Crumlin, Dublin, Ireland] (CHI), University College Dublin [Dublin] (UCD), Sheffield Children's NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust [London, UK], University Hospitals Leicester, and MORNET, Dominique
Subjects: [SDV] Life Sciences [q-bio], Ecology, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract: Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like geneDNM1L, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathologicalDNM1Lvariants impair mitochondrial network maintenance by divergent mechanisms.
Published: 2022
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18. Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis

Author: James M Gwinnutt, Sam Norton, Kimme L Hyrich, Mark Lunt, Bernard Combe, Nathalie Rincheval, Adeline Ruyssen-Witrand, Bruno Fautrel, Daniel F McWilliams, David A Walsh, Elena Nikiphorou, Patrick D W Kiely, Adam Young, Jacqueline R Chipping, Alex MacGregor, Suzanne M M Verstappen, Gestionnaire, HAL Sorbonne Université 5, University of Manchester [Manchester], King‘s College London, Manchester University NHS Foundation Trust (MFT), Université de Montpellier (UM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Rhumatologie [CHU Pitié Salpêtrière], 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), Pharmacoépidémiologie et évaluation des soins [iPLesp] (PEPITES), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Nottingham, UK (UON), St George’s University Hospitals, University of Hertfordshire [Hatfield] (UH), and University of East Anglia [Norwich] (UEA)
Subjects: Inflammation, [SDV]Life Sciences [q-bio], Pain, Antirheumatic Agents/therapeutic use, Severity of Illness Index, Biomedical Research Centre, Arthritis, Rheumatoid, [SDV] Life Sciences [q-bio], Disability Evaluation, Rheumatology, Arthritis, Rheumatoid/drug therapy, Pain/drug therapy, Antirheumatic Agents, Inflammation/drug therapy, Humans, Fatigue/drug therapy, Female, Pharmacology (medical), Prospective Studies, Arthritis Research Campaign National Pain Centre, Medical Science, Fatigue
Abstract: Objectives To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation. Methods Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, Results This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8); women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories. Conclusion Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.
Published: 2022
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19. Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Author: Yverneau, Mathilde, Leroux, Stéphanie, Imbard, Apolline, Gleich, Florian, Arion, Alina, Moreau, Caroline, Nassogne, Marie-Cécile, Szymanowski, Marie, Tardieu, Marine, Touati, Guy, Bueno, María, Chapman, Kimberly A, Chien, Yin-Hsiu, Huemer, Martina, Ješina, Pavel, Janssen, Mirian C H, Kölker, Stefan, Kožich, Viktor, Lavigne, Christian, Lund, Allan Meldgaard, Mochel, Fanny, Morris, Andrew, Pons, Mónica Ruiz, Porras-Hurtado, Gloria Liliana, Benoist, Jean-François, Damaj, Léna, Schiff, Manuel, E-HOD Consortium, CHU Pontchaillou [Rennes], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Heidelberg University Hospital [Heidelberg], Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hospital Universitario Virgen del Rocío [Sevilla], Children’s National Health System [Washington, DC, USA], National Taiwan University [Taiwan] (NTU), University Children’s Hospital Zurich, Charles University [Prague] (CU), Radboud University Medical Center [Nijmegen], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Copenhagen University Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Manchester University NHS Foundation Trust (MFT), Hospital Universitario N.S. de Candelaria [Santa Cruz de Tenerife, Spain], Hôpital Robert Debré Paris, Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), European Union [739543], EU-project phase [2012 12 02], SOBI, Recordati Rare Disease Foundation, Aeglea, and Jonchère, Laurent
Subjects: newborn screening, [SDV]Life Sciences [q-bio], MTHFR deficiency, Infant, Newborn, neurodevelopmental outcome, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], digestive system diseases, [SDV] Life Sciences [q-bio], Cohort Studies, homocystinuria, Psychotic Disorders, EHOD, Muscle Spasticity, Genetics, Humans, remethylation defects, Homocystinuria, Homocysteine, Genetics (clinical), Methylenetetrahydrofolate Reductase (NADPH2), Retrospective Studies
Abstract: Contains fulltext : 286882.pdf (Publisher’s version ) (Closed access) MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.
Published: 2022
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20. A New Approach to Objectively Evaluate Inherited Metabolic Diseases for Inclusion on Newborn Screening Programmes

Author: Alberto Burlina, Simon A. Jones, Anupam Chakrapani, Heather J. Church, Simon Heales, Teresa H. Y. Wu, Georgina Morton, Patricia Roberts, Erica F. Sluys, David Cheillan, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Manchester University NHS Foundation Trust (MFT), St Mary's Hospital [London], Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), ArchAngel MLD Trust [London, UK] (2A), Helvet Health [Nyon, Switzerland] (2H), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), and CarMeN, laboratoire
Subjects: congenital disorders, inherited disorder, newborn screening (NBS), Wilson and Jungner, [SDV]Life Sciences [q-bio], public health, Obstetrics and Gynecology, inherited metabolic disease, paediatrics, rare diseases, genetics, methodology, [SDV] Life Sciences [q-bio], Immunology and Microbiology (miscellaneous), Pediatrics, Perinatology and Child Health
Abstract: International audience; Newborn screening (NBS) programmes are essential in the diagnosis of inherited metabolic diseases (IMDs) and for access to disease modifying treatment. Most European countries follow the World Health Organisation (WHO) criteria to determine which disorders are appropriate for screening at birth; however, these criteria are interpreted and implemented by individual countries differently, creating disparities. Advances in research and diagnostics, together with the promise of new treatments, offer new possibilities to accelerate the expansion of evidence-based screening programmes. A novel and robust algorithm was built to objectively assess and prioritise IMDs for inclusion in NBS programmes. The Wilson and Jungner classic screening principles were used as a foundation to develop individual and measurable criteria. The proposed algorithm is a point-based system structured upon three pillars: condition, screening, and treatment. The algorithm was tested by applying the six IMDs currently approved in the United Kingdom NBS programme. The algorithm generates a weight-based score that could be used as the first step in the complex process of evaluating disorders for inclusion on NBS programmes. By prioritising disorders to be further evaluated, individual countries are able to assess the economic, societal and political aspects of a potential screening programme.
Published: 2022
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21. Treatment outcome definitions in chronic pulmonary aspergillosis: a CPAnet consensus statement

Author: Eva Van Braeckel, Iain Page, Jesper Rømhild Davidsen, Christian B. Laursen, Ritesh Agarwal, Ana Alastruey-Izquierdo, Aleksandra Barac, Jacques Cadranel, Arunaloke Chakrabarti, Oliver A. Cornely, David W. Denning, Holger Flick, Jean-Pierre Gangneux, Cendrine Godet, Yuta Hayashi, Christophe Hennequin, Martin Hoenigl, Muhammed Irfan, Koichi Izumikawa, Won-Jun Koh, Chris Kosmidis, Christoph Lange, Bernd Lamprecht, Francois Laurent, Oxana Munteanu, Rita Oladele, Thomas F. Patterson, Akira Watanabe, Helmut J.F. Salzer, Universiteit Gent = Ghent University (UGENT), University of Southern Denmark (SDU), Instituto de Salud Carlos III [Madrid] (ISC), University of Belgrade [Belgrade], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Post Graduate Institute of Medical Education & Research [Chandigarh, India], German Center for Infectious Research - partner site Tübingen [Tübingen, Allemagne] (DZIF), University of Cologne, University of Manchester [Manchester], Medical University of Graz, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California [San Diego] (UC San Diego), University of California (UC), The Aga Khan University, Nagasaki University, Sungkyunkwan University [Suwon] (SKKU), Manchester University NHS Foundation Trust (MFT), Karolinska Institute, Universität zu Lübeck = University of Lübeck [Lübeck], University Nicolae Testemitanu [Kishinev, Moldova] (UNT), University of Lagos, University of North Texas Health Science Center [Fort Worth], Chiba University, and Kepler University Hospital
Subjects: Pulmonary and Respiratory Medicine, Consensus, Treatment Outcome, [SDV]Life Sciences [q-bio], Medicine and Health Sciences, MANAGEMENT, Humans, Persistent Infection, Pulmonary Aspergillosis, GUIDELINES, DIAGNOSIS, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021
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22. Differential levels of IFNα subtypes in autoimmunity and viral infection

Author: Bondet, Vincent, Rodero, Mathieu, Posseme, Céline, Bost, Pierre, Decalf, Jérémie, Haljasmägi, Liis, Bekaddour, Nassima, Rice, Gillian, Upasani, Vinit, Herbeuval, Jean-Philippe, Reynolds, John, Briggs, Tracy, Bruce, Ian, Mauri, Claudia, Isenberg, David, Menon, Madhvi, Hunt, David, Schwikowski, Benno, Mariette, Xavier, Pol, Stanislas, Rozenberg, Flore, Cantaert, Tineke, Eric Gottenberg, J., Kisand, Kai, Duffy, Darragh, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Biologie systémique - Systems Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Tartu, University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Immunologie [Phnom Penh], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of Birmingham [Birmingham], Sandwell and West Birmingham NHS Trust (Sandwell General Hospital), University College of London [London] (UCL), University of Edinburgh, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Strasbourg (UNISTRA), We acknowledge support from the ANR (CE17001002) awarded to DD., ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Institut Pasteur [Paris], Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, TLR activation, Adolescent, Anti-IFNα autoantibodies, Infant, Interferon-alpha, Autoimmunity, Middle Aged, IFNα subtypes, Antiviral Agents, Young Adult, IFN function, Virus Diseases, Viral infection, Child, Preschool, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Child, Aged
Abstract: International audience; Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.
Published: 2021
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23. HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Author: John M. Graham, Anna Ardissone, Dieter Kotzot, Paul R. Mark, Anna Zachariou, Guillermo Lay-Son, Allyn McConkie-Rosell, John Pappas, Karen Low, Fiona Stewart, Chey Loveday, Brian G. Skotko, Melissa Lees, Helen Stewart, Ho Ming Luk, Cheryl Cytrynbaum, Rachel Horton, Siddharth Banka, Gerard Marion, Deborah J. Shears, Marie T. McDonald, Ricardo A. Verdugo, Christine Coubes, Yuri A. Zarate, Christophe Phillipe, Katrina Tatton-Brown, Clare Allen, Deepika D.Cunha Burkardt, Rosanna Weksberg, I. Karen Temple, Alexia Bourgois, David J. Amor, Frédéric Tran Mau-Them, Laurence Faivre, Case Western Reserve University [Cleveland], The institute of cancer research [London], University College London Hospitals (UCLH), Murdoch Children's Research Institute (MCRI), University of Melbourne, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The Hospital for sick children [Toronto] (SickKids), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), University Hospital Southampton NHS Foundation Trust, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Pontificia Universidad Católica de Chile (UC), Great Ormond Street Hospital for Children [London] (GOSH), University Hospitals Bristol, Department of Health Clinical Genetic Service Centre, Spectrum Health [Grand Rapids], Department of Molecular Genetics and Microbiology [Durham] (MGM), Duke University [Durham], New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Harvard Medical School [Boston] (HMS), Belfast City Hospital, Oxford University Hospitals NHS Trust, University of Oxford [Oxford], University of Southampton, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Universitad de Chile, Arkansas Children's Hospital, Cedars-Sinai Medical Center, St George’s University Hospitals, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Heterozygote, Bioinformatics, Corpus callosum, Rahman syndrome, Histones, 03 medical and health sciences, Frontal Bossing, 0302 clinical medicine, HIST1H1E, Gene cluster, Intellectual disability, Genetics, Humans, Learning, Medicine, Epigenetics, Genetics (clinical), 030304 developmental biology, Behavior, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, epigenetic regulator gene, biology, business.industry, Facies, Heterozygote advantage, Syndrome, medicine.disease, Phenotype, Histone, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Mutation, biology.protein, Growth and Development, business, 030217 neurology & neurosurgery
Abstract: International audience; Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.
Published: 2019
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24. Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability

Author: Janet Williams, Amanda G. Wood, Adam Jackson, Robert W.M. Walker, Neelo Aslam, John Dean, Myfanwy Rawson, Latha Hackett, Iain A. Bruce, Peter D. Turnpenny, Rebecca Bromley, Ruth Day, Verna Cuthbert, Lena Westbom, Hubert Journel, Jill Clayton-Smith, Gregory James, Sylvie Odent, Edmund J. Ladusans, Jane Ashworth, Gemma Arca Diaz, Sangeet Sidhu, Heli Malm, Daniel Hindley, Catrina Dyer, Manchester University NHS Foundation Trust (MFT), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Helsinki, CHAFEA [HP-ERN-SGA-2017 - 769045], HUS Emergency Medicine and Services, Department of Diagnostics and Therapeutics, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Expert consensus, lcsh:Medicine, CHILDREN, FOLIC-ACID, 030105 genetics & heredity, Guideline, 0302 clinical medicine, Fetal Valproate Spectrum Disorder, Pregnancy, Intellectual disability, Pharmacology (medical), Spectrum disorder, Prospective Studies, Position Statement, Genetics (clinical), EPILEPSY, ComputingMilieux_MISCELLANEOUS, Neuropsychology, 1184 Genetics, developmental biology, physiology, Cognition, General Medicine, 3. Good health, Management, Teratogens, PREGNANCY, Anticonvulsants, Female, Antiepileptic drug, COGNITIVE OUTCOMES, medicine.medical_specialty, Consensus, ANTIEPILEPTIC DRUG EXPOSURE, Fetal valproate syndrome, SPINA-BIFIDA, 03 medical and health sciences, Intellectual Disability, medicine, Humans, MAJOR MALFORMATIONS, Psychiatry, business.industry, Valproic Acid, Uterus, lcsh:R, SODIUM VALPROATE, Evidence-based medicine, medicine.disease, Teratogen, Teratology, Pregnancy Complications, IN-UTERO EXPOSURE, business, 030217 neurology & neurosurgery, Medical literature
Abstract: Background A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. Methods An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. Results Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. Conclusion The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals. Electronic supplementary material The online version of this article (10.1186/s13023-019-1064-y) contains supplementary material, which is available to authorized users.
Published: 2019
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25. Predictors of cognitive, behavioural and academic difficulties in NF1

Author: Annukka Lehtonen, Jonathan Green, Lauren Manderson, Marie-Maude Geoffray, Grace Vassallo, Louise Robinson, Shruti Garg, Kavitha Chinnappa Ramamurthy, Sylvie Tordjman, Julieta O’Flaherty, Centre Hospitalier le Vinatier [Bron], University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Faculty of Biology, Medicine and Health [Manchester, UK], Oxford University Hospitals NHS Trust, University of Oxford [Oxford], Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Centre Hospitalier Guillaume Régnier [Rennes], University of Oxford, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Université de Rennes (UR)
Subjects: Parents, congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, [SDV]Life Sciences [q-bio], Population, Socio-economic status, Psychological intervention, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Cognition, medicine, Early Intervention, Educational, Humans, Family history, Remedial education, education, Child, Socioeconomic status, Biological Psychiatry, education.field_of_study, medicine.disease, 3. Good health, 030227 psychiatry, nervous system diseases, Psychiatry and Mental health, Clinical research, NF1, Cognitive and behavioural development, Psychology, Cognition Disorders, 030217 neurology & neurosurgery, Clinical psychology
Abstract: International audience; The impact of the Neurofibromatosis type 1 (NF1) on cognition have been subject to much clinical investigation, but environmental modifiers of disease expression have not yet been systematically investigated. The aim of this paper is to determine the role of demographic and environmental factors such as age, sex, socioeconomic status, parental NF1 status and neurological complications on the cognitive, behavioural and academic outcomes in NF1. Participants included 206 children aged 4-18 years seen within the Manchester clinical research NF1 service. Multiple linear regression models were used to study the effect of the hypothesized predictor variables on cognitive, behavioural and academic outcomes. Relative to population norms, 80% of the NF1 sample demonstrated significantly lower scores in at least one cognitive, behavioural or academic domains. Family history of NF1 and lower SES were independently associated with poorer cognitive, behavioural and academic outcomes. Neurological problems such as epilepsy and hydrocephalus were associated with lower IQ and academic skills. Cognitive and behavioural phenotypes emerge commonly via a complex interplay between genes and environmental factors, and this is true also of a monogenic condition such as NF1. Early interventions and remedial education may be targeted to risk groups such those with familial NF1, families with lower SES and those with associated neurological comorbidities.
Published: 2021
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26. Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method

Author: Ognjen Gajic, Samuel M. Galvagno, Elie Azoulay, Adam M. Deane, Jan Bakker, Massimo Antonelli, Sangeeta Mehta, Pauline K. Park, Yaseen M. Arabi, David Pilcher, Krishnaswamy Sundararajan, Gopi C. Khilnani, Paolo Pelosi, Suveer Singh, Laurent Brochard, Younsuck Koh, Bin Du, Massimiliano Sorbello, Waleed Alhazzani, Jason Phua, Lise Piquilloud, John Victor Peter, Prashant Nasa, Sachin Gupta, Armand Mekontso-Dessap, Manu L N G Malbrain, Sharon Einav, Michael T. McCurdy, Manu Shankar-Hari, Claude Guérin, Yash Javeri, Jean-Baptiste Lascarrou, Samir Jaber, Ashish Khanna, Jordi Mancebo, Pradeep Rangappa, Deven Juneja, Andrés Esteban, Sheila Nainan Myatra, Marcus J. Schultz, Ravindranath Tiruvoipati, Andrew A. Udy, Brendan McGrath, Flávia Ribeiro Machado, Michael Nurok, Tobias Welte, Mervyn Mer, Ravi Jain, Peter Schellongowski, NMC Specialty Hospital, Al Nahda, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Mahatma Gandhi Hospital, Narayana Super Speciality Hospital, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, King Saud Bin Abdulaziz University for Health Sciences [Riyadh] (KSAU-HS), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Pontificia Universidad Católica de Chile (UC), Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], The Royal Melbourne Hospital, Peking Union Medical College Hospital [Beijing] (PUMCH), Shaare Zedek Medical Center [Jerusalem, Israel], CIBER de Epidemiología y Salud Pública (CIBERESP), Mayo Clinic, University of Maryland School of Medicine, University of Maryland System, 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), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Ulsan, Centre hospitalier universitaire de Nantes (CHU Nantes), Federal University of Sao Paulo (Unifesp), International Fluid Academy, Vrije Universiteit Brussel [Bruxelles] (VUB), Hospital Universitari Sant Pau, Barcelona, Manchester University NHS Foundation Trust (MFT), Manchester Academic Health Sciences Centre [Manchester, UK], Mount Sinai Health System, Hôpital Henri Mondor, Groupe de recherche clinique CARMAS (Cardiovascular and Respiratory Manifestations of Acute lung injury and Sepsis) (CARMAS), CHU Tenon [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)-CHU Henri Mondor, University of the Witwatersrand [Johannesburg] (WITS), Cedars-Sinai Medical Center, University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Ospedale Policlinico San Martino [Genoa], Università degli studi di Genova = University of Genoa (UniGe), Christian Medical College and Hospital Ludhiana [Punjab, India] (CMCHL), National and Kapodistrian University of Athens (NKUA), Monash University [Melbourne], Lausanne University Hospital, Medizinische Universität Wien = Medical University of Vienna, VU University Medical Center [Amsterdam], Mahidol University [Bangkok], University of Oxford [Oxford], Guy's and St Thomas' Hospital [London], King‘s College London, Royal Brompton Hospital, Chelsea and Westminster Hospital, Monash College [Melbourne], German Center for Lung Research - DZL [Munich, Germany], Tata Memorial Centre, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, ACS - Pulmonary hypertension & thrombosis, Intensive Care Medicine, AII - Infectious diseases, ACS - Diabetes & metabolism, ACS - Microcirculation, and Epidemiology
Subjects: medicine.medical_specialty, ARDS, COVID-19 acute respiratory distress syndrome, Consensus, Delphi Technique, medicine.medical_treatment, education, Delphi method, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Prone ventilation, 03 medical and health sciences, 0302 clinical medicine, Respiratory Insufficiency/therapy, COVID-19 high flow nasal oxygen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, COVID-19 respiratory management, medicine, Humans, COVID-19/complications, Respiratory Insufficiency/virology, COVID 19 invasive mechanical ventilation, COVID-19 ventilatory management, Respiratory distress syndrome adult, Intensive care medicine, Personal protective equipment, Positive end-expiratory pressure, 11 Medical and Health Sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, business.industry, Research, Tracheal intubation, lcsh:Medical emergencies. Critical care. Intensive care. First aid, COVID-19, 030208 emergency & critical care medicine, lcsh:RC86-88.9, medicine.disease, Emergency & Critical Care Medicine, COVID-19 high fow nasal oxygen, 3. Good health, 030228 respiratory system, Respiratory failure, Breathing, business, Respiratory Insufficiency
Abstract: Background Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. Methods Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p Results Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16–24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. Conclusion Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. Trial registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.
Published: 2021
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27. Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial

Author: Kerri A. Johannson, Marlies S. Wijsenbeek, Imre Noth, Tamera J. Corte, Andreas Michael, Anne-Marie Russell, Nazia Chaudhuri, Klaus B Rohr, Manuel Quaresma, Susanne Stowasser, Toby M. Maher, Vincent Cottin, Stéphane Jouneau, University of Virginia, Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Manchester University NHS Foundation Trust (MFT), The University of Sydney, University of Calgary, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Syneos Health Farnborough, Boehringer Ingelheim Pharma GmbH & Co. KG, University of Exeter Medical School, University of Exeter, Imperial College London, Royal Brompton Hospital, Keck School of Medicine [Los Angeles], University of Southern California (USC), Boehringer Ingelheim, National Institute for Health Research, British Lung Foundation, Pulmonary Medicine, Chard-Hutchinson, Xavier, University of Virginia [Charlottesville], Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Vital capacity, [SDV]Life Sciences [q-bio], Vital Capacity, Respiratory System, Placebo, Interstitial Lung Disease, law.invention, 03 medical and health sciences, chemistry.chemical_compound, FEV1/FVC ratio, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Original Research Articles, medicine, Humans, In patient, 030212 general & internal medicine, 11 Medical and Health Sciences, medicine.diagnostic_test, business.industry, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, 3. Good health, respiratory tract diseases, [SDV] Life Sciences [q-bio], Treatment Outcome, 030228 respiratory system, chemistry, Nintedanib, business, INMARK trial investigators
Abstract: Background Data from the INMARK trial were used to investigate the feasibility and validity of home spirometry as a measure of lung function decline in patients with idiopathic pulmonary fibrosis (IPF). Methods Subjects with IPF and preserved forced vital capacity (FVC) were randomised to receive nintedanib or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Clinic spirometry was conducted at baseline and weeks 4, 8, 12, 16, 20, 24, 36 and 52. Subjects were asked to perform home spirometry at least once a week and ideally daily. Correlations between home- and clinic-measured FVC and rates of change in FVC were assessed using Pearson correlation coefficients. Results In total, 346 subjects were treated. Mean adherence to weekly home spirometry decreased over time but remained above 75% in every 4-week period. Over 52 weeks, mean adherence was 86%. Variability in change from baseline in FVC was greater when measured by home rather than clinic spirometry. Strong correlations were observed between home- and clinic-measured FVC at all time-points (r=0.72–0.84), but correlations between home- and clinic-measured rates of change in FVC were weak (r=0.26 for rate of decline in FVC over 52 weeks). Conclusion Home spirometry was a feasible and valid measure of lung function in patients with IPF and preserved FVC, but estimates of the rate of FVC decline obtained using home spirometry were poorly correlated with those based on clinic spirometry., In a 52-week study in 346 subjects with idiopathic pulmonary fibrosis, mean adherence to weekly home spirometry was 86%. Estimates of the rate of decline in forced vital capacity obtained using home and clinic spirometry were poorly correlated. https://bit.ly/2WjIQ4b
Published: 2021
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28. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Bertrand Isidor, Ruth Armstrong, Thabo M. Yates, Susan M. White, Ruth Richardson, Solveig Heide, Katherine B. Burke, Tjitske Kleefstra, Marie Vincent, Meena Balasubramanian, Maria Irene Valenzuela Palafoll, Sébastien Küry, Rolph Pfundt, Ruth Newbury-Ecob, Sahar Mansour, Wendy K. Chung, Caroline Nava, Sofia Douzgou, Erika Leenders, Annachiara De Sandre-Giovannoli, Saba Sharif, Andrew E. Fry, Helen Stewart, Nicola K. Ragge, Alexander J. M. Dingemans, Pradeep C. Vasudevan, Alison Foster, Sahar Elouej, Shadi Albaba, François-Guillaume Debray, Boris Keren, Serwet Demirdas, Francis H. Sansbury, Thomas Scheffner, Arie van Haeringen, Alice S. Brooks, Meyke Schouten, Helen Cox, Kate Wilson, Sheffield Children's NHS Foundation Trust, University of Sheffield [Sheffield], Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Birmingham Children’s Hospital, Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], Addenbrooke's Hospital, Cambridge University NHS Trust, University Hospital of Wales, Oxford Brookes University, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), St. George’s Hospital University, Oxford University Hospitals NHS Foundation Trust, Partenaires INRAE, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Leiden University Medical Center (LUMC), Reutlingen University, Centre Hospitalier Universitaire de Liège (CHU-Liège), Murdoch Children's Research Institute (MCRI), University of Melbourne, Vall d'Hebron University Hospital [Barcelona], University Hospitals Bristol, Clinical Genetics, Institut Català de la Salut, [Balasubramanian M] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK. [Dingemans AJM] Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. [Albaba S] Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Richardson R] Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK. [Yates TM] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Cox H] West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK. [Palafoll MIV] Servei de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University Hospital of Wales (UHW), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Universiteit Leiden
Subjects: Male, Pediatrics, Genetic testing, Developmental Disabilities, Craniofacial Abnormalities, Intellectual disability, Missense mutation, Child, Genetics (clinical), trastornos mentales::trastornos del desarrollo neurológico::discapacidades del desarrollo [PSIQUIATRÍA Y PSICOLOGÍA], 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 030305 genetics & heredity, Cognition, Syndrome, Autism spectrum disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Fenotip, Sin3 Histone Deacetylase and Corepressor Complex, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Trastorns del desenvolupament - Aspectes genètics, Infants, medicine.medical_specialty, Adolescent, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, Mental Disorders::Neurodevelopmental Disorders::Developmental Disabilities [PSYCHIATRY AND PSYCHOLOGY], Intellectual Disability, Genetics, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Attention deficit hyperactivity disorder, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Autism, business, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS]
Abstract: Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation
Published: 2021
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29. Efficacy of parent-mediated communication-focused treatment in toddlers with autism (PACT) delivered via videoconferencing: A randomised controlled trial study protocol

Author: Jonathan Green, Anouck Amestoy, P. Occelli, S. Touzet, Marie-Joelle Oreve, Catherine Aldred, Carmen M. Schröder, Agathe Jay, Marie-Maude Geoffray, Anne Revah-Levy, Amaria Baghdadli, Lucie Jurek, Angélique Denis, Tom Dauchez, Amélie Zelmar, Thierry Maffre, Natacha Gallifet, Shruti Garg, Centre Hospitalier le Vinatier [Bron], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Hôpital Charles Perrens, CHU Toulouse [Toulouse], Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Lapeyronie [Montpellier] (CHU), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Research on Healthcare Performance (RESHAPE - Inserm U1290 - UCBL1), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier Charles Perrens [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Saclay, Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), and HAL UVSQ, Équipe
Subjects: Parents, medicine.medical_specialty, Telemedicine, Autism Spectrum Disorder, child & adolescent psychiatry, Telehealth, Pact, organisation of health services, law.invention, 03 medical and health sciences, 0302 clinical medicine, human resource management, Randomized controlled trial, law, medicine, Humans, Single-Blind Method, 0501 psychology and cognitive sciences, 030212 general & internal medicine, Autistic Disorder, Psychiatry, Randomized Controlled Trials as Topic, business.industry, Communication, 05 social sciences, Infant, Repeated measures design, Paediatrics, General Medicine, medicine.disease, 3. Good health, Autism spectrum disorder, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Child, Preschool, Cohort, Videoconferencing, Medicine, Autism, developmental neurology & neurodisability, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, telemedicine, business, medical education & training, 050104 developmental & child psychology
Abstract: IntroductionIntervention in the preschool period is currently recommended for autism spectrum disorder. Therapies delivered by parents are particularly suitable for young children. Preschool Autism Communication Trial (PACT) is a parent-mediated therapy that has shown a significant and sustained impact on autism symptom reduction. However, access to such evidence-based therapies for families is limited due to autism centres located in large urban areas. Using videoconferencing to deliver PACT training to parents may improve accessibility for families living in underserved areas.Methods and analysisThis single-blind randomised controlled trial, involving six sites in France, will investigate the efficacy of a telehealth, videoconferencing-based, parent-mediated PACT therapy on autism symptoms, over a 12-month period. It will compare PACT plus treatment as usual (TAU) against TAU only in a cohort of 238 toddlers (119 per group) aged 18–36 months at inclusion and living with their families more than 40 min away from the specialist centres for autism. Primary outcome will include change of overall autism score on the Autism Diagnostic Observation Scale (ADOS) at 12 months. Secondary outcomes will measure change in child skills, child functioning, impact on parents (stress, health, priorities) and implementation characteristics. Repeated measures analyses will be used to test the effect of PACT intervention on the overall ADOS module 1 score over the 12-month study period. Linear mixed models will be used with time, treatment allocation and the interaction between treatment and time as fixed effects and individual variation as random effect.Ethics and disseminationThis protocol (V.5, date: 25 October 2019) is approved by the French National Review Board (reference no 2018-A02516-49). The results will be disseminated via peer-reviewed journalsTrial registration numberNCT04244721.
Published: 2021
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30. The DIAMORFOSIS (DIAgnosis and Management Of lung canceR and FibrOSIS) survey. International survey and call for consensus

Author: Torsten Blum, Francesco Bonella, Paolo Spagnolo, Demosthenes Bouros, Daniel A. Culver, Katerina M. Antoniou, Venerino Poletti, Jacques Cadranel, Ganesh Raghu, Theodoros Karampitsakos, Athol U. Wells, Carlo Vancheri, Stefano Elia, Matthew Evison, Maria Molina-Molina, Elisabeth Bendstrup, Argyris Tzouvelekis, Bogdan Grigoriu, Nesrin Mogulkoc, Michael Kreuter, University of Patras, School of Medicine, University of Crete [Heraklion] (UOC), University of Heidelberg, Medical Faculty, Manchester University NHS Foundation Trust (MFT), HELIOS Klinikum Emil von Behring, Ospedale G.B.Morgagni-L. Pierantoni, Partenaires INRAE, Université libre de Bruxelles (ULB), Università degli studi di Catania [Catania], Azienda Ospedaliera di Padova, University of Duisburg-Essen, Royal Brompton and Harefield NHS Foundation Trust, University of Washington [Seattle], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Cleveland Clinic, Aarhus University Hospital, Ege university, Department of Physics, University of Rome Tor Vergata, Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [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), University of Athens Medical School [Athens], and Ege Üniversitesi
Subjects: squamous cell carcinoma, bronchoscopy, positron emission tomography, Medizin, lcsh:Medicine, diffusing capacity for carbon monoxide, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, chemoradiotherapy, computer assisted tomography, cystic fibrosis, low drug dose, Idiopathic pulmonary fibrosis, 0302 clinical medicine, DLCO, Diffusing capacity, thoracic surgeon, platinum, high resolution computer tomography, endobronchial ultrasonography, pulmonologist, multidisciplinary team, papillomavirus infection, Pulmonologists, tidal volume, Fibrosi pulmonar, respiratory system, Idiopathic pulmonary fibrosis (IPF) Lung Cancer Consensus statement, mass fragmentography, 3. Good health, drug therapy, medicine.anatomical_structure, female, Streptococcus pneumoniae, 030220 oncology & carcinogenesis, immunotherapy, Lung cancer, Pulmonary and Respiratory Medicine, medicine.medical_specialty, lobectomy, palliative therapy, Mediastinal lymphadenopathy, stereotactic radiosurgery, [SDV.CAN]Life Sciences [q-bio]/Cancer, carbon monoxide, Article, Pulmonary fibrosis, 03 medical and health sciences, Interstitial and orphan lung disease, breast cancer, male, forced vital capacity, Internal medicine, lymphadenopathy, medicine, human, oncologist, Lung, non small cell lung cancer, business.industry, hypoxia, lcsh:R, lung fibrosis, Cancer, noninvasive ventilation, dyspnea, medicine.disease, Original articles, Lung cancer and IPF, major clinical study, respiratory tract diseases, fibrosing alveolitis, 030228 respiratory system, [No Keyword], consensus, Settore MED/21, Càncer de pulmó, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, chronic obstructive lung disease
Abstract: Background Currently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue. Methods This was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions. Results Four hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (DLCO), The diagnosis and management of IPF-LC is heterogeneous with most survey respondents calling for a consensus statement https://bit.ly/2Smie0o
Published: 2020
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31. Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe

Author: Simon A. Jones, David Cheillan, Anupam Chakrapani, Heather J. Church, Simon Heales, Teresa H. Y. Wu, Georgina Morton, Patricia Roberts, Erica F. Sluys, Alberto Burlina, Manchester University NHS Foundation Trust (MFT), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK] (GOSHC), University College London Hospitals NHS Foundation Trust [London, UK] (UCLH), ArchAngel MLD Trust [London, UK] (2A), Helvet Health [Nyon, Switzerland] (2H), Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), and CarMeN, laboratoire
Subjects: newborn screening (NBS), inherited metabolic disorder (IMD), public health, genetics, congenital disorder, lysosomal storage disorder (LSD), inborn errors of metabolism, rare diseases, methodology, algorithm, [SDV]Life Sciences [q-bio], food and beverages, Obstetrics and Gynecology, [SDV] Life Sciences [q-bio], Immunology and Microbiology (miscellaneous), Pediatrics, Perinatology and Child Health
Abstract: International audience; Inherited metabolic disorders (IMDs) are mostly rare, have overlapping symptoms, and can be devastating and progressive. However, in many disorders, early intervention can improve long-term outcomes, and newborn screening (NBS) programmes can reduce caregiver stress in the journey to diagnosis and allow patients to receive early, and potentially pre-symptomatic, treatment. Across Europe there are vast discrepancies in the number of IMDs that are screened for and there is an imminent opportunity to accelerate the expansion of evidence-based screening programmes and reduce the disparities in screening programmes across Europe. A comprehensive list of IMDs was created for analysis. A novel NBS evaluation algorithm, described by Burlina et al. in 2021, was used to assess and prioritise IMDs for inclusion on expanded NBS programmes across Europe. Forty-eight IMDs, of which twenty-one were lysosomal storage disorders (LSDs), were identified and assessed with the novel NBS evaluation algorithm. Thirty-five disorders most strongly fulfil the Wilson and Jungner classic screening principles and should be considered for inclusion in NBS programmes across Europe. The recommended disorders should be evaluated at the national level to assess the economic, societal, and political aspects of potential screening programmes.
Published: 2022
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32. European confederation of medical mycology expert consult-An ECMM excellence center initiative

Author: Oliver A. Cornely, Jean-Michel Molina, Katrien Lagrou, Isabel Spriet, Dimitrios P. Kontoyiannis, Malcolm Richardson, Peter-Michael Rath, Riina Rautemaa-Richardson, David W. Denning, Sanja Pleško, Joerg Steinmann, Philipp Koehler, Esther Segal, Jean-Pierre Gangneux, Blandine Denis, Juergen Prattes, Danila Seidel, Robert Krause, Martin Hoenigl, Cornelia Lass-Flörl, Johan Maertens, Ivana Mareković, Jacques F. Meis, Paul E. Verweij, University of Cologne, Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Manchester [Manchester], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Karl-Franzens-Universität Graz, University of California [San Diego] (UC San Diego), University of California, Rice University [Houston], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Universität Innsbruck [Innsbruck], University of Zagreb, Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Manchester University NHS Foundation Trust (MFT), Tel Aviv University [Tel Aviv], Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Radboud University Medical Center [Nijmegen], Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California (UC), and Tel Aviv University (TAU)
Subjects: 0301 basic medicine, Antifungal Agents, Candida auris, Candidemia, aspergillosis, azole-resistance, candidosis, cryptococcosis, fusariosis, mucormycosis, [SDV]Life Sciences [q-bio], Treatment outcome, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030207 dermatology & venereal diseases, 0302 clinical medicine, Medicine, Registries, Referral and Consultation, media_common, Aspergillus species, Infectious Disease Medicine, Guideline adherence, Disease Management, General Medicine, 3. Good health, Outreach, [SDV] Life Sciences [q-bio], Europe, Infectious Diseases, Treatment Outcome, Guideline Adherence, Life Sciences & Biomedicine, medicine.medical_specialty, Medical mycology, media_common.quotation_subject, 030106 microbiology, Azole resistance, Dermatology, Mycology, 03 medical and health sciences, Excellence, Humans, Science & Technology, business.industry, Expert consultation, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Mycoses, Family medicine, business, Invasive Fungal Infections
Abstract: Contains fulltext : 220076.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Difficult-to-treat invasive fungal infections require infectious diseases expert consultation to improve treatment outcome and increase survival rates. METHODS: The European Confederation of Medical Mycology (ECMM) intends to provide expert help free of charge by a newly founded ECMM Expert Consultation Service for medical centres around the globe seeking advice when there is no fungal infection consultant available. The expert consult will provide recommendations and broad expertise on difficult-to-treat invasive fungal infections (eg azole-resistant Aspergillus species, Candida auris, mucormycosis) to improve diagnostic and therapeutic management and outcome. RESULTS: The initiative plans global outreach through video conferencing between ECMM Excellence Centers and treating physicians. FungiScope((R)) registries will be used to structure case information and to evaluate the impact of the collegial advice system at regular intervals. Advice will follow recent guidelines, and EQUAL Scores will be used to measure guideline adherence. CONCLUSIONS: Infectious diseases expert consultation should be an integral component of care for patients with difficult-to-treat invasive fungal infections. The ECMM Expert Consult will attend to this matter on a global scale.
Published: 2020
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33. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N., Antoniou, A.C., Mooij, T.M., Hooning, M.J., Heemskerk-Gerritsen, B.A., Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J.P., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T.D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J.M., Maugard, C., Bignon, Y.J., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Barrowdale, D., Frost, D., Evans, D.G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., Hogervorst, F.B.L., Collee, J.M., Asperen, C.J. van, Mensenkamp, A.R., Ausems, M.G.E.M., Meijers-Heijboer, H.E.J., Engelen, K. van, Blok, M.J., Oosterwijk, J.C., Verloop, J., Broek, E. van den, Mourits, M.J.E., Koppert, L.B., Hopper, J.L., John, E.M., Chung, W.K., Andrulis, I.L., Daly, M.B., Buys, S.S., Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C.F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A.M., Roos-Blom, M.J., Leeuwen, F.E. van, Arver, B., Olsson, H., Schmutzler, R.K., Engel, C., Kast, K., Phillips, K.A., Terry, M.B., Milne, R.L., Goldgar, D.E., Rookus, M.A., Andrieu, N., Easton, D.F., GENEPSO, EMBRACE, HEBON, kConFab Investigators, IBCCS, kConFab, BCFR, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Erasmus MC Cancer Institute, Rotterdam, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie [Paris], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Catherine-de-Sienne [Nantes] (CCS), Manchester University NHS Foundation Trust (MFT), Guy's & St Thomas' NHS Foundation Trust, Chapel Allerton Hospital, University of Leeds, Royal Marsden NHS Foundation Trust, Royal Devon & Exeter Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Wessex clinical genetics service, Vrije Universiteit Amsterdam [Amsterdam] (VU), University Medical Center Groningen [Groningen] (UMCG), Department of Medical Genetics, University Medical Center [Utrecht], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Department of Epidemiology, Cancer Prevention Institute of California, Columbia University [New York], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Division of Population Science, Fox Chase Cancer Center, Department of Internal Medicine, Huntsman Cancer Institute, Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Medizinische Universität Wien = Medical University of Vienna, National Institute of Oncology, Masaryk Memorial Cancer Institute (MMCI), Masaryk University [Brno] (MUNI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, The Netherlands Cancer Institute [Amsterdam, The Netherlands], Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Cancer Epidemiology Centre, Cancer Council Victoria, International Agency for Cancer Research (IACR), Netherlands Cancer Institute, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Andrieu, Nadine, Human genetics, Epidemiology and Data Science, Mavaddat, Nasim [0000-0003-0307-055X], Eeles, Ros [0000-0002-3698-6241], Engel, Christoph [0000-0002-7247-282X], Apollo - University of Cambridge Repository, Pomeranian Medical University-International Hereditary Cancer Centre, Masaryk Memorial Cancer Institute (RECAMO), Columbia Mailman School of Public Health-Columbia University [New York], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Antoniou, Antonis [0000-0001-9223-3116], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Medical Oncology, Surgery, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), United States Department of Health and Human Services, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea. European Research Council (ERC), Norwegian EEA Financial Mechanism, Hungarian Scientific Research Fund (Hungría), Ministry of Education, Youth and Sports (República Checa), MH CZ -DRO (MMCI), National Health and Medical Research Council (Australia), Australian National Breast Cancer Foundation, Cancer Australia, ERA-NET TRANSAN JTC 2012 Cancer, Transcan grant, Biotechnology and Biological Sciences Research Council (Reino Unido), Pink Ribbons Project, Netherlands Organisation of Scientific Research, Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Deutsche Krebshilfe, National Institute for Health Research (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Ministry of Economic Development, Innovation and Export Trade-grant, Canadian Institutes of Health Research, Cancer Research UK, NIH National Cancer Institute (NCI), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Ministerio de Economia y Competividad (MINECO), European Research Council (ERC), Hungarian Research Grants, MEYS -NPS I, National Health and Medical Research Council of Australia, BBMRI grant, Pink Ribbon grants, Netherlands Organisation of Scientific Research grant, KWF Kankerbestrijding, Instituto de Salud Carlos III - ISCIII, National Institute for Health Research (NIHR), European Union Seventh Framework Program (2007-2013), Canadian Institutes of Health Research (CIHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), United States of Department of Health & Human Services, European Research Council, APH - Quality of Care, APH - Methodology, Graduate School, ARD - Amsterdam Reproduction and Development, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: endocrine system diseases, SURGERY, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, BRCA2 Mutation, Breast cancer, Surgical oncology, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Salpingo-oophorectomy/methods, 0303 health sciences, Natural menopause, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics, BRCA1 Protein, Breast Neoplasms/epidemiology, Incidence (epidemiology), Incidence, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, OVARIAN, BRCA2 Protein/genetics, 3. Good health, Menopause, Risk-reducing salpingo-oophorectomy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SURVIVAL, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Salpingo-oophorectomy, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:RC254-282, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, METAANALYSIS, 030304 developmental biology, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, CONSORTIUM, risk-reducing salpingo-oophorectomy, International Agencies, medicine.disease, BRCA1, BRCA2, KCONFAB, REDUCTION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, LINK, Mutation, BRCA1 Protein/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Risk Reduction Behavior
Abstract: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. The BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant #CRN-87521-and the Ministry of Economic Development, Innovation and Export Trade-grant #PSR-SIIRI-701. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by the Cancer Research UK grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí
Published: 2020
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34. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author: Bertrand Isidor, Rami Abou Jamra, Virginie Carmignac, Yannis Duffourd, Helio Pedro, Eriko Koshimizu, Maja Hempel, Tobias Bartolomaeus, Martin Chevarin, Floor A. M. Duijkers, Maria J. Guillen Sacoto, Erin Torti, David Geneviève, David J. Harris, Valerie Loik Ramey, Klaske D. Lichtenbelt, Arthur Sorlin, Miriam Maik, Anne Guimier, Paul Kuentz, Tatjana Bierhals, Orly Elpeleg, Yoshiko Murakami, Laurence Faivre, Jean Baptiste Rivière, Jill Clayton-Smith, Laurent Pasquier, Yuichi Abe, Edgard Verdura, Aviva Fattal, Judith St-Onge, Daphné Lehalle, Joerg Betschinger, Krista Sondergaard-Schatz, Laurie Simone, Christa W. Habela, Ivon Cusco, Mieke M. van Haelst, Pierre Vabres, Laurence Duplomb, Magali Avila, Sakoto Miyakate, Koen L.I. van Gassen, Julien Thevenon, Eveline S. J. M. de Bont, Benjamin Cogné, Pia Zacher, Silvana van Koningsbruggen, Thibaud Jouan, Irene Valenzuela, Christel Thauvin-Robinet, Salvy-Córdoba, Nathalie, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique médicale [CHU Pitié-Salpêtrière], 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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), GeneDx [Gaithersburg, MD, USA], National Center for Child Health and Development [Tokyo], University Hospital Leipzig, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Vall d'Hebron University Hospital [Barcelona], University Medical Center Groningen [Groningen] (UMCG), VU University Medical Center [Amsterdam], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Tel Aviv Sourasky Medical Center [Te Aviv], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Boston Children's Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Hackensack University Medical Center [Hackensack], Yokohama City University (YCU), Osaka University [Osaka], CHU Pontchaillou [Rennes], Johns Hopkins University School of Medicine [Baltimore], Child Health and Human Development Program [Montréal, QC, Canada], McGill University Health Center [Montreal] (MUHC), Centre Hospitalier Universitaire [Grenoble] (CHU), University Hospital Erlangen = Uniklinikum Erlangen, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Kleinwachau - Saxon Epilepsy Center Radeberg, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intellectual disability, TFE3, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Intellectual Disability, 03 medical and health sciences, Exon, 0302 clinical medicine, MESH: Whole Exome Sequencing, MESH: Child, Genetics, medicine, Missense mutation, Gene, Genetics (clinical), Exome sequencing, Pigmentary mosaicism, MESH: Pathology, Molecular, MESH: Adolescent, MESH: Humans, Alternative splicing, Lysosomal metabolism, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Adult, medicine.disease, Phenotype, MESH: Infant, MESH: Male, Storage disorder, 030104 developmental biology, MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, MESH: Epilepsy, MESH: Mosaicism, MESH: Pigmentation Disorders, MESH: Female, 030217 neurology & neurosurgery
Abstract: IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.
Published: 2020
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35. The Fungal PCR Initiative’s evaluation of in-house and commercial Pneumocystis jirovecii qPCR assays: towards a standard for a diagnostics assay

Author: Gits-Muselli, Maud, White, P. Lewis, Mengoli, Carlo, Chen, Sharon, Crowley, Brendan, Dingemans, Gijs, Fréalle, Emilie, Gorton, Rebecca, Guiver, Malcom, Hagen, Ferry, Halliday, Catriona, Johnson, Gemma, Lagrou, Katrien, Lengerova, Martina, Melchers, Willem Jg, Novak-Frazer, Lily, Rautemaa-Richardson, Riina, Scherer, Emeline, Steinmann, Joerg, Cruciani, Mario, Barnes, Rosemary, Donnelly, J. Peter, Loeffler, Juergen, Bretagne, Stéphane, Alanio, Alexandre, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), International University of Health and Welfare Hospital (IUHW Hospital), Universita degli Studi di Padova, The University of Sydney, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Manchester University NHS Foundation Trust (MFT), University Medical Center [Utrecht], University Hospitals Leuven [Leuven], Mendel University in Brno (MENDELU), Radboud University Medical Center [Nijmegen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Duisburg-Essen, Ospedale Fracastoro San Bonifacio [Verona], Cardiff University, Radboud university [Nijmegen], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), We would like to thank Aude Sturny-Leclère, Marion Benazra, and Dirk Schmid for technical assistance and Dr Samia Hamane for her aid in managing the routine diagnosis of PCP. We also thank Pr Anne Bergeron who is in charge of the broncho-alveolar lavage procedure at Saint-Louis hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Radboud University [Nijmegen], and Julius-Maximilians-Universität Würzburg (JMU)
Subjects: [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract: Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal qPCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicentre and monocentre evaluation of PCP qPCR assays was performed. For the multicentre study, 16 reference laboratories from eight different countries, performing 20 assays analysed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads respectively). The monocentre study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, Reverse Transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation
Published: 2019

36. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [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), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019
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37. Adherence to home spirometry among patients with IPF: results from the INMARK trial

Author: Kerri A. Johannson, Nazia Chaudhuri, Imre Noth, Susanne Stowasser, Vincent Cottin, Toby M. Maher, Stéphane Jouneau, Andreas Michael, Manuel Quaresma, Klaus B Rohr, Virginia Polytechnic Institute and State University [Blacksburg], Imperial College London, University of Calgary, Manchester University NHS Foundation Trust (MFT), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Syneos Health Farnborough, Boehringer Ingelheim Pharma GmbH & Co. KG, Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de Lyon, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Spirometry, medicine.medical_specialty, Monitoring, [SDV]Life Sciences [q-bio], Idiopathic pulmonary fibrosis, Placebo, 03 medical and health sciences, chemistry.chemical_compound, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, medicine, In patient, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, business.industry, Disease progression, respiratory system, medicine.disease, respiratory tract diseases, 3. Good health, Clinical trial, 030228 respiratory system, chemistry, Nintedanib, business
Abstract: Introduction: Frequent home spirometry may offer advantages over intermittent clinic spirometry in patients with IPF by providing a more accurate estimate of lung function and enabling earlier detection of disease progression or acute exacerbations. However, poor adherence may limit feasibility. Aim: To assess adherence to home spirometry in subjects with IPF in the INMARK trial. Methods: Subjects with IPF and FVC ≥80% predicted were randomised to receive nintedanib or placebo for 12 weeks, followed by open-label nintedanib for 40 weeks. Subjects were asked to perform home spirometry at least once a week and ideally daily. Adherence was assessed as the number of weeks that a subject provided ≥1 home spirometry measurement divided by the number of weeks they were followed in the study. Analyses included all subjects who received ≥1 dose of trial medication. Results: Among 346 subjects, the proportion of subjects with 100% adherence decreased over the trial but remained above 50% (Figure). Over 52 weeks, mean adherence was 86% and median adherence was 96%. The mean number of home spirometry measurements was 3.4 per subject per week. Conclusions: In subjects with IPF and preserved FVC, adherence to home spirometry over 52 weeks decreased over time but remained at a level suggesting that home spirometry might have a role in monitoring lung function in patients with IPF in clinical trials and clinical practice.
Published: 2019
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38. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome

Author: Louis O'Dea, Sotirios Tsimikas, Qingqing Yang, Erik S.G. Stroes, Daniel Gaudet, Fernando Civeira, Handrean Soran, Dirk J. Blom, Linda C. Hemphill, Steven D. Freedman, Jean Bergeron, Joseph L. Witztum, Steven Hughes, Richard S. Geary, Eric Bruckert, Andres Digenio, Veronica J. Alexander, Marcello Arca, Karren R Williams, University of California [San Diego] (UC San Diego), University of California, Université de Montréal (UdeM), Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université Laval [Québec] (ULaval), Manchester University NHS Foundation Trust (MFT), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Massachusetts General Hospital [Boston], University of Cape Town, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Injections, Subcutaneous/adverse effects, 030204 cardiovascular system & hematology, Triglycerides blood, Hyperlipoproteinemia Type I/blood, familial chylomicronemia, volanesorsen, triglycerides, therapy, apoCIII, familial chylomicronemia, Injections, Oligonucleotides/administration & dosage, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, apoCIII, Internal medicine, Humans, Medicine, volanesorsen, 030212 general & internal medicine, triglycerides, Aged, RNA, Messenger/antagonists & inhibitors, therapy, Analysis of Variance, Triglyceride, Platelet Count, Thrombocytopenia/chemically induced, business.industry, Genetic disorder, General Medicine, Middle Aged, Familial Chylomicronemia, medicine.disease, 3. Good health, Triglycerides/blood, Endocrinology, Multicenter study, chemistry, RNA, Female, Subcutaneous/adverse effects, Apolipoprotein C-III/antagonists & inhibitors, business, Lipoprotein lipase activity, Messenger/antagonists & inhibitors
Abstract: Background Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. Methods We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. Results Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P
Published: 2019
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39. Diagnosis and management of pseudohypoparathyroidism and related disorders:first international Consensus Statement

Author: Susanne Thiele, Eileen M. Shore, Luisa De Sanctis, Thomas Eggermann, Serap Turan, Murat Bastepe, Gabriel Á. Martos-Moreno, Aurora Garcia Ramirez, Vrinda Saraff, Nina Knight, Caroline Silve, Outi Mäkitie, Agnès Linglart, Marie Laure Kottler, Emily L. Germain-Lee, Rebecca Rodado, Philip Murray, Peter Kamenický, Lars Rejnmark, Masanori Minagawa, Anya Rothenbuhler, Kathleen Freson, Timothee Choplin, Alessia Usardi, Francesca Elli, Regina Matsunaga Martin, M. Carola Zillikens, Guillemette Devernois, Harald Jüppner, David Monk, Arrate Pereda, Neveen A. T. Hamdy, Gianpaolo de Filippo, Lionel Groussin, Elvire Le Norcy, Robert J. Pignolo, Ashley H. Shoemaker, Giovanna Mantovani, Olaf Hiort, Roberto Bufo, Guiomar Perez de Nanclares, Michael A. Levine, Beatriz Lecumberri, Philip Woods, Patrick Hanna, S Faisal Ahmed, Mantovani, Giovanna, Bastepe, Murat, Monk, David, de Sanctis, Luisa, Thiele, Susanne, Usardi, Alessia, Ahmed, S. Faisal, Bufo, Roberto, Choplin, Timothee, De Filippo, Gianpaolo, Devernois, Guillemette, Eggermann, Thomas, Elli, Francesca M., Freson, Kathleen, Garcia Ramirez, Aurora, Germain-Lee, Emily L., Groussin, Lionel, Hamdy, Neveen, Hanna, Patrick, Hiort, Olaf, Juppner, Harald, Kamenicky, Peter, Knight, Nina, Kottler, Marie-Laure, Le Norcy, Elvire, Lecumberri, Beatriz, Levine, Michael A., Makitie, Outi, Martin, Regina, Angel Martos-Moreno, Gabriel, Minagawa, Masanori, Murray, Philip, Pereda, Arrate, Pignolo, Robert, Rejnmark, Lars, Rodado, Rebecca, Rothenbuhler, Anya, Saraff, Vrinda, Shoemaker, Ashley H., Shore, Eileen M., Silve, Caroline, Turan, Serap, Woods, Philip, Zillikens, M. Carola, Perez de Nanclares, Guiomar, Linglart, Agnes, Clinicum, Lastentautien yksikkö, Children's Hospital, HUS Children and Adolescents, Internal Medicine, UAM. Departamento de Medicina, UAM. Departamento de Pediatría, Instituto de Investigación del Hospital de La Princesa (IP), Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), Università degli Studi di Milano = University of Milan (UNIMI), Harvard Medical School [Boston] (HMS), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Università degli studi di Torino = University of Turin (UNITO), Lübeck University of Applied Sciences, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Glasgow, Italian Progressive Osseous Heteroplasia Association (IPOHA), Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Connecticut Children's Medical Center, University of Connecticut (UCONN), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université Paris Descartes - Paris 5 (UPD5), Leiden University Medical Center (LUMC), Universiteit Leiden, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Endocrine Unit, Massachusetts General Hospital [Boston], Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Service de Génétique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Hospital Universitario La Paz, Department of Statistics [West Lafayette], Purdue University [West Lafayette], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Universidade de São Paulo = University of São Paulo (USP), Chiba University Hospital, Manchester University NHS Foundation Trust (MFT), Bioaraba Health Research Institute, Mayo Clinic [Rochester], Aarhus University Hospital, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Birmingham Children’s Hospital, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Pennsylvania, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marmara University [Kadıköy - İstanbul], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departments of Medicine and Pediatrics, Department of Pediatrics, University of Turin, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Center for Molecular and Vascular Biology, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], Endocrine Unit, Department of Medicine, and Pediatric Neprology Unit, MassGeneral Hospital for Children, Servicio de Endocrinología, Hospital Universitario La Paz, Hospital for Children and Adolescents, Helsinki University Central Hospital, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Laboratorio de Genética Molecular, Unidad de Investigación, Hospital de Txagorritxu, University of Milan, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), University of Helsinki, University of São Paulo (USP), University of Pennsylvania [Philadelphia], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Pediatrics, Delayed Diagnosis, Endocrinology, Diabetes and Metabolism, Endocrinology, Statement (logic), Drug Resistance, Parathyroid hormone, MESH: Risk Assessment, Pseudohypoparathyroidism/diagnosis, STIMULATORY G-PROTEIN, Neonatal Screening/organization & administration, 0302 clinical medicine, MESH: Practice Guidelines as Topic, Program Development, BRACHYDACTYLY TYPE-E, PARATHYROID-HORMONE RESISTANCE, Disorders, IMPRINTING CONTROL ELEMENT, MESH: Infant, Newborn, MESH: Pseudohypoparathyroidism, MESH: Genetic Predisposition to Disease, Prognosis, 3. Good health, Diabetes and Metabolism, MESH: Parathyroid Hormone, IDENTIFIES PDE4D MUTATIONS, Parathyroid Hormone, NUCLEOTIDE REGULATORY PROTEIN, Consensus statement, Pseudohypoparathyroidism, Practice Guidelines as Topic, MESH: Drug Resistance, Female, medicine.symptom, Parathyroid Hormone/therapeutic use, medicine.medical_specialty, Consensus, Delayed Diagnosis/adverse effects, Medicina, 030209 endocrinology & metabolism, PROGRESSIVE OSSEOUS HETEROPLASIA, Parathyroid Hormone Resistance, Risk Assessment, Short stature, PATERNAL UNIPARENTAL DISOMY, Article, MESH: Prognosis, Growth hormone deficiency, GNAS INACTIVATING MUTATIONS, 03 medical and health sciences, Neonatal Screening, BECKWITH-WIEDEMANN SYNDROME, MESH: Program Development, medicine, Humans, Genetic Predisposition to Disease, MESH: Consensus, MESH: Neonatal Screening, [SDV.GEN]Life Sciences [q-bio]/Genetics, GS-ALPHA-GENE, MESH: Humans, ALBRIGHT HEREDITARY OSTEODYSTROPHY, business.industry, Brachydactyly, Infant, Newborn, Type 2 Diabetes Mellitus, medicine.disease, MESH: Male, MESH: Delayed Diagnosis, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Diagnosis and management, DEPENDENT PROBE AMPLIFICATION, Family medicine, 3121 General medicine, internal medicine and other clinical medicine, business, MESH: Female, Neurocognitive
Abstract: This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders, This Consensus Statement and the series of consensus meetings were supported by funds from the European Cooperation in Science and Technology (COST) action BM1208 on imprinting disorders (www.imprinting- disorders.eu), the European Society for Paediatric Endocrinology (ESPE) and the European Society for Endocrinology (ESE). Travel costs and housing of the representatives of the Asian Pacific Paediatric Endocrine Society (APPES) and of the Pediatric Endocrine Society (PES) were supported by their societies. The authors received no funding from pharmaceutical companies
Published: 2018
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40. Corrigendum: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author: Rosaline Caumes, Andrea Berger, John Stone, Roberta Battini, Charles Marques Lourenço, Gerardine Quaghebeur, Nicholas A. Fletcher, Elliott H. Sherr, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Marco Henneke, Kanaga R. Sinnathuray, Pierre Landrieu, James O'Sullivan, Calvin Soh, Himanshu Goel, Patrick Ferreira, Katrin Õunap, Cheryl Hemingway, Laurence C. Goosey, Graham D. Pavitt, Hilde Van Esch, Prab Prabhakar, Yoann Rose, Jill E. Urquhart, Yanick J. Crow, Gabriela M. Baerlocher, Simon G. Williams, Mathieu P Rodero, Ram L. Kumar, Emma M. Jenkinson, Gillian I. Rice, Sarju G. Mehta, Adeline Vanderver, Timothy J. Malpas, Christopher J. Kershaw, Imke Metz, Edward Blair, Paul R. Kasher, Imelda Hughes, Patrick Revy, David Cassiman, Duccio Maria Cordelli, Angela Barnicoat, Andrea Whitney, Janice E. Brunstrom-Hernandez, Axel Panzer, Kristin W. Barañano, Liesbeth De Waele, Geraldine Aubert, Raphael Schiffmann, H. Stewart, Monika Haubitz, Rosalind J. Jefferson, Alan Fryer, Anthony Oojageer, Carolina Uggenti, John H. Livingston, Sam Griffiths-Jones, Christine E. G. van Mol, Johannes A. Buckard, Raymond T. O'Keefe, Lieven Lagae, Emma Wakeling, Sakkubai Naidu, Alex J. Fay, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Department of Medical Genetics, and HMNC Brain Health
Subjects: 0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Biology, medicine.disease, Article, 3. Good health, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Cerebral microangiopathy, Genetics, medicine, 610 Medicine & health, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Published: 2017
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41. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

Author: Johann, Böhm, Monica, Bulla, Jill E, Urquhart, Edoardo, Malfatti, Simon G, Williams, James, O'Sullivan, Anastazja, Szlauer, Catherine, Koch, Giovanni, Baranello, Marina, Mora, Michela, Ripolone, Raffaella, Violano, Maurizio, Moggio, Helen, Kingston, Timothy, Dawson, Christian G, DeGoede, John, Nixon, Anne, Boland, Jean-François, Deleuze, Norma, Romero, William G, Newman, Nicolas, Demaurex, Jocelyn, Laporte, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Université de Genève = University of Geneva (UNIGE), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Royal Preston Hospital [Preston, UK] (RPH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), and univOAK, Archive ouverte
Subjects: Male, Orai1, ORAI1 Protein, Migraine Disorders, Mutation, Missense, Erythrocytes, Abnormal, [SDV.GEN] Life Sciences [q-bio]/Genetics, Dyslexia, Animals, Humans, Amino Acid Sequence, Stromal Interaction Molecule 1, ddc:612, Cells, Cultured, Soce, Mice, Knockout, [SDV.GEN]Life Sciences [q-bio]/Genetics, calcium, Base Sequence, Sequence Homology, Amino Acid, Ichthyosis, tubular aggregate myopathy, Miosis, Neoplasm Proteins, Pedigree, HEK293 Cells, Microscopy, Fluorescence, Stim1, Muscle Fatigue, Female, Blood Platelet Disorders, Ion Channel Gating, Spleen, Myopathies, Structural, Congenital, Stormorken syndrome
Abstract: Calcium (Ca(2+) ) is a physiological key factor, and the precise modulation of free cytosolic Ca(2+) levels regulates multiple cellular functions. Store-operated Ca(2+) entry (SOCE) is a major mechanism controlling Ca(2+) homeostasis, and is mediated by the concerted activity of the Ca(2+) sensor STIM1 and the Ca(2+) channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, while recessive loss-of-function mutations are associated with immunodeficiency. Here we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI channels, while T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggest that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca(2+) homeostasis and leading to muscle dysfunction. This article is protected by copyright. All rights reserved.
Published: 2017
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42. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author: Elliott H. Sherr, Edward Blair, Charles Marques Lourenço, James O'Sullivan, Imke Metz, Paul R. Kasher, Gabriela M. Baerlocher, Adeline Vanderver, David Cassiman, Himanshu Goel, Nicholas A. Fletcher, Patrick Ferreira, Patrick Revy, Emma Wakeling, Ram L. Kumar, Lieven Lagae, Christopher J. Kershaw, Pierre Landrieu, Andrea Whitney, Calvin Soh, Christine E. G. van Mol, Sakkubai Naidu, John H. Livingston, Geraldine Aubert, H. Stewart, Laurence C. Goosey, Liesbeth De Waele, Kristin W. Barañano, Rosalind J. Jefferson, Axel Panzer, Gerardine Quaghebeur, Raphael Schiffmann, Yanick J. Crow, Hilde Van Esch, Raymond T. O'Keefe, Jill E. Urquhart, Alan Fryer, Mathieu P Rodero, Alex J. Fay, Monika Haubitz, Andrea Berger, Johannes A. Buckard, Cheryl Hemingway, Angela Barnicoat, Sam Griffiths-Jones, Duccio Maria Cordelli, Imelda Hughes, Katrin Õunap, Graham D. Pavitt, Roberta Battini, Yoann Rose, Marjo S. van der Knaap, Sanjeev S. Bhaskar, John Stone, Gillian I. Rice, Marco Henneke, Kanaga R. Sinnathuray, Emma M. Jenkinson, Timothy J. Malpas, Simon G. Williams, Anthony Oojageer, Carolina Uggenti, Rosaline Caumes, Prab Prabhakar, Sarju G. Mehta, Janice E. Brunstrom-Hernandez, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Manchester [Manchester], Department of Medical Genetics, HMNC Brain Health, Other departments, Jenkinson, Emma M., Rodero, Mathieu P., Kasher, Paul R., Uggenti, Carolina, Oojageer, Anthony, Goosey, Laurence C., Rose, Yoann, Kershaw, Christopher J., Urquhart, Jill E., Williams, Simon G., Bhaskar, Sanjeev S., O'Sullivan, Jame, Baerlocher, Gabriela M., Haubitz, Monika, Aubert, Geraldine, Barañano, Kristin W., Barnicoat, Angela J., Battini, Roberta, Berger, Andrea, Blair, Edward M., Brunstrom-Hernandez, Janice E., Buckard, Johannes A., Cassiman, David M., Caumes, Rosaline, Cordelli, Duccio M., De Waele, Liesbeth M., Fay, Alexander J., Ferreira, Patrick, Fletcher, Nicholas A., Fryer, Alan E., Goel, Himanshu, Hemingway, Cheryl A., Henneke, Marco, Hughes, Imelda, Jefferson, Rosalind J., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre G., Lourenço, Charles M., Malpas, Timothy J., Mehta, Sarju G., Metz, Imke, Naidu, Sakkubai, Õunap, Katrin, Panzer, Axel, Prabhakar, Prab, Quaghebeur, Gerardine, Schiffmann, Raphael, Sherr, Elliott H., Sinnathuray, Kanaga R., Soh, Calvin, Stewart, Helen S., Stone, John, Van Esch, Hilde, Van Mol, Christine E. G., Vanderver, Adeline, Wakeling, Emma L., Whitney, Andrea, Pavitt, Graham D., Griffiths-Jones, Sam, Rice, Gillian I., Revy, Patrick, Van Der Knaap, Marjo S., Livingston, John H., O'Keefe, Raymond T., Crow, Yanick J., Pediatric surgery, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Subjects: 0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Ribosome biogenesis, medicine.disease_cause, Leukoencephalopathy, Leukoencephalopathie, Cohort Studies, 0302 clinical medicine, Leukoencephalopathies, Exome, Small nucleolar RNA, 610 Medicine & health, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Genome, Cysts, Calcinosis, Middle Aged, Phenotype, Child, Preschool, Calcinosi, Female, Sequence Analysis, Human, Adult, Adolescent, Biology, Chromosomes, Cell Line, 03 medical and health sciences, Young Adult, medicine, RNA, Small Nucleolar, Humans, Preschool, Gene, Small Nucleolar, Genome, Human, Pair 17, RNA, Infant, Sequence Analysis, DNA, DNA, Cerebral Small Vessel Diseases, Chromosomes, Human, Pair 17, medicine.disease, Cerebral Small Vessel Disease, 030104 developmental biology, Cyst, Cohort Studie, 030217 neurology & neurosurgery
Abstract: Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Published: 2016
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43. Development steps of multimodal exercise interventions for older adults with multimorbidity: A systematic review.

Author: Forsyth F, Soh CL, Elks N, Lin H, Bailey K, Brooman-White R, Rowbotham S, Mant J, Hartley P, and Deaton C
Abstract: Background and Aims: Multicomponent exercise interventions are recommended for older adults and for those with chronic diseases. While multiple programs have been tested, no one has yet explored how these programs were developed. This review set out to determine what development steps multicomponent exercise intervention studies that include older adults with multimorbidity have taken., Methods: Systematic review and narrative synthesis., Results: One hundred and thirty-eight studies meeting review criteria ( Population : adults ≥60 years with multimorbidity; Intervention : exercise interventions with ≥2 components; Comparator : any considered; Outcome : any considered) were retrieved. Most studies (70%) do not report intervention development actions as suggested by available guidance. Notable deviations from recommendations include limited performance of systematic review of previously published evidence, lack of engagement with theory, and few examples of design then refine., Conclusions: Exercise interventions for older adults with multimorbidity do not appear to follow best practice in terms of their developing. Disregard of development recommendations risks contributing to research redundancy and/or avoidable waste, as important steps that make sure the intervention is warranted, suitable for the population in question, and tested using optimal methods and outcome measures are overlooked., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)
Published: 2024
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44. Hydroxyapatite ceramic-coated femoral components in younger patients followed up for 27 to 32 years.

Author: Upadhyay PK, Shah N, Kumar V, and Mirza SB
Abstract: Aims: This study reports the results of 38 total hip arthroplasties (THAs) in 33 patients aged less than 50 years, using the JRI Furlong hydroxyapatite ceramic (HAC)-coated femoral component., Methods: We describe the survival, radiological, and functional outcomes of 33 patients (38 THAs) at a mean follow-up of 27 years (25 to 32) between 1988 and 2018., Results: Of the surviving 30 patients (34 THAs), there were four periprosthetic fractures: one underwent femoral revision after 21 years, two had surgical fixation as the stem was deemed stable, and one was treated nonoperatively due to the patient's comorbidities. The periprosthetic fracture patients showed radiological evidence of change in bone stock around the femoral stem, which may have contributed to the fractures; this was reflected in change of the canal flare index at the proximal femur. Two patients (two hips) were lost to follow-up. Using aseptic loosening as the endpoint, 16 patients (18 hips; 48%) needed acetabular revision. None of the femoral components were revised for aseptic loosening, demonstrating 100% survival. The estimate of the cumulative proportion surviving for revisions due to any cause was 0.97 (standard error 0.03)., Conclusion: In young patients with high demands, the Furlong HAC-coated femoral component gives excellent long-term results., Competing Interests: The authors have no COI disclosures to declare., (© 2024 Upadhyay et al.)
Published: 2024
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45. Intraoral Microvascular Anastomosis in Immediate Free Flap Reconstruction for Midfacial Tumor Defects: A Retrospective Multicenter Study.

Author: Kämmerer PW, Tavakoli M, Gaggl A, and Maranzano M
Abstract: (1) Background: The current landscape of midface reconstruction is marked by ongoing evolution, with notable advancements in surgical techniques, microvascular procedures, and the implementation of multidisciplinary approaches, all of which have significantly enhanced both functional and aesthetic outcomes. Conventionally, microvascular anastomoses for free flaps in midfacial reconstruction have been executed using cervical vessels. However, this approach necessitates neck access, resulting in extraoral scars and a substantial pedicle length. In light of these considerations, using intraoral anastomoses via the facial vessels emerges as a promising alternative. This retrospective multicentric study aims to provide a comprehensive account of immediate midface reconstruction through intraoral anastomoses. (2) Methods: Between 2020 and 2023, patients were included who underwent intraoral resection of midface/orbit segments (Brown Classes I-VI) as a result of malignant diseases. In all cases, immediate reconstruction was accomplished by utilizing the facial vessels through an intraoral approach. Outcome criteria were identification of vessels, parotid duct or facial nerve damage, success of vascular anastomoses, and flap survival. (3) Results: A total of 117 patients with 132 flaps (91 osseous and 41 cutaneous) were included. The intraoral preparation of facial vessels was successfully completed in less than 1 h, and no complications related to the dissection or anastomoses were observed. In two cases, the vessel diameter was insufficient to facilitate anastomoses, necessitating adopting an extraoral approach. During a follow-up period of 48 months, two osseous flaps were lost, accounting for a 1.5% loss rate out of 132 flaps used. Additionally, 3 flaps experienced partial loss, including a skin island of a scapula, the border zone of a femur, and a rectus flap, resulting in a 2.3% partial loss rate out of 130 flaps utilized. (4) Conclusions: This case series underscores the feasibility of employing intraoral anastomoses for immediate complex midface reconstruction following oncological resection. This approach is particularly advantageous for flaps with shorter pedicles, as it helps mitigate external scarring and minimizes the risk of facial nerve injury.
Published: 2023
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46. What do women think about having received their breast cancer risk as part of a risk-stratified NHS Breast Screening Programme? A qualitative study.

Author: McWilliams L, Ruane H, Ulph F, Woof VG, Harrison F, Evans DG, and French DP
Subjects: Humans, Female, Mass Screening, Qualitative Research, State Medicine, England, Risk Assessment, Middle Aged, Aged, Breast Neoplasms psychology, Early Detection of Cancer
Abstract: Background: Risk-stratified screening is being considered for national breast screening programmes. It is unclear how women experience risk-stratified screening and receipt of breast cancer risk information in real time. This study aimed to explore the psychological impact of undergoing risk-stratified screening within England's NHS Breast Screening Programme., Methods: Individual telephone interviews were conducted with 40 women who participated in the BC-Predict study and received a letter indicating their estimated breast cancer risk as one of four risk categories: low (<2% 10-year risk), average (2-4.99%), above average (moderate; 5-7.99%) or high (≥8%). Audio-recorded interview transcriptions were analysed using reflexive thematic analysis., Results: Two themes were produced: 'From risk expectations to what's my future health story?' highlights that women overall valued the opportunity to receive risk estimates; however, when these were discordant with perceived risk, this causes temporary distress or rejection of the information. 'Being a good (woman) citizen' where women felt positive contributing to society but may feel judged if they then cannot exert agency over the management of their risk or access follow-up support CONCLUSIONS: Risk-stratified breast screening was generally accepted without causing long-lasting distress; however, issues related to risk communication and access to care pathways need to be considered for implementation., (© 2023. The Author(s).)
Published: 2023
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47. Circadian regulation of pulmonary disease: the importance of timing.

Author: Cunningham PS, Jackson C, Chakraborty A, Cain J, Durrington HJ, and Blaikley JF
Subjects: Humans, Asthma physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Fibrosis physiopathology, Respiratory Tract Infections physiopathology, Time Factors, Clinical Trials as Topic, Research Design, Circadian Clocks physiology, Lung Diseases physiopathology
Abstract: Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms., (© 2023 The Author(s).)
Published: 2023
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48. The Use of Human Amniotic Membrane (hAM) as a Treatment Strategy of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Systematic Review and Meta-Analysis of the Literature.

Author: Sacco R, Akintola O, Sacco N, Acocella A, Calasans-Maia MD, Maranzano M, and Olate S
Subjects: Humans, Amnion, Denosumab adverse effects, Diphosphonates adverse effects, Bisphosphonate-Associated Osteonecrosis of the Jaw surgery, Bisphosphonate-Associated Osteonecrosis of the Jaw epidemiology, Bone Density Conservation Agents adverse effects
Abstract: Background and objectives : Although it is very uncommon, medication-induced osteonecrosis of the jaw (also known as MRONJ) can have serious consequences. Traditionally, this adverse event has been recognised in patients who were treated with bisphosphonate (BP) drugs. Nevertheless, in recent years, it has been established that individuals having treatment with various types of medications, such as a receptor activator of nuclear factor kappa-Β ligand inhibitor (denosumab) and antiangiogenic agents, have had the same issue. The purpose of this research is to determine if the application of human amniotic membrane (hAM) may be used as a therapy for MRONJ. Material and Methods : A multi-source database (MEDLINE, EMBASE, AMED, and CENTRAL) systematic search was performed. The major objective of this study is to obtain an understanding of the efficacy of hAM when it is employed as a treatment modality for MRONJ. The protocol of this review was registered in the INPLASY register under the number NPLASY202330010. Results : The authors were able to include a total of five studies for the quality analysis, whereas for the quantity evaluation, only four studies were eligible. A total of 91 patients were considered for the investigation. After treatment with human amniotic membrane (hAM), a recurrence of osteonecrosis was observed in n = 6 cases (8.8%). The combined efficacy of surgical therapy and the use of hAM resulted in an overall success rate of 91.2%. Intraoperative complications were only documented in one article, and they were mostly caused by the positioning of the hAM, which led to wound breakdown at the surgical site. Conclusions: Based on the small amount of data and low-quality research included in this study, using human amniotic membranes to treat MRONJ might represent a feasible option. Nevertheless, further studies with a wider patient population are required to understand the long-term impacts.
Published: 2023
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49. Clinician acceptability of an antibiotic prescribing knowledge support system for primary care: a mixed-method evaluation of features and context.

Author: Hurley R, Jury F, van Staa TP, Palin V, and Armitage CJ
Subjects: Humans, Communication, Medical Records, Primary Health Care, Anti-Bacterial Agents therapeutic use, Health Personnel
Abstract: Background: Overprescribing of antibiotics is a major concern as it contributes to antimicrobial resistance. Research has found highly variable antibiotic prescribing in (UK) primary care, and to support more effective stewardship, the BRIT Project (Building Rapid Interventions to optimise prescribing) is implementing an eHealth Knowledge Support System. This will provide unique individualised analytics information to clinicians and patients at the point of care. The objective of the current study was to gauge the acceptability of the system to prescribing healthcare professionals and highlight factors to maximise intervention uptake., Methods: Two mixed-method co-design workshops were held online with primary care prescribing healthcare professionals (n = 16). Usefulness ratings of example features were collected using online polls and online whiteboards. Verbal discussion and textual comments were analysed thematically using inductive (participant-centred) and deductive perspectives (using the Theoretical Framework of Acceptability)., Results: Hierarchical thematic coding generated three overarching themes relevant to intervention use and development. Clinician concerns (focal issues) were safe prescribing, accessible information, autonomy, avoiding duplication, technical issues and time. Requirements were ease and efficiency of use, integration of systems, patient-centeredness, personalisation, and training. Important features of the system included extraction of pertinent information from patient records (such as antibiotic prescribing history), recommended actions, personalised treatment, risk indicators and electronic patient communication leaflets. Anticipated acceptability and intention to use the knowledge support system was moderate to high. Time was identified as a focal cost/ burden, but this would be outweighed if the system improved patient outcomes and increased prescribing confidence., Conclusion: Clinicians anticipate that an eHealth knowledge support system will be a useful and acceptable way to optimise antibiotic prescribing at the point of care. The mixed method workshop highlighted issues to assist person-centred eHealth intervention development, such as the value of communicating patient outcomes. Important features were identified including the ability to efficiently extract and summarise pertinent information from the patient records, provide explainable and transparent risk information, and personalised information to support patient communication. The Theoretical Framework of Acceptability enabled structured, theoretically sound feedback and creation of a profile to benchmark future evaluations. This may encourage a consistent user-focused approach to guide future eHealth intervention development., (© 2023. The Author(s).)
Published: 2023
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50. A qualitative study to explore the acceptability and feasibility of implementing person-focused evidence-based pain education concepts in pre-registration physiotherapy training.

Author: Thompson K, Milligan J, Briggs M, Deane JA, and Johnson MI
Abstract: Objectives: The purpose of this study was to engage with physiotherapy clinicians, academics, physiotherapy students and patients to explore the acceptability, feasibility, and practical considerations of implementing person-focused evidence-based pain education concepts, identified from our previous research, in pre-registration physiotherapy training., Design: This qualitative study took a person-focused approach to ground pain education in the perspectives and experiences of people who deliver and use it. Data was collected via focus groups and in-depth semi-structured interviews. Data was analysed using the seven stage Framework approach., Setting: Focus groups and interviews were conducted either face to face, via video conferencing or via telephone. This depended on geographical location, participant preference, and towards the end of data collection the limitations on in-person contact due to the Covid-19 pandemic., Participants: UK based physiotherapy clinicians, physiotherapy students, academics and patients living with pain were purposively sampled and invited to take part., Results: Five focus groups and six semi-structured interviews were conducted with twenty-nine participants. Four key dimensions evolved from the dataset that encapsulate concepts underpinning the acceptability and feasibility of implementing pain education in pre-registration physiotherapy training. These are (1) make pain education authentic to reflect diverse, real patient scenarios, (2) demonstrate the value that pain education adds, (3) be creative by engaging students with content that requires active participation, (4) openly discuss the challenges and embrace scope of practice., Conclusions: These key dimensions shift the focus of pain education towards practically engaging content that reflects people experiencing pain from diverse sociocultural backgrounds. This study highlights the need for creativity in curriculum design and the importance of preparing graduates for the challenges that they will face in clinical practice., Competing Interests: In the previous 5 years, MIJ's employer has received income for expert consultancy activities from GSK, TENSCare, and LifeCare Ltd. that lie outside of the submitted work. MIJ declares book royalties from Oxford University Press. The remaining 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., (© 2023 Thompson, Milligan, Briggs, Deane and Johnson.)
Published: 2023
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