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1. Discovering the Interwoven Health Inequities in Aboriginal and Torres Strait Islander Children with an Acute Burns Injury

Author: Ivers, Rebecca, Public Health & Community Medicine, Faculty of Medicine, UNSW, Mackean, Tamara, Public Health & Community Medicine, Faculty of Medicine, UNSW, Holland, Andrew, Children’s Hospital at Westmead, University of Sydney, Hunter, Catherine, Public Health & Community Medicine, Faculty of Medicine, UNSW, Ryder, Courtney, Community Medicine, Faculty of Medicine, UNSW, Ivers, Rebecca, Public Health & Community Medicine, Faculty of Medicine, UNSW, Mackean, Tamara, Public Health & Community Medicine, Faculty of Medicine, UNSW, Holland, Andrew, Children’s Hospital at Westmead, University of Sydney, Hunter, Catherine, Public Health & Community Medicine, Faculty of Medicine, UNSW, and Ryder, Courtney, Community Medicine, Faculty of Medicine, UNSW
Abstract: Background: In Australia, Aboriginal and Torres Strait Islander children have a greater burden of burn injury than other Australian children, yet to date, no research has examined this from an Indigenous perspective. This is the first thesis to use Indigenous research methodologies to provide a detailed examination of how health inequity impacts on Aboriginal and Torres Strait Islander children with an acute burn injury.Methods: The research comprised a systematic review of international injury literature, two epidemiological studies using Burns Registry of Australia and New Zealand data, a quantitative study with Aboriginal families and psychometric assessment of a survey. Indigenous research methodologies (decolonising, knowledge interface) woven with quantitative research methods were employed throughout.Results: Inequities in injury burden are greatest in children from low socio-economic status backgrounds and those who experience longer hospital length of stay (LOS). Aboriginal and Torres Strait Islander children have a hospital LOS 4 days longer than other Australian children with acute burns. Remoteness, flame burns, percentage total body surface area are contributing factors. These health inequities, low socio-economic status and Streptococcus sp. infection are greater in Aboriginal and Torres Strait Islander children than other Australian children. While knowledge interface methodology acted to decolonise outcomes, there were limitations in data in the data source, a Western epidemiological data repository and its employed classification codes.The manifestation of these inequities creates additional burden through Out-of-Pocket Healthcare Expenditure (OOPHE) on Aboriginal and Torres Strait Islander families. Travel, accommodation and medication are all OOPHE costs impacting families for their child’s burns treatment. Financial stain was reported through inability to pay bills and social isolation. The modification of a pre-existing OOPHE survey was found to
Published: 2021

2. Lifestyle factors affecting the health of children with intellectual disability

Author: Broderick, Carolyn, Medical Sciences, Faculty of Medicine, UNSW, Simar, David, Medical Sciences, Faculty of Medicine, UNSW, Louise, Hardy, Prevention Research Collaboration, The University of Sydney, Silove, Natalie, Child Development Unit, The Children's Hospital at Westmead, Puusepp Benazzouz, Helen, Paediatric Registrar, The Children's Hospital at Westmead, Bellamy, Jessica, Medical Sciences, Faculty of Medicine, UNSW, Broderick, Carolyn, Medical Sciences, Faculty of Medicine, UNSW, Simar, David, Medical Sciences, Faculty of Medicine, UNSW, Louise, Hardy, Prevention Research Collaboration, The University of Sydney, Silove, Natalie, Child Development Unit, The Children's Hospital at Westmead, Puusepp Benazzouz, Helen, Paediatric Registrar, The Children's Hospital at Westmead, and Bellamy, Jessica, Medical Sciences, Faculty of Medicine, UNSW
Abstract: Background: People with Intellectual Disability (ID) are at increased risk of secondary health conditions, reduced quality of life and life expectancy. Children and adolescents with ID have high prevalence of obesity, which is a modifiable risk factor associated with secondary health conditions including type-2 diabetes and cardiovascular disease. Interventions to address weight and weight-related behaviours in this population are challenging and limited. This project involved three discrete studies with four primary aims:1. To quantify overweight/obesity prevalence and cardio-metabolic risk in children with ID in South-West Sydney.2. To report the prevalence of children with ID meeting physical activity, nutrition, and screen-time recommendations. 3. To assess parental knowledge and attitudes towards child physical activity, nutrition and screen-time.4. To assess the feasibility of delivering a school-based group exercise intervention to children with ID.Methods: Study 1 was a cross-sectional survey involving a convenience sample of parents of children with ID. Parents completed a validated questionnaire on their child’s physical activity, dietary patterns and sedentary behaviours. Anthropometric measures were used to determine child overweight, obesity and cardio-metabolic risk prevalence. For study 2 parents completed a validated questionnaire on their awareness and knowledge of weight-related behaviours. Study 3 assessed the feasibility of delivering a 16-week school-based group exercise intervention to children with moderate to severe ID.Results: Overall, 20.5% of children were overweight and 28.2% obese, with 61.5% at increased cardio-metabolic risk. More than half of these children did not meet the Australian physical activity (80%), screen time (80%) or nutritional (>65%) recommendations. Only 13% of parents correctly identified these guidelines, and 97% of parents reported barriers towards child physical activity participation. Process evaluation of our int
Published: 2016

3. Mucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells

Author: National Health and Medical Research Council (Australia), Cancer Institute NSW (Australia), Dutch Cancer Society, Ministerio de Educación y Ciencia (España), Dr. Saal van Zwanenberg Foundation, Oncology Children's Foundation, Children's Hospital at Westmead, Fanayan, Susan, Shehata, Mona, Agterof, Annelies P., McGuckin, Michael A., Alonso, Miguel A., Byrne, Jennifer A., National Health and Medical Research Council (Australia), Cancer Institute NSW (Australia), Dutch Cancer Society, Ministerio de Educación y Ciencia (España), Dr. Saal van Zwanenberg Foundation, Oncology Children's Foundation, Children's Hospital at Westmead, Fanayan, Susan, Shehata, Mona, Agterof, Annelies P., McGuckin, Michael A., Alonso, Miguel A., and Byrne, Jennifer A.
Abstract: Background: The MAL2 gene, encoding a four-transmembrane protein of the MAL family, is amplified and overexpressed in breast and other cancers, yet the significance of this is unknown. MAL-like proteins have trafficking functions, but their molecular roles are largely obscure, partly due to a lack of known binding partners. Methods: Yeast two-hybrid screening of a breast carcinoma cDNA expression library was performed using a full-length MAL2 bait, and subsequent deletion mapping experiments were performed. MAL2 interactions were confirmed by co-immunoprecipitation analyses and confocal microscopy was employed to compare protein subcellular distributions. Sucrose density gradient centrifugation of membranes extracted in cold Triton X-100 was employed to compare protein distributions between Triton X-100-soluble and -insoluble fractions. Results: The tumor-associated protein mucin 1 (MUC1) was identified as a potential MAL2 partner, with MAL2/ MUC1 interactions being confirmed in myc-tagged MAL2-expressing MCF-10A cells using coimmunoprecipitation assays. Deletion mapping experiments demonstrated a requirement for the first MAL2 transmembrane domain for MUC1 binding, whereas the MAL2 N-terminal domain was required to bind D52-like proteins. Confocal microscopy identified cytoplasmic co-localisation of MUC1 and MAL2 in breast cell lines, and centrifugation of cell lysates to equilibrium in sucrose density gradients demonstrated that MAL2 and MUC1 proteins were co-distributed between Triton X-100-soluble and -insoluble fractions. However coimmunoprecipitation analyses detected MAL2/MUC1 interactions in Triton X-100-soluble fractions only. Myc- MAL2 expression in MCF-10A cells was associated with both increased MUC1 detection within Triton X-100- soluble and -insoluble fractions, and increased MUC1 detection at the cell surface. Conclusion: These results identify MUC1 as a novel MAL2 partner, and suggest a role for MAL2 in regulating MUC1 expression and/or localisation.
Published: 2009

4. D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile

Author: Valleix, S., Guglielmo Verona, Jourde-Chiche, N., Nédelec, B., Mangione, P. P., Bridoux, F., Mangé, A., Dogan, A., Goujon, J. -M, Lhomme, M., Dauteuille, C., Chabert, M., Porcari, R., Waudby, C. A., Relini, A., Talmud, P. J., Kovrov, O., Olivecrona, G., Stoppini, M., Christodoulou, J., Hawkins, P. N., Grateau, G., Delpech, M., Kontush, A., Gillmore, J. D., Kalopissis, A. D., Bellotti, V., Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Bocconi University, Bocconi University [Milan, Italy], Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie de l'Endothelium, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Pavia = University of Pavia (UNIPV), Service de Néphrologie CHU Poitiers, 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), Mayo Clinic, Service d’Anapathomopathologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU), University College of London [London] (UCL), University of London [London], Università degli studi di Genova = University of Genoa (UniGe), Centre For Cardiovascular Genetics, Royal Free and UCL Medical School, Umeå University, Dept Mol Med, Genetic Metabolic Disorders Research Unit, Kids Research Institute-Westmead Hospital [Sydney], Discipline of Paediatrics & Child Health, The University of Sydney, Discipline of Genetic Medicine, Sydney Medical School-The University of Sydney, Western Sydney Genetics Program, Westmead Hospital [Sydney], CHU Tenon [AP-HP], CHU Saint-Antoine [AP-HP], UCL, Ctr Amyloidosis & Acute Phase Prot, University College of London [London] (UCL)-University ofLondon, l’Association Franc ̧aise contre l’Amylose, the Institut Nationalde la Sante ́et de la Recherche Me ́dicale (INSERM) and the French National ReferenceCenter for AL amyloidosis, the UK NHS Research and Development funds, theUniversity College London Amyloidosis Research Fund and grants from the UK MedicalResearch Council (MR/K000187/1), the Rosetrees Trust/Royal Free Charity PhDprogramme (M427), the British Heart Foundation (PG08/008), the Wellcome TrustInvestigator Award (097806/Z/11/Z), the Cariplo Foundation Projects (2014–0700 and2013-0964), the Telethon Grant GG14127, the INBB (National Institute of Biostructuresand Biosystems), the Italian Ministry of Health and the Italian Ministry of University andResearch (Projects FIRB RBFR109EOS), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], DIGNAT-GEORGE, Françoise, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Université Montpellier 1 ( UM1 ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], University of Genoa ( UNIGE ), University of Pavia, Children's Hospital at Westmead-Kids Research Institute, The University of Sydney [Sydney], Sydney Medical School-The University of Sydney [Sydney], Children's Hospital at Westmead, University College of London [London] ( UCL ) -University ofLondon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Genoa (UNIGE), and Westmead Hospital [Sydney]-Kids Research Institute
Subjects: Adult, Male, Hyperlipoproteinemias, Science, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Mutation, Missense, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Lipoproteins, VLDL, bcs, Article, LIPASE ACTIVITY, OF-FUNCTION MUTATIONS, Humans, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), Aged, Aged, 80 and over, Apolipoprotein C-III, CELLULAR CHOLESTEROL EFFLUX, [ SDV ] Life Sciences [q-bio], Base Sequence, Amyloidosis, Middle Aged, LIPID-BINDING, ANTIOXIDATIVE ACTIVITY, Pedigree, [SDV] Life Sciences [q-bio], HDL PARTICLES, A-I, ELEVATED OXIDATIVE STRESS, Cardiovascular Diseases, Female, lipids (amino acids, peptides, and proteins), France, Lipoproteins, HDL, DENSE LDL, TRIGLYCERIDE-RICH LIPOPROTEINS
Abstract: Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients., Decrease in Apolipoprotein C-III (ApoC-III) yields a cardioprotective lipoprotein profile. Here, Valleix et al. reveal a novel ApoC-III variant conferring low plasma ApoC-III concentration and cardioprotection despite renal insufficiency, and, unexpectedly, causing dominant hereditary systemic amyloidosis due to its fibrillogenic nature.
Published: 2016

5. Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia

Author: Sandra T. Cooper, Minal Menezes, Joëlle Rudinger-Thirion, Lisa G. Riley, Rachael M. Duff, Mark R. Davis, Michel Tchan, Pascale de Lonlay, John Christodoulou, Agnès Rötig, Genetic Metabolic Disorders Research Unit, Westmead Hospital [Sydney]-Kids Research Institute, Discipline of Paediatrics & Child Health, The University of Sydney, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre for Medical Research, The University of Western Australia (UWA)-Western Australian Institute for Medical Research, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetic Medicine, Westmead Hospital [Sydney], Discipline of Genetic Medicine, Sydney Medical School-The University of Sydney, Diagnostic Genomics, QEII Medical Centre, Institute for Neuroscience and Muscle Research, Kids Research Institute-Westmead Hospital [Sydney], Western Sydney Genetics Program, This research was supported by a March of Dimes Research Grant, and National Health and Medical Research Council of Australia Project Grant 1026891. M.M. is an Australian Mitochondrial Diseases Foundation (AMDF) Postgraduate Research Scholar, and the AMDF also provided financial support to RD and MD., Sydney Medical School, March of Dimes Research Grant, National Health and Medical Research Council of Australia Project Grant 1026891. M.M. is an Australian Mitochondrial Diseases Foundation (AMDF) Postgraduate Research Scholar, and the AMDF also provided financial support to RD and MD., Children's Hospital at Westmead-Kids Research Institute, The University of Sydney [Sydney], Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), The University of Western Australia ( UWA ) -Western Australian Institute for Medical Research, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Westmead Hospital, Children's Hospital at Westmead, BMC, Ed., Architecture et Réactivité de l'ARN, Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), and Sydney Medical School-The University of Sydney [Sydney]
Subjects: Adult, Mitochondrial respiratory chain, Muscle diseases, Adolescent, Myopathy with lactic acidosis and sideroblastic anemia, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, DNA, Mitochondrial, Lactic acidaemia, 03 medical and health sciences, Young Adult, Mitochondrial myopathy, Tyrosine-tRNA Ligase, Aminoacyl tRNA-synthetase, medicine, Humans, Genetics(clinical), Pharmacology (medical), Myopathy, Child, Gene, Genetics (clinical), Hydro-Lyases, 030304 developmental biology, Acidosis, Medicine(all), Genetics, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Research, 030305 genetics & heredity, Infant, Newborn, Infant, General Medicine, Inborn error of metabolism, medicine.disease, Anemia, Sideroblastic, Lactic acidosis, Child, Preschool, Acidosis, Lactic, Female, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Mitochondrial myopathies
Abstract: Background Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. Methods Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. Results PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. Conclusion In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.
Published: 2013

6. Outcome measures for technique survival reported in peritoneal dialysis: A systematic review

Author: Thu Nguyen, Simon J. Davies, David W. Johnson, Mark Lambie, Yeoungjee Cho, Karine E. Manera, Josephine Chow, Adrian Liew, Allison Tong, Tess Harris, Matthew Holmes, Neil Boudville, Jeffrey Perl, Arsh K. Jain, Angela Yee-Moon Wang, Daniela Ponce, Emma Elphick, Matthew Tabinor, Annie Claire Nadeau-Fredette, Keele University, Princess Alexandra Hospital, The University of Queensland, Translational Research Institute, Auckland City Hospital, Polycystic Kidney Disease International, Polycystic Kidney Disease Charity, Queen Mary Hospital, Western University, Universidade Estadual Paulista (Unesp), South Western Sydney Local Health District, University of Sydney, University of New South Wales, University of Tasmania, Maisonneuve-Rosemont Research Centre and Hospital, Mount Elizabeth Novena Hospital, University of Western Australia, The Children’s Hospital at Westmead, and University of Toronto
Subjects: medicine.medical_specialty, Health professionals, business.industry, medicine.medical_treatment, Peritoneal dialysis, Outcome measures, General Medicine, Outcome (game theory), RC845, RC902, systematic review, Nephrology, Renal Dialysis, Outcome Assessment, Health Care, technique survival, medicine, Humans, Intensive care medicine, business, transfer to haemodialysis, Peritoneal Dialysis
Abstract: Made available in DSpace on 2021-06-25T10:28:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Background: Peritoneal dialysis (PD) technique survival is an important outcome for patients, caregivers and health professionals, however, the definition and measures used for technique survival vary. We aimed to assess the scope and consistency of definitions and measures used for technique survival in studies of patients receiving PD. Method: MEDLINE, EMBASE and CENTRAL databases were searched for randomised controlled studies (RCTs) conducted in patients receiving PD reporting technique survival as an outcome between database inception and December 2019. The definition and measures used were extracted and independently assessed by two reviewers. Results: We included 25 RCTs with a total of 3645 participants (41–371 per trial) and follow up ranging from 6 weeks to 4 years. Terminology used included ‘technique survival’ (10 studies), ‘transfer to haemodialysis (HD)’ (8 studies) and ‘technique failure’ (7 studies) with 17 different definitions. In seven studies, it was unclear whether the definition included transfer to HD, death or transplantation and eight studies reported ‘transfer to HD’ without further definition regarding duration or other events. Of those remaining, five studies included death in their definition of a technique event, whereas death was censored in the other five. The duration of HD necessary to qualify as an event was reported in only four (16%) studies. Of the 14 studies reporting causes of an event, all used a different list of causes. Conclusion: There is substantial heterogeneity in how PD technique survival is defined and measured, likely contributing to considerable variability in reported rates. Standardised measures for reporting technique survival in PD studies are required to improve comparability. School of Medicine Keele University Department of Nephrology Princess Alexandra Hospital Australasian Kidney Studies Network The University of Queensland Translational Research Institute Department of Renal Medicine Auckland City Hospital Polycystic Kidney Disease International Polycystic Kidney Disease Charity Department of Medicine The University of Hong Kong Queen Mary Hospital Department of Medicine Western University Botucatu School of Medicine University of Sao Paulo State—UNESP Clinical Innovation and Business Unit South Western Sydney Local Health District Faculty of Nursing University of Sydney UNSW Faculty of Medicine University of New South Wales School of Health Science University of Tasmania Maisonneuve-Rosemont Research Centre and Hospital The Kidney and Transplant Practice Mount Elizabeth Novena Hospital Medical School University of Western Australia Sydney School of Public Health University of Sydney and Centre for Kidney Research The Children’s Hospital at Westmead Division of Nephrology St Michael’s Hospital and the Keenan Research Centre in the Li Ka Shing Knowledge Institute St Michael’s Hospital University of Toronto Botucatu School of Medicine University of Sao Paulo State—UNESP
Published: 2021

7. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Author: Nicola Marziliano, H. Plauchu, Peter N. Robinson, Catherine Boileau, Bert Callewaert, Uta Francke, P Comeglio, Christine Binquet, J. De Backer, Guillaume Jondeau, Dorothy Halliday, Christophe Béroud, Paul Coucke, A. De Paepe, Katherine Holman, Kenneth H. Mayer, B. Benetts, Andrew Biggin, Eloisa Arbustini, Hal Dietz, Anne H. Child, Gwenaëlle Collod-Béroud, Christine Muti, Laurence Faivre, Mireille Claustres, A Kiotsekoglou, Lesley C. Adès, Mine Arslan-Kirchner, Maggie Brett, Bart Loeys, Claire Bonithon-Kopp, Elodie Gautier, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Genetics [Ghent], Ghent University Hospital, Howard Hughes Medical Institute (HHMI), Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Molecular Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Cardiological Sciences, Saint George's Hospital Medical School, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], The Children's Hospital ant Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and COLLOD-BEROUD, Gwenaëlle
Subjects: Marfan syndrome, Proband, Male, MESH: Epidermal Growth Factor, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Severity of Illness Index, Marfan Syndrome, MESH: Protein Structure, Tertiary, MESH : Exons, 0302 clinical medicine, Transforming Growth Factor beta, Genotype, Missense mutation, MESH : Female, Genetics(clinical), Ectopia lentis, Genetics (clinical), MESH : Epidermal Growth Factor, Genetics, 0303 health sciences, MESH : Prognosis, Microfilament Proteins, Exons, MESH : Adult, Prognosis, 3. Good health, MESH : Phenotype, Phenotype, Mutation (genetic algorithm), MESH : Severity of Illness Index, Female, MESH : Mutation, Haploinsufficiency, MESH : Protein Structure, Tertiary, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Biology, MESH: Phenotype, Fibrillins, MESH: Prognosis, Article, MESH: Marfan Syndrome, MESH: Microfilament Proteins, 03 medical and health sciences, MESH : Adolescent, MESH: Severity of Illness Index, medicine, Humans, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, Epidermal Growth Factor, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH : Transforming Growth Factor beta, Inframe Mutation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Exons, MESH: Female
Abstract: International audience; Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.
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8. Further delineation of the KAT6B molecular and phenotypic spectrum

Author: DDD study, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan FM, Smith, Janine, Clayton-Smith, Jill, Regional Genetic Service, St Mary's Hospital, Manchester, Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Haukeland University Hospital, Royal Brsibane and Womens' Hospital, The University of Queensland, Department of Clinical Genetics, Children’s Hospital at Westmead, Service de génétique médicale, AP-HP Hôpital Necker - Enfants Malades [Paris], Institute of Human Genetics, Universität Ulm, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Karolinska University Hospital, Karolinska University Hospital [Stockholm], University Hospitals Bristol, University of Birmingham [Birmingham], Hacettepe University Children's Hospital, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Division of Genetics, Birth Defects and Metabolism, Children's hospital of Chicago, Clinical Genetics, Guy's Hospital [London], North West london hospitals NHS Trust, Department of Clinical Genetics, Northampton General Hospital, Northampton, Barzilai Medical Center, Cliniques Universitaires St Luc, Université Catholique de Louvain (UCL), Service de génétique [Tours], Hôpital Bretonneau - CHRU Tours, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1) - 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 clinique [Rennes], Université de Rennes 1 (UR1) - CHU Pontchaillou [Rennes] - Hôpital Sud, Pediatrics, Istanbul University Cerrahpasa, Birmingham Women’s Hospital, University of Groningen [Groningen], Belfast City Hospital, Centre For Medical Genetics, Clinical Genetic Service, Department of Health, Institute of Medical Genetics, Heath Park, Cardiff, National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Dipartimento di Medicina Molecolare, University of Pavia, UZ Leuven - campus Gasthuisberg, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children’s Hospital, Service de Génétique, CHU Reims - Hôpital Maison Blanche - IFR 53, Leiden University Medical Center, Service de Génétique humaine, Université de Lausanne (UNIL), Çocuk Sağlığı ve Hastalıkları, University of Bergen (UiB), Westmead Hospital [Sydney], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, 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 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Sheffield Children's NHS Foundation Trust, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Leiden University Medical Center (LUMC), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Nottingham University Hospitals NHS Trust (NUH), 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 ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Università degli Studi di Pavia = University of Pavia (UNIPV), Universiteit Leiden-Universiteit Leiden, Université de Lausanne = University of Lausanne (UNIL), DDD study, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Male, DNA Mutational Analysis, Medizin, Gene Expression, Kidney, Severity of Illness Index, Craniofacial Abnormalities, Missense mutation, Exome, Genetics (clinical), Histone Acetyltransferases, Genetics, OHDO SYNDROME, Patella, Exons, Hypotonia, 3. Good health, Blepharophimosis/diagnosis, Blepharophimosis/genetics, Child, Preschool, Congenital Hypothyroidism/diagnosis, Congenital Hypothyroidism/genetics, Craniofacial Abnormalities/diagnosis, Craniofacial Abnormalities/genetics, Diagnosis, Differential, Facies, Female, Genetic Association Studies, Genotype, Heart Defects, Congenital/diagnosis, Heart Defects, Congenital/genetics, Histone Acetyltransferases/genetics, Humans, Intellectual Disability/diagnosis, Intellectual Disability/genetics, Joint Instability/diagnosis, Joint Instability/genetics, Kidney/abnormalities, Kidney/pathology, Mutation, Patella/abnormalities, Patella/pathology, Phenotype, Psychomotor Disorders/diagnosis, Psychomotor Disorders/genetics, Scrotum/abnormalities, Scrotum/pathology, Urogenital Abnormalities/diagnosis, Urogenital Abnormalities/genetics, Scrotum, Medical genetics, genitopatellar, Say-Barber-Biesecker, medicine.symptom, Psychomotor disorder, Haploinsufficiency, Heart Defects, Congenital, Joint Instability, medicine.medical_specialty, Biology, Blepharophimosis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, KAT6B, Article, Intellectual Disability, medicine, Congenital Hypothyroidism, CAUSE GENITOPATELLAR SYNDROME, medicine.disease, blepharophimosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Urogenital Abnormalities, Genitopatellar syndrome, HISTONE ACETYLTRANSFERASE KAT6B, Psychomotor Disorders, MENTAL-RETARDATION
Abstract: International audience; KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.
Published: 2015

9. In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

Author: Anne H. Child, Christophe Béroud, Catherine Boileau, Jaime Sanchez del Pozo, Julie De Backer, Cyril Goizet, Jeanne Amiel, Lesley C. Adès, Pierre Vabres, Anne De Paepe, Julien Thevenon, Laurence Duplomb, Katherine Holman, Christel Thauvin-Robinet, Clarisse Baumann, Frédéric Huet, Ghislaine Plessis, Gwenaëlle Collod-Béroud, Bert Callewaert, Eloisa Arbustini, Henri Plauchu, Bernard Aral, Peter N. Robinson, Sophie Julia, Jean Baptiste Rivière, Valérie Cormier-Daire, Gavin Arno, Nadège Gigot, Marjolijn Renard, Lucie Gueneau, Guillaume Jondeau, Patrick Callier, Jean Benoît Courcet, Maja Di Rocco, Laurence Faivre, Virginie Carmignac, Estelle Lopez, Maurizia Grasso, 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 medical genetics, Royal Alexandra Children's Hospital, Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de pédiatrie (CHU de Dijon), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Marfan Research Group, Westmead Hospital [Sydney], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Cardiac & Vascular Sciences, St Georges, University of London, Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de Biologie Moléculaire, Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, IRCCS - Pavia, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Service de Génétique Médicale du CHU de Bordeaux, Hôpital Robert Debré Paris, Hôpital Robert Debré, Université de Technologie de Compiègne (UTC), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Médicale et Génomique Fonctionnelle (GMGF), 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)-Centre National de la Recherche Scientifique (CNRS), Head of the Department of Medical Genetics, Center for Medical Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), 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 ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), The Children's Hospital at Westmead, Service de Génétique, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hôtel Dieu, Service de génétique, CHU Caen-Hôpital Clémenceau, Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Université de Technologie de Compiègne [Compiègne] ( UTC ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Ghent University [Belgium] ( UGENT ), COLLOD-BEROUD, Gwenaëlle, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), 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)-Arts et Métiers Sciences et Technologies, 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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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)-Centre National de la Recherche Scientifique (CNRS), and Universiteit Gent = Ghent University (UGENT)
Subjects: Male, Models, Molecular, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Marfan Syndrome, Arachnodactyly, Exon, 0302 clinical medicine, Gene Order, Missense mutation, Genetics(clinical), Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Exome sequencing, Genes, Dominant, Genetics, 0303 health sciences, Mutation, Shprintzen–Goldberg syndrome, Exons, Phenotype, Pedigree, DNA-Binding Proteins, Child, Preschool, Female, medicine.symptom, Adult, Adolescent, Molecular Sequence Data, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Camptodactyly, Craniosynostoses, Young Adult, stomatognathic system, Report, Proto-Oncogene Proteins, medicine, Humans, Amino Acid Sequence, 030304 developmental biology, Facies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Molecular biology, Protein Structure, Tertiary, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sequence Alignment, human activities, 030217 neurology & neurosurgery
Abstract: International audience; Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.
Published: 2012

10. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias

Author: Angela F. Brady, Louise Zylberberg, Yasemin Alanay, Gwenaëlle Collod-Béroud, Andrea Superti-Furga, Sally Ann Lynch, Michel Polak, Avinash Abhyankar, André Mégarbané, Martine Le Merrer, Suneel S. Apte, Marie-Pierre Cordier, Carine Le Goff, Arnold Munnich, Clémentine Mahaut, David Sillence, Sacha A. Jensen, Pelin Özlem Şimşek Kiper, Christine Bole-Feysot, Lauren W. Wang, David L. Rimoin, Vicken Topouchian, Patrick Nitschke, Slimane Allali, Koenraad Devriendt, Penny A. Handford, Catherine Boileau, Sylvie Odent, Deborah Krakow, Irene Stolte-Dijkstra, Damien Bonnet, Geert Mortier, Valérie Cormier-Daire, Sheila Unger, Jean-Laurent Casanova, Bernhard Zabel, Marianne Rohrbach, Hiroshi Kitoh, David Geneviève, Çocuk Sağlığı ve Hastalıkları, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Department of Biochemistry [Oxford], University of Oxford, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de cardiologie 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), Department of Pediatrics, Hacettepe University = Hacettepe Üniversitesi, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Institute of Child Health, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Department of Orthopaedic Surgery, Nagoya University, Department of Molecular Cellular and Developmental Biology, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-Howard Hughes Medical Institute (HHMI), Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Genetics, Universiteit Gent = Ghent University (UGENT), hôpital Sud, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics, Academic Department of Medical Genetics, Westmead Hospital [Sydney], Department of Clinical Genetics, Service de Pédiatrie, Université de Lausanne = University of Lausanne (UNIL), Service de chirurgie orthopédique pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de Génétique humaine, Centre for Pediatrics and Adolescent Medicine, University of Freiburg [Freiburg]-University Hospital Freiburg, Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Génétique Humaine des Maladies Infectieuses (Inserm U980), Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Department of Biomedical Engineering, Cleveland Clinic-Lerner Research Institute, University of Oxford [Oxford], Institut des Sciences de la Terre de Paris (iSTeP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Référence Malformations Cardiaques Congénitales Complexes, North West Thames Regional Genetics, Northwick Park Hospital, Service de Génétique, Hospices Civils de Lyon (HCL), Center for Human Genetics, Université Catholique de Louvain (UCL)-Cliniques Universitaires Saint-Luc [Bruxelles], Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departments of Orthopedic Surgery and Human Genetics, University of California-University of California, National Centre for Medical Genetics, Antwerp University Hospital [Edegem] (UZA), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), service d'endocrinologie, gynécologie, diabétologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Division of Metabolism, University Children's Hospital, Clinical genetics, University Medical Center Groningen [Groningen] (UMCG), Université de Lausanne (UNIL), Medical Genetics Institute, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Bioinformatique, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré [AP-HP], Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California-University of California-Howard Hughes Medical Institute (HHMI), Universiteit Gent = Ghent University [Belgium] (UGENT), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Génomique et Physiologie de la Lactation (GPL), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Ghent University [Belgium] (UGENT), Hôpital Sud, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cleveland Clinic Foundation-Lerner Research Institute, St Giles laboratory of Human Genetics and Infectious Diseases, Institut des Sciences de la Terre de Paris ( iSTeP ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hospices Civils de Lyon ( HCL ), Université Catholique de Louvain ( UCL ) -Cliniques Universitaires Saint-Luc [Bruxelles], Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of California at Los Angeles [Los Angeles] ( UCLA ), Université Saint-Joseph de Beyrouth ( USJ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University Hospital Antwerp, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Sud, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], The Children's Hospital at Westmead, University Medical Center Groningen, Université de Lausanne ( UNIL ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris Descartes - Paris 5 ( UPD5 ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, University of Zurich, and Cormier-Daire, V
Subjects: MESH: Extracellular Matrix Proteins, DNA Mutational Analysis, Fluorescent Antibody Technique, Marfan Syndrome, MESH : Dwarfism, MESH: Protein Structure, Tertiary, Arachnodactyly, 0302 clinical medicine, MESH : Child, MESH: Child, Acromicric dysplasia, Genetics(clinical), Eye Abnormalities, MESH: DNA Mutational Analysis, MESH: Dwarfism, Child, MESH: Fluorescent Antibody Technique, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Exome sequencing, Genetics & Heredity, Inclusion Bodies, 0303 health sciences, Mutation, Extracellular Matrix Proteins, MESH: Middle Aged, 3. Good health, MESH : Connective Tissue, MESH : Phenotype, MESH: Young Adult, Child, Preschool, MESH : Protein Structure, Tertiary, musculoskeletal diseases, MESH : Heterozygote, MESH: Connective Tissue, MESH : Young Adult, Limb Deformities, Congenital, Dwarfism, MESH : DNA Mutational Analysis, MESH: Phenotype, Fibrillins, Article, 03 medical and health sciences, 1311 Genetics, MESH : Adolescent, Genetics, Humans, MESH : Middle Aged, MESH: Adolescent, MESH: Bone Diseases, Developmental, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bone Diseases, Developmental, MESH : Bone Diseases, Developmental, MESH: Humans, MESH : Humans, MESH: Child, Preschool, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Protein Structure, Tertiary, MESH : Microfibrils, MESH : Fluorescent Antibody Technique, Human medicine, MESH : Transforming Growth Factor beta1, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, MESH: Signal Transduction, Candidate gene, Fibrillin-1, MESH : Child, Preschool, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, MESH: Transforming Growth Factor beta1, MESH : Exons, Genetics (clinical), MESH: Heterozygote, Microfilament Proteins, Exons, MESH : Adult, Middle Aged, MESH: Eye Abnormalities, Weill–Marchesani syndrome, MESH: Microfibrils, Phenotype, Connective Tissue, MESH : Mutation, medicine.symptom, Fibrillin, Signal Transduction, MESH : Limb Deformities, Congenital, Adult, 2716 Genetics (clinical), congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, MESH: Limb Deformities, Congenital, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, 610 Medicine & health, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Short stature, MESH: Marfan Syndrome, Transforming Growth Factor beta1, MESH: Microfilament Proteins, Young Adult, MESH : Extracellular Matrix Proteins, MESH : Eye Abnormalities, medicine, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, 030304 developmental biology, MESH : Signal Transduction, MESH : Marfan Syndrome, MESH: Inclusion Bodies, GENE, MESH : Inclusion Bodies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 10036 Medical Clinic, Microfibrils, MESH: Exons, MATRIX
Abstract: International audience; Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFb-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFb signaling were consistent features in GD and AD fibro-blasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFb signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
Published: 2011

11. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion

Author: Bert Callewaert, A. De Paepe, Mireille Claustres, Laurence Faivre, Lesley C. Adès, Anne H. Child, Eloisa Arbustini, O Bouchot, Uta Francke, P. Comeglio, A. Kiotsekoglou, Maurizia Grasso, Christophe Béroud, Peter N. Robinson, Guillaume Jondeau, Mine Arslan-Kirchner, Claire Bonithon-Kopp, J. De Backer, Gwenaëlle Collod-Béroud, Elodie Gautier, Bart Loeys, Christine Binquet, Catherine Boileau, Paul Coucke, Chantal Stheneur, Kenneth H. Mayer, Jean-Eric Wolf, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré [AP-HP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de chirurgie cardio-vasculaire, Institut für Medizinische Genetik, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics and Pediatrics, Stanford University [Stanford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM), Service d'Ophtalmologie (CHU de Dijon), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut für Physik, Humboldt-Universität zu Berlin, Newtonstr. 15, D-12489 Berlin, Germany, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital du Bocage, Karlsruhe Institute of Technology (KIT), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), 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)-Hôpital Bichat, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université de Montpellier ( UM ), Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe Appl. Phys. ( GAP ), GAP, Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Karlsruhe Institute of Technology ( KIT ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Humboldt University Of Berlin, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, UFR Paris-Ile-de-France-Ouest (PIFO), Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Service de biochimie, d'hormonologie et de génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and COLLOD-BEROUD, Gwenaëlle
Subjects: Marfan syndrome, Nosology, Adult, Male, Pediatrics, medicine.medical_specialty, Systemic disease, Fibrillin-1, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Fibrillins, Ectopia Lentis, Marfan Syndrome, Cohort Studies, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetics, medicine, Missense mutation, Humans, Ectopia lentis, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, 030305 genetics & heredity, Microfilament Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.disease, Connective tissue disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cohort, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business
Abstract: International audience; Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.
Published: 2009

12. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation

Author: Mine Arslan-Kirchner, Eloisa Arbustini, A. De Paepe, Paul Coucke, Jean-Eric Wolf, O Bouchot, Bart Loeys, P Khau-Van-Kien, Chantal Stheneur, Peter N. Robinson, Elodie Gautier, Nicola Marziliano, Bert Callewaert, Karin Mayer, Christophe Béroud, P Comeglio, Mireille Claustres, A Kiotsekoglou, Claire Bonithon-Kopp, Laurence Faivre, Lesley C. Adès, Guillaume Jondeau, Anne H. Child, Gwenaëlle Collod-Béroud, Catherine Boileau, Uta Francke, J. De Backer, Christine Binquet, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Institute of Genetic Medicine and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Hôpital Ambroise Paré [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie [CHU de Dijon], Service de chirurgie cardio-vasculaire, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Centre de reference national pour le syndrome de Marfan et apparentés, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by a grant from the French ministry of health (PHRC 2004), GIS maladies rares 2004, Bourse de la Société Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005 and ANR-05-PCOD-014. BC and BL are respectively a research fellow and a senior clinical investigator of the Fund for Scientific Research – Flanders. AC and PC thank the Marfan Trust and the Bluff Field Charitable Fund for support., 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)-Arts et Métiers Sciences et Technologies, 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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie cardio-vasculaire et thoracique (CHU Dijon), COLLOD-BEROUD, Gwenaëlle, Université de Bourgogne (UB) - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 (UM1) - IFR3 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de Montpellier (UM), Centre for Medical Genetics, Hannover Medical School [Hannover] (MHH) - Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Laboratoire Electronique, Informatique et Image (Le2i), Centre National de la Recherche Scientifique (CNRS) - Université de Bourgogne (UB) - AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Cardiologie II, Centre Hospitalier Universitaire, Laboratoire de Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) - Hôpital Arnaud de Villeneuve, Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat - Claude Bernard [Paris], Service de biochimie, d'hormonologie et de génétique moléculaire, Handicaps génétiques de l'enfant, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), UFR P.I.F.O, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), and HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: Proband, Marfan syndrome, clinical and mutation-type analysis, congenital, hereditary, and neonatal diseases and abnormalities, Fibrillin-1, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Fibrillins, Article, Ectopia Lentis, [SHS.INFO] Humanities and Social Sciences/Library and information sciences, Neonatal Marfan syndrome, 03 medical and health sciences, Exon, Genetics, medicine, Humans, Ectopia lentis, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, 030305 genetics & heredity, Microfilament Proteins, Exons, exons 24–32, medicine.disease, Phenotype, 3. Good health, Codon, Nonsense, Mutation (genetic algorithm), Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, FBN1 mutations
Abstract: International audience; Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.
Published: 2009

13. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations

Author: Frédéric Huet, Peter N. Robinson, Guillaume Jondeau, Karin Mayer, Claire Bonithon-Kopp, Bertrand Chevallier, Uta Francke, Elodie Gautier, Laurence Faivre, Anne H. Child, Anatoli Kiotsekoglou, Christophe Béroud, Mireille Claustres, Bart Loeys, Maurizia Grasso, Gwenaëlle Collod-Béroud, Mine Arslan-Kirchner, Christine Binquet, Alice Masurel-Paulet, Catherine Boileau, Eloisa Arbustini, Julie De Backer, Anne De Paepe, Lesley C. Adès, Bert Callewaert, Dorothy Halliday, P Comeglio, Paul Coucke, Chantal Stheneur, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Howard Hughes Medical Institute (HHMI), Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by a grant from the French Ministry of Health (grant Programme Hospitalier de Recherche Clinique 2004), Groupement d’Intérêt Scientifique Maladies Rares 2004, Bourse de la Société Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005, and ANR-05-PCOD-014. Drs Callewaert and Loeys are a research fellow and a senior clinical investigator, respectively, of the Fund for Scientific ResearchFlanders. Drs Child and Comeglio thank the Marfan Trust and the Bluff Field Charitable Fund for support., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Service de biochimie, d'hormonologie et de génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, and Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 )
Subjects: Male, Proband, Marfan syndrome, Pediatrics, CI— confidence interval, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, MESH : Child, Preschool, PTC—premature termination codon, AAD—ascending aortic dilation, 0302 clinical medicine, MESH: Genetic Screening, MESH : Child, MESH: Child, Medicine, MESH : Female, Family history, Child, Ectopia lentis, Aortic dissection, education.field_of_study, Dural ectasia, Microfilament Proteins, MESH: Follow-Up Studies, Connective tissue disease, 3. Good health, MFS—Marfan syndrome, Child, Preschool, Female, MESH : Mutation, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Adolescent, MESH : Microfilament Proteins, Abbreviations, MESH : Male, Population, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH: Microfilament Proteins, MESH : Adolescent, Humans, Genetic Testing, FBN1, education, childhood, MESH : Genetic Screening, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, MESH : Follow-Up Studies, medicine.disease, EL— ectopia lentis, MESH: Male, Surgery, Mutation, Pediatrics, Perinatology and Child Health, international criteria, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients
Published: 2009

14. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands

Author: Guillaume Jondeau, Mine Arslan-Kirchner, Christophe Béroud, Peter N. Robinson, Christine Binquet, Anne H. Child, J. De Backer, Paul Coucke, Eloisa Arbustini, Gwenaëlle Collod-Béroud, Elodie Gautier, Chantal Stheneur, Laurence Faivre, Mireille Claustres, Karin Mayer, Claire Bonithon-Kopp, H. Plauchu, Uta Francke, Catherine Boileau, A De Paepe, A Kiotsekoglou, Lesley C. Adès, Bart Loeys, Nicola Marziliano, Bert Callewaert, P Comeglio, Dorothy Halliday, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Cardiological Sciences, St George's Hospital, Center for Medical Genetics [Ghent], Ghent University Hospital, Institute of Genetic Medicine and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Department of Biochemistry [Oxford], University of Oxford [Oxford], Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], This work was supported by a grant from the French ministry of health (PHRC 2004), GIS maladies rares 2004, Bourse de la Socie´te´ Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005, and ANR-05-PCOD-014. BC and BL are respectively a research fellow and a senior clinical investigator of the Fund for Scientific Research – Flanders. AC and PC thank the Marfan Trust, and the Bluff Field Charitable Fund for support., COLLOD-BEROUD, Gwenaëlle, University of Oxford, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], Department of Genetics and Pediatrics, Stanford University [Stanford], and Service de biochimie, d'hormonologie et de génétique moléculaire
Subjects: Proband, Nosology, Marfan syndrome, Male, Pediatrics, Systemic disease, MESH : International Cooperation, Fibrillin-1, International Cooperation, MESH : Aged, [SDV.GEN] Life Sciences [q-bio]/Genetics, Marfan Syndrome, MESH : Child, MESH: Child, Epidemiology, MESH : Female, Ectopia lentis, Child, Genetics (clinical), Aorta, Aortic dissection, MESH: Aged, 0303 health sciences, 030305 genetics & heredity, Microfilament Proteins, MESH: Aorta, MESH : Adult, Connective tissue disease, 3. Good health, Female, MESH : Mutation, musculoskeletal diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH: Microfilament Proteins, MESH : Adolescent, Genetics, medicine, Humans, 030304 developmental biology, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, business.industry, MESH : Humans, MESH : Aorta, MESH: Adult, medicine.disease, MESH: Male, MESH: International Cooperation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, MESH: Female
Abstract: International audience; BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p
Published: 2008

15. Interventions to improve gross motor performance in children with neurodevelopmental disorders: a meta-analysis

Author: Sarah Westcott McCoy, Rafael Z. Pinto, Barbara R. Lucas, Sarah Coggan, Tracy Jirikowic, Elizabeth J Elliott, Jane Latimer, Clinical School, University of Sydney, The University of Sydney, Physiotherapy Department, The Sydney Children's Hospital Networks (Westmead), Curtin University, University of Sydney at Royal North Shore Hospital, Universidade Estadual Paulista (Unesp), Division of Occupational Therapy, and Division of Physical Therapy
Subjects: 030506 rehabilitation, medicine.medical_specialty, Developmental Disabilities, Gross motor skill, Psychological intervention, Motor skills, Infant, Premature, Diseases, Developmental Coordination Disorder, Motor skills disorders, Cerebral palsy, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Pediatrics, Perinatology, and Child Health, Child, Acquired brain injury, Child development, Physiotherapy, Motor skill, Physical Therapy Modalities, business.industry, Cerebral Palsy, Neurodevelopmental disorders, Infant, Newborn, Gross Motor Function Classification System, medicine.disease, 3. Good health, Clinical trial, Treatment Outcome, Fetal Alcohol Spectrum Disorders, Meta-analysis, Brain Injuries, Pediatrics, Perinatology and Child Health, Physical therapy, 0305 other medical science, business, 030217 neurology & neurosurgery, Infant, Premature, Research Article
Abstract: Made available in DSpace on 2018-12-11T17:08:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-11-29 National Institute on Alcohol Abuse and Alcoholism Background: Gross motor skills are fundamental to childhood development. The effectiveness of current physical therapy options for children with mild to moderate gross motor disorders is unknown. The aim of this study was to systematically review the literature to investigate the effectiveness of conservative interventions to improve gross motor performance in children with a range of neurodevelopmental disorders. Methods: A systematic review with meta-analysis was conducted. MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, PEDro, Cochrane Collaboration, Google Scholar databases and clinical trial registries were searched. Published randomised controlled trials including children 3 to ≤18 years with (i) Developmental Coordination Disorder (DCD) or Cerebral Palsy (CP) (Gross Motor Function Classification System Level 1) or Developmental Delay or Minimal Acquired Brain Injury or Prematurity (
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16. Mucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells

Author: Annelies P Agterof, Miguel A. Alonso, Jennifer A. Byrne, Mona Shehata, Michael A. McGuckin, Susan Fanayan, National Health and Medical Research Council (Australia), Cancer Institute NSW (Australia), Dutch Cancer Society, Ministerio de Educación y Ciencia (España), Dr. Saal van Zwanenberg Foundation, Oncology Children's Foundation, and Children's Hospital at Westmead
Subjects: Cytoplasm, DNA, Complementary, Immunoprecipitation, Proteolipids, Breast carcinoma, Vesicular Transport Proteins, Breast Neoplasms, Biology, Cell Line, Tumor, Two-Hybrid System Techniques, Humans, Deletion mapping, lcsh:QH573-671, skin and connective tissue diseases, Lipid raft, MUC1, lcsh:Cytology, Myelin and Lymphocyte-Associated Proteolipid Proteins, Carcinoma, Mucin-1, Mucin, Cell Biology, Molecular biology, Transmembrane domain, Cell culture, Mucin 1, Female, Research Article
Abstract: Background: The MAL2 gene, encoding a four-transmembrane protein of the MAL family, is amplified and overexpressed in breast and other cancers, yet the significance of this is unknown. MAL-like proteins have trafficking functions, but their molecular roles are largely obscure, partly due to a lack of known binding partners. Methods: Yeast two-hybrid screening of a breast carcinoma cDNA expression library was performed using a full-length MAL2 bait, and subsequent deletion mapping experiments were performed. MAL2 interactions were confirmed by co-immunoprecipitation analyses and confocal microscopy was employed to compare protein subcellular distributions. Sucrose density gradient centrifugation of membranes extracted in cold Triton X-100 was employed to compare protein distributions between Triton X-100-soluble and -insoluble fractions. Results: The tumor-associated protein mucin 1 (MUC1) was identified as a potential MAL2 partner, with MAL2/ MUC1 interactions being confirmed in myc-tagged MAL2-expressing MCF-10A cells using coimmunoprecipitation assays. Deletion mapping experiments demonstrated a requirement for the first MAL2 transmembrane domain for MUC1 binding, whereas the MAL2 N-terminal domain was required to bind D52-like proteins. Confocal microscopy identified cytoplasmic co-localisation of MUC1 and MAL2 in breast cell lines, and centrifugation of cell lysates to equilibrium in sucrose density gradients demonstrated that MAL2 and MUC1 proteins were co-distributed between Triton X-100-soluble and -insoluble fractions. However coimmunoprecipitation analyses detected MAL2/MUC1 interactions in Triton X-100-soluble fractions only. Myc- MAL2 expression in MCF-10A cells was associated with both increased MUC1 detection within Triton X-100- soluble and -insoluble fractions, and increased MUC1 detection at the cell surface. Conclusion: These results identify MUC1 as a novel MAL2 partner, and suggest a role for MAL2 in regulating MUC1 expression and/or localisation., This work was supported by a National Health and Medical Research Council of Australia Peter Doherty Fellowship (to SF), a Cancer Institute NSW Fellow (to JAB), funding from the Dr. Saal van Zwanenberg Foundation and the KWF Kankerbestrijding (to APA), donations to the Oncology Department of the Children's Hospital at Westmead, and the Oncology Children's Foundation. MAA is the recipient of grants BFU2006- 01925 and GEN2003-20662-C07-02 from the Spanish Ministry of Education and Science.
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17. Phase 1 trial of an investigational Tdap booster vaccine with CpG 1018 adjuvant compared with Boostrix in healthy adults and adolescents.

Author: Richmond P, Nolan T, McGirr A, Napier-Flood F, Kim J, Leah A, Xie F, Campbell JD, Godeaux O, Henry O, Wood N, and Janssen RS
Subjects: Humans, Adolescent, Female, Male, Adult, Young Adult, Child, Antibodies, Neutralizing blood, Diphtheria-Tetanus-Pertussis Vaccine immunology, Diphtheria-Tetanus-Pertussis Vaccine administration & dosage, Diphtheria-Tetanus-Pertussis Vaccine adverse effects, Tetanus prevention & control, Tetanus immunology, Healthy Volunteers, Immunogenicity, Vaccine, Antibodies, Bacterial blood, Immunization, Secondary methods, Diphtheria-Tetanus-acellular Pertussis Vaccines immunology, Diphtheria-Tetanus-acellular Pertussis Vaccines administration & dosage, Diphtheria-Tetanus-acellular Pertussis Vaccines adverse effects, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic adverse effects, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides immunology, Whooping Cough prevention & control, Whooping Cough immunology
Abstract: This phase 1 trial assessed the safety and immunogenicity of an investigational tetanus/diphtheria/acellular pertussis vaccine combined with CpG 1018 adjuvant 1500 μg (Tdap-1018 1500 μg) or 3000 μg (Tdap-1018 3000 μg) in adults and adolescents. In this randomized, active-controlled, multicenter, dose-escalation trial, healthy participants aged 10 to 22 years received 1 dose of Tdap-1018 1500 μg, Tdap-1018 3000 μg, or Boostrix. Geometric mean concentrations (GMCs) and booster response rates (BRRs) for antibodies against pertussis (pertussis toxin, filamentous hemagglutinin, pertactin), tetanus, and diphtheria antigens, and neutralizing antibodies against pertussis toxin were assessed 4 weeks after vaccination. Safety and tolerability were assessed for solicited post-injection reactions within 7 days after vaccination and unsolicited adverse events up to 12 weeks after vaccination. Of 117 enrolled participants, 80 adults (92%) and 30 adolescents (100%) completed the study. Both Tdap-1018 formulations were generally well tolerated, with no vaccine-related serious adverse events. Frequency and severity in post-injection reactions after Tdap-1018 administration were similar to Boostrix except for higher proportions of moderate pain for Tdap-1018. In adults at week 4, ratio of GMCs and BRRs for all antigens in the 3000-μg group were similar to or higher than Boostrix, with significantly higher GMC ratios for anti-pertussis toxin (2.1 [1.5-3.0]) and anti-tetanus (1.8 [1.1-2.9]) and significantly higher BRRs for anti-pertussis toxin (difference [95% CI]: 34.5% [13.4-54.6]), anti-pertactin (19.2% [4.4-38.1]), and anti-tetanus (30.0% [3.6-52.7]) antibodies. For adolescents, in the 3000-μg group, ratio of GMCs and BRRs were similar to or higher than Boostrix for all antigens. Both Tdap-1018 formulations showed acceptable safety and tolerability profiles. Tdap-1018 3000 μg induced similar or higher immune responses than Boostrix. ACTRN12620001177943 (Australian New Zealand Clinical Trials Registry; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12620001177943p)., Competing Interests: Declaration of competing interest F.X. and O.G. are consultants for Dynavax Technologies Corporation. J.D.C., O.H., and R.S.J. are employees of Dynavax Technologies Corporation and may hold company stock. P.R. has served on pertussis vaccine scientific advisory boards on behalf of his institution for GlaxoSmithKline and Sanofi outside the submitted work. T.N. has served on vaccine scientific advisory boards for GSK, Sanofi, Pfizer, CSL Seqirus, MSD, Moderna, and AstraZeneca, and on clinical trial data and safety monitoring boards for GSK, CSL Seqirus, Statens Serum Institute, SK Bioscience Korea, Zeria Pharmaceuticals, Clover, Novavax, Serum Institute of India, and Moderna. A.M., F.N-F., J.K., A.L., and N.W. report no potential conflicts., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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18. Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity.

Author: Bognàr T, Garcia-Rosa M, Lalmohamed A, Güngör T, Hauri-Hohl M, Prockop S, Oram L, Pai SY, Brooks J, Savic RM, Dvorak CC, Long-Boyle JR, Krajinovic M, Bittencourt H, Teyssier AC, Théorêt Y, Martinez C, Egberts TCG, Morales E, Slatter M, Cuvelier GDE, Chiesa R, Wynn RF, Coussons M, Cicalese MP, Ansari M, Long SE, Ebens CL, Lust H, Chaudhury S, Nath CE, Shaw PJ, Keogh SJ, van der Stoep MYEC, Bredius R, Lindemans CA, Boelens JJ, and Bartelink IH
Subjects: Humans, Male, Infant, Female, Child, Preschool, Child, Treatment Outcome, Adolescent, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Transplantation, Homologous, Busulfan therapeutic use, Busulfan administration & dosage, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods
Abstract: Abstract: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)
Published: 2024
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19. Trends in Hospitalisations for Vaccine Preventable Respiratory Infections Following Emergency Department Presentations in New South Wales, Australia, 2012-2022.

Author: Hossain FB, Muscatello D, Jayasinghe S, and Liu B
Subjects: Humans, New South Wales epidemiology, Aged, Middle Aged, Child, Preschool, Adult, Child, Infant, Adolescent, Young Adult, Female, Male, Aged, 80 and over, Vaccination statistics & numerical data, Vaccine-Preventable Diseases epidemiology, Vaccine-Preventable Diseases prevention & control, Infant, Newborn, COVID-19 prevention & control, COVID-19 epidemiology, COVID-19 mortality, Influenza, Human prevention & control, Influenza, Human epidemiology, Influenza, Human mortality, Respiratory Tract Infections prevention & control, Respiratory Tract Infections epidemiology, Respiratory Tract Infections mortality, Hospitalization statistics & numerical data, Hospitalization trends, Emergency Service, Hospital statistics & numerical data
Abstract: Background: Vaccine-preventable respiratory infections impact on healthcare systems globally. Despite availability of vaccines, fluctuations in vaccination rates, pathogen virulence and community transmission dynamics mean that these respiratory infections continue to pose substantial public health risks. To understand trends in vaccine-preventable respiratory infections, we analysed linked data from emergency department (ED), hospitalisations and deaths in New South Wales, Australia, from 2012 to 2022., Methods: ED presentations with respiratory infection like illness were linked to hospitalisation and death records. Age-standardised rates of ED presentations, proportions subsequently hospitalised for acute respiratory infection (ARI) and specific vaccine-preventable disease diagnoses and 28-day mortality rates were estimated by year and age., Results: From 2012 to 2022, there were 3,127,090 ARI-like ED presentations. Age-standardised rates increased until 2020, declined in 2021 and rebounded in 2022. Across all years, of these ARI-like ED presentations, 16.6% were hospitalised for acute respiratory infections, including pneumonia (7.9%), influenza (1.1%), RSV disease (1.3%), COVID-19 (0.8%) and pneumococcal disease (0.3%). Proportions hospitalised were highest in those aged 65+ years, except for RSV, which was highest in children aged 0-4 years. The highest 28-day mortality post-ARI-like ED presentation was observed with COVID-19 in adults aged 65+ years at 13.1%., Conclusions: This study highlights the continuing burden of vaccine-preventable respiratory infections on an Australian healthcare system. These data can be used to monitor the effectiveness of vaccination programmes and other public health interventions. Future efforts should focus on enhancing surveillance and data linkage to improve precision and guide targeted public health strategies., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)
Published: 2024
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20. GFAP expression in the BRAIN during human postnatal development.

Author: Luijerink L, Waters K, Rodriguez M, and Machaalani R
Subjects: Humans, Male, Infant, Female, Infant, Newborn, Gliosis pathology, Gliosis metabolism, Glial Fibrillary Acidic Protein metabolism, Brain metabolism, Brain growth & development, Brain pathology, Sudden Infant Death pathology
Abstract: Glial fibrillary acidic protein (GFAP) immunohistochemistry was investigated in the developing human brain using two measures; the number of GFAP-positive cells (density, GFAP+/mm 2 ), and a reactivity score (R-score), which we recently introduced to indicate astrogliosis, with scores ≥120 indicative of pathological processes. The primary aim was to report on GFAP expression and cell soma size in 26 microscopically defined regions of the amygdala, basal ganglia, cerebellum, hippocampus and medulla, and to determine whether they are affected by postconceptional age (PCA) from 40 to 83 weeks. The secondary aim was to determine if GFAP expression differs according to the classification of sudden infant death syndrome (SIDS) as opposed to infant deaths of known causes, or for the presence of major SIDS risk factors of male sex, cigarette smoke exposure, upper respiratory tract infection (URTI), bed-sharing and prone sleeping. The cerebellar molecular layer was void of GFAP+ cells, while the internal granular layer (IGL) had the highest density, with >60% of infants having an R-Score >120. GFAP expression decreased with increasing PCA in the entorhinal and temporal cortex, subiculum and regions of the cerebellum and medulla. GFAP cell soma size corresponded with astrogliosis score and no effect of PCA was evident. Various region-dependent GFAP expressional differences were seen according to SIDS classification and the risk factors studied. The findings indicate that the density of GFAP decreases in specific regions of the brain within the first year of postnatal development, and that reactive astrocytes are common, particularly within the early postnatal months., (© 2024 The Author(s). Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
Published: 2024
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21. Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Author: Carroll A, Bayes A, Montebello M, Brett J, Arunogiri S, Saunders JB, and Loo CK
Subjects: Humans, New Zealand, Australia, Antidepressive Agents therapeutic use, Ketamine therapeutic use, Depressive Disorder, Treatment-Resistant drug therapy, Substance-Related Disorders epidemiology
Abstract: Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: A.C. has none to declare with respect to this work. A.B. set up Spravato early access programme at BDI, and involved in ketamine treatment programme at BDI. M.M. has been an advisory board member for AbbVie Australia and Pfizer Australia, both unrelated to this project. J.B. has none to declare with respect to this work. S.A. has none to declare with respect to this work, and other disclosures are as follows: she has received speaker honoraria from Gilead, Janssen, Indivior and Camurus unrelated to this work. J.B.S. was a member of the WHO Expert Committee on Drug Dependence in 2012 and 2014 which adjudicated on ketamine as a drug of abuse. Note that the Committee had a global orientation (in Australia ketamine was barely used as an human anaesthetic) and this was before its value in TRD was known. He has no other disclosures or conflicts of interest to declare. C.K.L. has received competitive research grant funding from the Australian NHMRC and MRFF to conduct clinical trials on ketamine in TRD, and has served as an advisory board member for Janssen and Douglas Pharmaceuticals, which manufacture formulations of ketamine.
Published: 2024
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22. Child Opportunity Index and Pediatric Extracorporeal Membrane Oxygenation Outcomes; the Role of Diagnostic Category.

Author: Alizadeh F, Gauvreau K, Barreto JA, Hall M, Bucholz E, Nathan M, Newburger JW, Vitali S, Thiagarajan RR, Chan T, and Moynihan KM
Subjects: Humans, Retrospective Studies, Male, Female, Child, Child, Preschool, Infant, Adolescent, Infant, Newborn, Social Determinants of Health, United States, Extracorporeal Membrane Oxygenation statistics & numerical data, Hospital Mortality
Abstract: Objectives: To study the impact of social determinants of health (SDoH) on pediatric extracorporeal membrane oxygenation (ECMO) outcomes., Design, Setting, and Patients: Retrospective study of children (< 18 yr) supported on ECMO (October 1, 2015 to March 1, 2021) using Pediatric Health Information System (44 U.S. children's hospitals). Patients were divided into five diagnostic categories: neonatal cardiac, pediatric cardiac, neonatal respiratory, pediatric respiratory, and sepsis. SDoH included the Child Opportunity Index (COI; higher indicates social advantage), race, ethnicity, payer, and U.S. region. Children without COI were excluded. Diagnostic category-specific clinical variables related to baseline health and illness severity were collected., Interventions: None., Measurements and Main Results: Children supported on ECMO experienced a 33% in-hospital mortality (2863/8710). Overall, children with lower COI, "other" race, Hispanic ethnicity, public insurance and from South or West regions had greater mortality. Associations between SDoH and ECMO outcomes differed between diagnostic cohorts. Bivariate analyses found that only pediatric cardiac patients had an association between COI or race and mortality. Multivariable logistic regression analyses examined relationships between SDoH, clinical variables and mortality within diagnostic categories. Pediatric cardiac patients had 5% increased odds of death (95% CI, 1.01-1.09) for every 10-point decrement in COI, while Hispanic ethnicity was associated with higher survival (adjusted odds ratio [aOR] 0.72 [0.57-0.89]). Children with heart disease from the highest COI quintile had less cardiac-surgical complexity and earlier cannulation. Independent associations with mortality were observed in sepsis for Black race (aOR 1.62 [1.06-2.47]) and other payer in pediatric respiratory patients (aOR 1.94 [1.23-3.06])., Conclusions: SDoH are statistically associated with pediatric ECMO outcomes; however, associations differ between diagnostic categories. Influence of COI was observed only in cardiac patients while payer, race, and ethnicity results varied. Further research should investigate differences between diagnostic cohorts and age groups to understand drivers of inequitable outcomes., Competing Interests: Dr. Newburger’s institution received funding from Pfizer, Bristol Myers Squibb, and Daiichi-Sankyo; she received funding from Bristol Myers Squibb, Novartis, and UpToDate; she disclosed that she is on the Steering Committee for ENOBLATE trial. Dr. Thiagarajan’s institution received funding from the U.S. Department of Defense Clinical Trial (award W81XWH2210301); he received funding from the Society of Critical Care Medicine and Extracorporeal Life Support Organization. Dr. Moynihan received funding from Edwards Life Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)
Published: 2024
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23. "Heart" Outcome in Organ Transplant Recipients With Diabetes: Is GLP-1-RA the Leader of the Pack?

Author: Lim WH and Wong G
Subjects: Humans, Organ Transplantation adverse effects, Treatment Outcome, Hypoglycemic Agents therapeutic use, Diabetes Mellitus, Transplant Recipients, Glucagon-Like Peptide-1 Receptor agonists
Abstract: Competing Interests: The authors declare no funding or conflicts of interest.
Published: 2024
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24. Antecedent Cardiac Arrest Status of Donation After Circulatory Determination of Death (DCDD) Kidney Donors and the Risk of Delayed Graft Function After Kidney Transplantation: A Cohort Study.

Author: Philipoff A, Lin Y, Teixeira-Pinto A, Gately R, Craig JC, Opdam H, Chapman JC, Pleass H, Rogers NM, Davies CE, McDonald S, Yang J, Lopez P, Wong G, and Lim WH
Subjects: Humans, Male, Female, Middle Aged, Adult, Australia epidemiology, Risk Factors, Time Factors, Graft Survival, Glomerular Filtration Rate, Risk Assessment, New Zealand epidemiology, Tissue and Organ Procurement, Donor Selection, Kidney Transplantation adverse effects, Heart Arrest etiology, Heart Arrest mortality, Heart Arrest diagnosis, Delayed Graft Function etiology, Delayed Graft Function physiopathology, Tissue Donors
Abstract: Background: The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF)., Methods: Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF., Results: A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF., Conclusions: This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest., Competing Interests: G.W. is supported by an NHMRC Career Development Fellowship. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Published: 2024
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25. Impact of Cardiovascular Imaging Results on Medication Use and Adherence: A Systematic Review and Meta-Analysis.

Author: Anokye R, Via JD, Dimmock J, Jackson B, Schultz C, Schæffer M, Dickson JM, Blekkenhorst LC, Stanley M, Hodgson JM, and Lewis JR
Subjects: Humans, Antihypertensive Agents therapeutic use, Antihypertensive Agents administration & dosage, Hypolipidemic Agents therapeutic use, Hypolipidemic Agents administration & dosage, Platelet Aggregation Inhibitors therapeutic use, Platelet Aggregation Inhibitors administration & dosage, Medication Adherence statistics & numerical data, Cardiovascular Diseases
Abstract: Introduction: Cardiovascular imaging results offer valuable information that can guide health decisions, but their impact on medication use and adherence is unclear. This systematic review and meta-analysis aimed to determine the downstream impact of cardiovascular imaging results on medication use and adherence., Methods: Searches were conducted across databases, including MEDLINE, PsychINFO, EMBASE, and relevant references up to 2024. Data were extracted from studies comparing outcomes for individuals with diseased versus normal arteries and trials comparing outcomes for individuals who were provided imaging results versus those with no access to imaging results and analysed in 2023 and 2024. Pooled odds ratios (ORs) for outcomes were calculated., Results: The analysis included 29 studies with 24 contributing data points. Initiation (OR:2.77;95% CI:1.82-4.20) and continuation (OR:2.06;95% CI:1.28-3.30) of lipid-lowering medications (LLMs), antihypertensives (OR:2.02;95% CI:1.76-2.33), and antiplatelets (OR:2.47;95% CI:1.68-3.64) were significantly higher in individuals with diseased arteries. The proportion of individuals on LLM increased by 2.7-fold in those with diseased arteries and 1.5-fold in those with normal arteries post-screening. The proportion on LLM increased by 4.2 times in the imaging group and 2.2 times in the "no imaging group" post-screening. There was a significant increase in LLM initiation (OR:2.37;95% CI: 1.17-4.79) in the imaging group, but medication continuation did not significantly differ between the imaging and "no imaging group"., Discussion: Cardiovascular imaging results can prompt initiation of medications, particularly lipid-lowering medications, reflecting a proactive response to identified risk factors. However, evidence regarding medication continuation is mixed, and further research is required., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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26. Early Dysglycemia Is Detectable Using Continuous Glucose Monitoring in Very Young Children at Risk of Type 1 Diabetes.

Author: Haynes A, Tully A, Smith GJ, Penno MAS, Craig ME, Wentworth JM, Huynh T, Colman PG, Soldatos G, Anderson AJ, McGorm KJ, Oakey H, Couper JJ, and Davis EA
Subjects: Humans, Child, Preschool, Female, Male, Child, Infant, Infant, Newborn, Continuous Glucose Monitoring, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 diagnosis, Blood Glucose Self-Monitoring, Blood Glucose analysis
Abstract: Objective: Continuous glucose monitoring (CGM) can detect early dysglycemia in older children and adults with presymptomatic type 1 diabetes (T1D) and predict risk of progression to clinical onset. However, CGM data for very young children at greatest risk of disease progression are lacking. This study aimed to investigate the use of CGM data measured in children being longitudinally observed in the Australian Environmental Determinants of Islet Autoimmunity (ENDIA) study from birth to age 10 years., Research Design and Methods: Between January 2021 and June 2023, 31 ENDIA children with persistent multiple islet autoimmunity (PM Ab+) and 24 age-matched control children underwent CGM assessment alongside standard clinical monitoring. The CGM metrics of glucose SD (SDSGL), coefficient of variation (CEV), mean sensor glucose (SGL), and percentage of time >7.8 mmol/L (>140 mg/dL) were determined and examined for between-group differences., Results: The mean (SD) ages of PM Ab+ and Ab- children were 4.4 (1.8) and 4.7 (1.9) years, respectively. Eighty-six percent of eligible PM Ab+ children consented to CGM wear, achieving a median (quartile 1 [Q1], Q3) sensor wear period of 12.5 (9.0, 15.0) days. PM Ab+ children had higher median (Q1, Q3) SDSGL (1.1 [0.9, 1.3] vs. 0.9 [0.8, 1.0] mmol/L; P < 0.001) and CEV (17.3% [16.0, 20.9] vs. 14.7% [12.9, 16.6]; P < 0.001). Percentage of time >7.8 mmol/L was greater in PM Ab+ children (median [Q1, Q3] 8.0% [4.4, 13.0] compared with 3.3% [1.4, 5.3] in Ab- children; P = 0.005). Mean SGL did not differ significantly between groups (P = 0.10)., Conclusions: CGM is feasible and well tolerated in very young children at risk of T1D. Very young PM Ab+ children have increased SDSGL, CEV, and percentage of time >7.8 mmol/L, consistent with prior studies involving older participants., (© 2024 by the American Diabetes Association.)
Published: 2024
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27. 18 F-FDG PET/CT in Pediatric ALK-Positive Histiocytosis With Isolated CNS Involvement.

Author: Singh K, London K, Ryan J, Wright DC, and Moghimi A
Subjects: Humans, Female, Child, Anaplastic Lymphoma Kinase metabolism, Central Nervous System diagnostic imaging, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Histiocytosis diagnostic imaging
Abstract: Abstract: An 11-year-old girl presented with focal impaired awareness seizures. MRI brain demonstrated a T2 hyperintense cortical lesion in the left temporal lobe with surrounding vasogenic edema. 18 F-FDG PET/CT was arranged to assess metabolic activity of the cerebral lesion, to screen the whole body for other metabolically active lesions, and to assist biopsy planning. The study demonstrated intensely increased FDG uptake within the left temporal lobe lesion without evidence of hypermetabolic lesions elsewhere on the whole-body acquisition. The brain lesion was excised, and histopathology and molecular testing were consistent with ALK-positive histiocytosis., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2024
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28. Improving Diverse and Equitable Involvement of Patients and Caregivers in Research in CKD: Report of a Better Evidence and Translation-Chronic Kidney Disease (BEAT-CKD) Workshop.

Author: Cazzolli R, Sluiter A, Bateman S, Candler H, Cho Y, Cooper T, Craig JC, Dominello A, Duncanson E, Guha C, Hawley CM, Hewawasam E, Hickey L, Hill K, Howard K, Howell M, Huuskes BM, Irish GL, Jesudason S, Johnson DW, Kelly A, Leary D, Manera K, Mazis J, McDonald S, McLennan H, Muthuramalingam S, Pummeroy M, Scholes-Robertson N, Teixeira-Pinto A, Tunnicliffe DJ, van Zwieten A, Viecelli AK, Wong G, and Jaure A
Subjects: Humans, Australia, Translational Research, Biomedical, Biomedical Research, Caregivers psychology, Renal Insufficiency, Chronic therapy, Renal Insufficiency, Chronic psychology, Patient Participation
Abstract: Patient and caregiver involvement can enhance the uptake and impact of research, but the involvement of patients and caregivers who are underserved and marginalized is often limited. A better understanding of how to make involvement in research more broadly accessible, supportive, and inclusive for patients with chronic kidney disease (CKD) and caregivers is needed. We conducted a national workshop involving patients, caregivers, clinicians, and researchers from across Australia to identify strategies to increase the diversity of patients and caregivers involved in CKD research. Six themes were identified. Building trust and a sense of safety was considered pivotal to establishing meaningful relationships to support knowledge exchange. Establishing community and connectedness was expected to generate a sense of belonging to motivate involvement. Balancing stakeholder goals, expectations, and responsibilities involved demonstrating commitment and transparency by researchers. Providing adequate resources and support included strategies to minimize the burden of involvement for patients and caregivers. Making research accessible and relatable was about nurturing patient and caregiver interest by appealing to intrinsic motivators. Adapting to patient and caregiver needs and preferences required tailoring the approach for individuals and the target community. Strategies and actions to support these themes may support more diverse and equitable involvement of patients and caregivers in research in CKD., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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29. The randomized controlled trial (NAVKIDS 2 ) of a patient navigator program created for children with chronic kidney disease.

Author: Wong G, Guha C, Mallitt KA, van Zwieten A, Khalid R, Francis A, Jaure A, Kim S, Teixeira-Pinto A, Aquino M, Bernier-Jean A, Johnson DW, Hahn D, Reidlinger D, Ryan EG, Mackie F, McCarthy H, Varghese J, Kiriwandeniya C, Howard K, Larkins N, Macauley L, Walker A, Howell M, Caldwell P, Woodleigh R, Jesudason S, Carter S, Kennedy S, Alexander S, McTaggart S, Craig JC, and Hawley CM
Subjects: Humans, Male, Female, Child, Adolescent, Child, Preschool, Infant, Caregivers psychology, Health Services Accessibility organization & administration, Patient Satisfaction, Infant, Newborn, Renal Dialysis, Kidney Transplantation, Patient Navigation organization & administration, Renal Insufficiency, Chronic therapy, Renal Insufficiency, Chronic psychology, Quality of Life
Abstract: Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects of a patient navigation program in children with chronic kidney disease (CKD). In this multi-center, randomized controlled trial, we randomly assigned children (aged 0-16 years) with CKD stages 1-5 (including children on dialysis or with kidney transplants), from low socioeconomic status backgrounds, and/or residing in remote areas, to receive patient navigation at randomization (immediate) or at six months (waitlist). The primary outcome was self-rated health (SRH) of participating children at six months, using intention to treat analysis. Secondary outcomes included caregivers' SRH and satisfaction with health care, children's quality of life, hospitalizations, and missed school days. Repeated measures of the primary outcome from baseline to six months were analyzed using cumulative logit mixed effects models. Semi-structured interviews were thematically evaluated. Of 398 screened children, 162 were randomized (80 immediate and 82 waitlist); mean age (standard deviation) of 8.8 (4.8) years with 64.8% male. SRH was not significantly different between the immediate and wait-listed groups at six months. There were also no differences across all secondary outcomes between the two groups. Caregivers' perspectives were reflected in seven themes: easing mental strain, facilitating care coordination, strengthening capacity to provide care, reinforcing care collaborations, alleviating family tensions, inability to build rapport and unnecessary support. Thus, in children with CKD, self-rated health may not improve in response to a navigator program, but caregivers gained skills related to providing and accessing care., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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30. Safety and tolerability of bronchoscopic and nebulised administration of bacteriophage.

Author: Singh J, Lynch S, Iredell J, and Selvadurai H
Subjects: Humans, Female, Adolescent, Male, Child, Nebulizers and Vaporizers, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents therapeutic use, Phage Therapy methods, Treatment Outcome, Bacteriophages, Administration, Inhalation, Pseudomonas Infections therapy, Pseudomonas aeruginosa virology, Pseudomonas aeruginosa drug effects, Cystic Fibrosis therapy, Bronchoscopy
Abstract: Introduction: Pseudomonas aeruginosa is an organism well known for causing significant morbidity and mortality in people living with chronic lung conditions such as cystic fibrosis. We describe the safety, tolerability, and potential efficacy of bronchoscopic and nebulised bacteriophage administration, offering insights into a potential breakthrough for the treatment of chronic infections particularly in children and adolescents., Method: A 12-year-old female (F12) and a 17-year-old male (M17), both diagnosed with cystic fibrosis and chronic P. aeruginosa lung infection, underwent bacteriophage treatment (BT). The administration involved bronchoscopic instillation and subsequent nebulisation. This was performed concurrently with intravenous antibiotics and regular physiotherapy delivered in an in-patient setting for 14 days. Microbiological, clinical, and lung function assessments were conducted to assess this treatment modality., Results: No adverse events (fever, localised reaction, wheeze or bronchospasm) occurred during BT. F12 demonstrated a 4% increase, while M17 showed a 5% improvement in FEV1% from their best FEV1% over the past three years following BT. A 12% (F12) and an 8% (M17) improvement from baseline FEV1% was observed. For F12 P. aeruginosa was not isolated from her sputum despite 12 previous hospitalisations for intravenous antibiotics., Conclusion: Bronchoscopic and nebulised routes of bacteriophage administration were well-tolerated in these two adolescents. This early report underscores the potential of this treatment modality and encourages clinicians and researchers to actively explore this innovative approach., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)
Published: 2024
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31. Transcatheter occlusion of venovenous collaterals in the total cavopulmonary Fontan circulation.

Author: Baker DW, Uthayakumaran G, Polwart N, Lee MGY, Wilson W, Ayer J, Tanous D, D'Udekem Y, Celermajer DS, O'Donnell C, and Cordina R
Abstract: Background: Venovenous collaterals are abnormal connections between the systemic and pulmonary venous systems. They are commonly seen in the Fontan circulation and may lead to significant hypoxaemia. Transcatheter closure of venovenous collaterals is a potential but controversial treatment as the long-term benefits and outcomes are not well understood., Methods: This retrospective cohort study utilised data from the Australian and New Zealand Fontan Registry. Patients who underwent transcatheter venovenous collateral occlusion for hypoxemia from the year 2000 onwards were included. Atriopulmonary and Kawashima-type Fontan circulations were excluded to reflect a more contemporary Fontan cohort., Results: Nineteen patients (age 19.3 ± 7.8 years, 53% female) underwent transcatheter venovenous collateral occlusion. Compared to baseline, mean oxygen saturation was improved at latest follow-up (90.5% vs 87.0%; p = 0.003). Nine patients achieved a clinically significant response (defined as an increase of at least 5% to 90% or greater), and this was associated with lower baseline Fontan pressures (12.9 v 15.6 mmHg; p = 0.02). No heart failure hospitalisations, arrhythmia, transplant referrals, or mortality were observed during the median follow-up period of 4 years. Two patients experienced thromboembolic events and five patients underwent re-intervention., Conclusion: Transcatheter occlusion of venovenous collaterals in Fontan patients with chronic hypoxaemia resulted in a modest increase in oxygenation over a median follow-up of 4 years and longer-term prognosis did not appear to be adversely affected. Lower Fontan pressures at baseline were associated with a greater improvement in oxygenation.
Published: 2024
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32. The Australian Frailty Network: Development of a consumer-focussed national response to frailty.

Author: Reid N, Young A, Baldassar L, Christoffersen A, Comans T, Conroy S, Etherton-Beer C, Ferris J, Singh MF, Fox S, Gordon EH, Ghosh M, Guha C, Hilmer S, Kouladjian O'Donnell L, Logan B, Ludlow K, Miller M, Morgan M, Mudge A, Muscedere J, Reidlinger D, Rockwood K, Saunders R, Ward D, Yates P, and Hubbard RE
Abstract: Frailty is an important concept in the care of older adults. Over the past two decades, significant advances have been made in measuring frailty. While it is now well-recognised that frailty status is an important determinant of outcomes from medical illnesses or surgical interventions, frailty measurement is not currently routinely integrated into clinical practice. In the community setting, it is uncommon for general practitioners to deliver frailty-optimised care. In hospitals, there is substantial variability in how people living with frailty are managed. This variability is notable between and even within disciplines. Furthermore, gains from understanding frailty mechanisms and risk factors are not yet applied/implemented at scale to delay the progression of frailty in community-dwellers. The Australian Frailty Network (AFN) is a national collaborative group of researchers, clinicians, non-government organisations, consumers and policymakers, in which the engagement and active involvement of consumers has been embedded from the outset. The AFN aims to generate new knowledge to improve health outcomes, to ensure evidence-based management is translated into clinical practice and to build capacity in multidisciplinary and translational frailty research. Here, we describe the development of the AFN, highlighting important milestones: (i) securing funding for the network and flagship elements; (ii) an inaugural summit to establish the strategic vision, values and scope with end-users; (iii) sabbatical visits to learn from international examples; and (iv) developing the governance structure and an actionable plan encompassing consumer engagement, research, education and policy and practice to maximise impact., (© 2024 AJA Inc.)
Published: 2024
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33. The iSEARCH randomised controlled trial protocol: a pragmatic Australian phase III clinical trial of intrapartum sildenafil citrate to improve outcomes potentially related to intrapartum hypoxia.

Author: Kumar S, Tarnow-Mordi W, Mol BW, Flenady V, Liley H, Badawi N, Walker SP, Hyett J, Seidler L, Callander E, and O'Connell R
Subjects: Humans, Female, Pregnancy, Australia, Cesarean Section, Pragmatic Clinical Trials as Topic, Hypoxia prevention & control, Fetal Distress, Sildenafil Citrate therapeutic use, Sildenafil Citrate administration & dosage
Abstract: Introduction: We showed in a phase II randomised controlled trial (RCT) that oral sildenafil citrate in term labour halved operative birth for fetal distress. We outline the protocol for a phase III RCT (can i ntrapartum S ild E nafil safely A vert the R isks of C ontraction-induced H ypoxia? (iSEARCH)) of 3200 women in Australia to assess if sildenafil citrate reduces adverse perinatal outcomes related to intrapartum hypoxia., Methods and Analysis: iSEARCH will enrol 3200 Australian women in term labour to determine whether up to three 50 mg oral doses of sildenafil citrate versus placebo reduce the relative risk of a primary composite end point of 10 perinatal outcomes potentially related to intrapartum hypoxia by 35% (from 7% to 4.55%). Secondary aims are to evaluate reductions in the relative risk of emergency caesarean section or instrumental vaginal birth for fetal distress by 25% (from 20% to 15%) and in healthcare costs. To detect a 35% reduction in the primary outcome for an alpha of 0.05 and power of 80% with 10% dropout in each arm requires 3200 women (1600 in each arm). This sample size will also yield >90% power to detect a 25% reduction for the secondary outcome of any operative birth (caesarean section or instrumental vaginal birth) for fetal distress., Ethics and Dissemination: Ethical approval for the iSEARCH RCT was granted by the Hunter New England Human Research Ethics Committee (ref no: 2020/ETH02791). Results will be disseminated through websites, peer-reviewed publications, scientific meetings and social media, news outlets, television and radio., Trial Registration Number: ACTRN12621000231842., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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34. IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis.

Author: Vivarelli M, Samuel S, Coppo R, Barratt J, Bonilla-Felix M, Haffner D, Gibson K, Haas M, Abdel-Hafez MA, Adragna M, Brogan P, Kim S, Liu I, Liu ZH, Mantan M, Shima Y, Shimuzu M, Shen Q, Trimarchi H, Hahn D, Hodson E, Pfister K, Alladin A, Boyer O, and Nakanishi K
Abstract: IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children., (© 2024. The Author(s).)
Published: 2024
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35. Contributions of digital technologies for resilience capacity in a type 1 diabetes transition clinic: A qualitative study.

Author: Carrigan A, Holmes-Walker DJ, Farrell K, Maguire AM, Lyng HB, Wiig S, Guise V, Long JC, Ellis LA, Wijekulasuriya S, Dharmayani PNA, Singh N, Simone Z, Davis E, Jones TW, Braithwaite J, and Zurynski Y
Abstract: A type 1 diabetes (T1D) transition clinic in Sydney, Australia, provides age specific care for young adults (aged 16-25 years) and for adults (aged 21 years and above), and has reported improved clinical outcomes post transition to adult care over a 21-year period. This study investigated the contribution of digital technology to long-term resilient capacity of the clinic. Clinic observations and interviews with eight providers and 17 young adults were conducted. Using a framework to analyze resilient capacity in healthcare, seven strong themes emerged from the data: Leadership, Involvement, Communication, Coordination, Risk Awareness, Competence and Alignment with three themes, Structure, Learning and Facilitators also supported. Patient service adaptations included offering out of hours appointment times and telehealth to accommodate young adults' availability. This study provides evidence for the important role that digital technologies contribute to a system of care with capacity for resilience. Our findings contribute to the understanding of the factors needed to support young adults with T1D and may be valuable to inform models of care for young adults living with other chronic health conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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36. Parent-young person lived experience of sensory dysregulation in children with tic disorders: a qualitative study.

Author: Soler N, Perkes IE, Dale RC, and Bray P
Abstract: Purpose: To understand the breadth of sensory dysregulation on participation in daily tasks for young people with tic disorders, as research identified that sensory dysregulation experiences are broader than the symptoms being assessed., Methods: Eighteen semi-structured interviews were conducted with 16 families with children (5-16 years) with tic disorders. Interviews ranged from 45 to 120 min and were transcribed verbatim. Data collected from parents and young people were analysed and coded together. Thematic analysis using inductive and open coding methods was implemented using NVivo., Results: The impact of sensory dysregulation on daily life may be understood through the higher-order theme: ''sensory, emotions and tics; it's a ticking time bomb'', and three subthemes: (1) we sacrifice and adapt to get daily activities done in the home, (2) my child's experience of the community environment hinders participation, and (3) sensory preferences impact our entire family., Conclusion: Sensory dysregulation experiences impact the entire family's quality of life, yet patient-reported sensory measures do not adequately capture the impact on the family unit and breath of symptoms. A sensory-based measure for children with tics is needed to comprehensively assess sensory dysregulation sensitivities for this population, ensuring patients' needs and effectiveness of therapy can be measured.
Published: 2024
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37. The Kids Heart BioBank: supporting 20 years of patient care and research into CHD.

Author: Hilton DCK, O'Malley BR, Cole AD, Harvey RP, Dunwoodie SL, Sholler GF, Winlaw DS, and Blue GM
Abstract: Introduction: The cause of most CHD is unknown and considered complex, implicating genetic and environmental factors in disease causation. The Kids Heart BioBank was established in 2003 to accelerate genetic investigations into CHD., Methods: Recruitment includes patients undergoing interventions for CHD at The Children's Hospital at Westmead. Informed consent is obtained from parents/guardians, and blood is collected at the time of cardiac intervention from which DNA is extracted and stored. Associated detailed clinical information and a family history are stored in the purpose-designed database., Results: To date, the Kids Heart BioBank contains biospecimens and associated clinical information from over 4,900 patients with CHD and their families. Two-thirds (64.1%) of probands have been included in research studies with 28.9% of participants who underwent genomic sequencing receiving a molecular diagnosis with direct clinical utility. The value of this resource to patients and families is highlighted by the high consent rate (94.6%) and the low withdrawal of consent rate (0.4%). The Kids Heart BioBank has supported many large national and international collaborations and contributed significantly to CHD research., Conclusions: The Kids Heart BioBank is an invaluable resource and, together with other similar resources, the resulting research has paved the way for clinical genetic testing options for CHD patients, previously not possible. With research in the field moving away from diagnosing monogenic disease, the Kids Heart BioBank is ideally placed to support the next chapter of research efforts into complex disease mechanisms, requiring large patient cohorts with detailed phenotypic information.
Published: 2024
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38. Attitudes and Experiences of Community Palliative Care Nurses Regarding Pediatric Home-Based End-of-Life Care: A Statewide Survey.

Author: Helyar M, Eamens M, Coombs S, Smeal T, Mherekumombe M, and Jaaniste T
Abstract: Objectives: Pediatric end-of-life (EOL) care at home is often provided by community palliative care (CPC) nurses who do not specialize in pediatrics. This study aimed to better understand the challenges CPC nurses face when providing EOL care to children at home. Methods: A total of 52 CPC nurses across New South Wales (NSW), Australia, participated in an online survey about their training, attitudes, and experiences regarding the provision of home-based pediatric EOL care. Participants were asked to reflect back over a "negative" experience of caring for a child at EOL, where things did not go as well as hoped, and a "positive" EOL care experience, where nurses perceived that care of the child and family went well, and respond to questions about these experiences. Results: Confidence of CPC nurses when providing EOL care to pediatric patients was significantly lower than when caring for adults ( p 's < .05). Most respondents expressed the desire for more training in pediatric EOL care. Cases identified as negative by CPC nurses did not significantly differ from positive cases in terms of the timing of the referral to CPC, clinical symptoms at EOL, or how well informed the nurses felt. Siblings were present at EOL in 74% of the negative experiences and 86% of the positive experiences, reportedly receiving significantly poorer support in the negative experiences ( p = .002). Conclusion: This research contributes to an improved understanding of the challenges associated with home-based pediatric EOL care and highlights potential areas for improvement in CPC service delivery and training., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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39. Neonatal encephalopathy: a systematic review of reported treatment outcomes.

Author: Quirke F, Biesty L, Battin M, Bloomfield FH, Daly M, Finucane E, Healy P, Hurley T, Kirkham JJ, Molloy E, Haas DM, Meher S, Ní Bhraonáin E, Walker K, Webbe J, and Devane D
Subjects: Humans, Infant, Newborn, Treatment Outcome, Infant, Newborn, Diseases therapy, Randomized Controlled Trials as Topic, Outcome Assessment, Health Care, Hypothermia, Induced methods, Brain Diseases therapy
Abstract: Background: Neonatal encephalopathy (NE) is a multi-organ condition potentially leading to death or long-term neurodisability. Therapeutic hypothermia is the standard treatment for NE; however, long-term impairments remain common. Studies of new treatments for NE often measure and report different outcomes. Core outcome sets (COSs), a minimum set of outcomes to be measured and reported in all studies for a condition, address this problem. This paper aimed to identify outcomes reported (primary, secondary, adverse events and other reported outcomes) in (1) randomised trials and (2) systematic reviews of randomised trials of interventions for the treatment of NE in the process of developing a COS for interventions for the treatment of NE., Methods: We completed a systematic search for outcomes used to evaluate treatments for NE using MEDLINE, Embase, Cochrane CENTRAL, the Cochrane Database of Systematic Reviews and the WHO International Clinical Trials Registry Platform. Two reviewers screened all included articles independently. Outcomes were extracted verbatim, similar outcomes were grouped and outcome domains were developed., Results: 386 outcomes were reported in 116 papers, from 85 studies. Outcomes were categorised into 18 domains. No outcome was reported by all studies, a single study reported 11 outcomes and it was not explicitly stated that outcomes had input from parents., Discussion: Heterogeneity in reported outcomes means that synthesis of studies evaluating new treatments for NE remains difficult. A COS, that includes parental/family input, is needed to ensure consistency in measuring and reporting outcomes, and to enable comparison of randomised trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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40. Inguinal hernias in children: Update on management guidelines.

Author: Morgado M and Holland AJ
Abstract: Inguinal hernia repair is one of the most performed procedures in children, but aspects of care remain controversial. The aim of this review was to provide a critical appraisal of recently published guidelines on the management of inguinal hernias in children, by the American Academy of Pediatrics (2023) and the European Pediatric Surgeons' Association Evidence and Guideline Committee (2022). This was achieved by delineating areas of controversy and reviewing the most relevant recent literature on these topics. Currently available moderate-to-low quality evidence recommends postponing hernia repair in premature infants until after discharge, to reduce the risk of respiratory difficulties and recurrence. Laparoscopic repair provides similar outcomes to open but may shorten operative time in bilateral cases. No clear recommendation can be made for contralateral exploration, therefore should be evaluated case by case. In preterm infants, consideration of regional anaesthesia may reduce post-operative apnoea and pain, with no difference in neurodevelopment outcomes., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)
Published: 2024
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41. Does insulin pump therapy offer benefits for behaviour, mood, cognition and HbA1c in children and adolescents with type 1 diabetes? A randomised controlled trial with observational follow-up.

Author: O'Connell MA, Northam EA, Brown A, Papoutsis J, Schuster T, Skinner T, Jenkins AJ, Ambler GR, and Cameron FJ
Subjects: Humans, Child, Adolescent, Female, Male, Follow-Up Studies, Child Behavior drug effects, Treatment Outcome, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 psychology, Glycated Hemoglobin analysis, Glycated Hemoglobin metabolism, Insulin Infusion Systems, Insulin administration & dosage, Insulin therapeutic use, Cognition drug effects, Affect drug effects, Hypoglycemic Agents administration & dosage, Hypoglycemic Agents therapeutic use
Abstract: Aims: Improved behaviour, mood, cognition and HbA1c have been reported with short-term use of continuous subcutaneous insulin infusion (CSII) in youth with type 1 diabetes (T1D). We sought to re-examine these findings in a randomised controlled trial (RCT), with longitudinal follow-up., Methods: RCT of youth aged 7-15 years with T1D, at two tertiary paediatric centres. Participants were randomised to commence CSII or continue multiple daily injections (MDI). Behaviour, mood, cognition and HbA1c were assessed. Primary outcome was difference in parent-reported behaviour (BASC-2) at 4 months. After the 4-month RCT, MDI participants commenced CSII; outcomes were reassessed at +2 years., Results: Participating youth (n=101) were randomised to CSII (n=56) or MDI (n=45). Significant differences favouring CSII were found at 4 months in parent-reported behaviour problems (Cohen's d 0.41 (95% CI 0.004 to 0.795); p=0.048) and HbA1c (mean (95% CI) difference: 7 (2.3 to 11.7) mmol/mol (0.6% (0.2 to 1.0%); p=0.001)). Improvements from baseline were documented in mood and cognitive outcomes in both study groups over the 4-month RCT; however, no between-group differences were evident at 4 months. Sixteen of 76 (21%) participants completing assessments at +2 years had discontinued CSII. In n=60 still using CSII, measurements of behaviour, mood and HbA1c were comparable to baseline., Conclusions: Parent-reported behaviour problems and HbA1c, but not mood or neurocognitive outcomes, were clinically significantly lower with CSII, relative to MDI, after 4 months. Observational follow-up indicated no impact of treatment modality at +2 years, relative to baseline levels. Taken together, these data indicate that use of CSII alone does not comprehensively benefit neuropsychological outcomes in childhood T1D., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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42. Predicting the Difficult Neonatal Airway in Fetuses With Micrognathia, Oropharyngeal or Neck Mass Lesions: Two-Center Experience With Fetal MRI.

Author: Goergen S, Christie J, Jackson T, Smet ME, Robertson S, Malhotra A, Kroushev A, and Lovell M
Abstract: Objective: Neonatal airway compromise requiring intubation, due to micrognathia or a mass lesion obstructing the fetal airway, remains difficult but important to predict prenatally. We aimed to validate MR predictors of difficult neonatal airway (DNA) in a multicentre retrospective cohort of fetuses with micrognathia and oropharyngeal/neck masses., Method: The radiology databases of two large Australian maternal-fetal medicine centers were searched for subjects meeting inclusion criteria: Pregnancies of > 18 weeks' gestation evaluated with prenatal ultrasound and MRI between 2007 and 2022 where either fetal micrognathia or a fetal cervical, oral or oropharyngeal mass was identified on prenatal ultrasound and MRI, and details of delivery/postnatal course were available including: nature of delivery, need for the fetal airway to be secured at delivery, degree of difficulty in airway securement, survival > 24 h postnatally. Imaging predictors of a difficult neonatal airway (DNA) were assessed blinded to these neonatal outcomes., Results: Twenty-six fetuses met the inclusion criteria. Oropharyngeal and neck mass location with polyhydramnios was 100% sensitive and 82% specific for DNA. JI < 5th centile with polyhydramnios was 83% sensitive and 70% specific. JI < 5th centile with polyhydramnios was associated with DNA in 80% of cases delivered by ex utero intrapartum (EXIT) delivery and none with non-EXIT delivery mode., Conclusion: A cervical or oropharyngeal mass with polyhydramnios predicted a difficult neonatal airway. Polyhydramnios with jaw index < 5th centile was less sensitive and less specific for a difficult neonatal airway., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)
Published: 2024
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43. Multiple developmental disabilities among American children: prevalence and secular trends 2016-2022.

Author: Lin J, Xu X, Li C, Kendrick T, and He WQ
Abstract: Objectives: We aimed to estimate the prevalence of multiple developmental disabilities, identify associated characteristics, and examine trends among American children from 2016 to 2022., Study Design: This was a cross-sectional study., Methods: Using the National Survey of Children's Health data from 2016 to 2022, we estimated the prevalence of multiple developmental disabilities among children aged 3-17 years. Multiple developmental disabilities were defined as two or more concurrent disabilities from 12 common disabilities. Trends were investigated using log-linear regression. Multivariate log-binominal regression was used to compare the prevalence prior to the COVID-19 pandemic (2016-2019) with prevalence during the COVID-19 pandemic (2020-2022)., Results: From 239,534 eligible children (mean age = 10.1 years; male = 51.7%), we found the overall prevalence of multiple developmental disabilities was 10.6%. The most predominant phenotype was attention-deficit/hyperactivity disorder concurrent with behavioural problems (2.1%). Higher prevalence was found among boys, non-Hispanic black children, those from low-household-income families and from families with lower education levels. Prevalence of multiple developmental disabilities increased from 9.8% in 2016 to 11.5% in 2022 (P = 0.014) with significantly higher prevalence during COVID-19 pandemic than before (11.2% vs 10.1%). These increases were found consistently across most sociodemographic groups., Conclusions: Children from certain socio-disadvantaged groups were disproportionally affected by multiple developmental disabilities, highlighting the need for targeted strategies to improve health. The increasing prevalence during the pandemic suggests the need for ongoing monitoring of the trend and the impact of these conditions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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44. An outbreak of reactive infectious mucocutaneous eruption (RIME) after Mycoplasma pneumoniae infections in Sydney, 2024: retrospective case series.

Author: Joseph J, Truong K, Tatian A, and Wargon O
Published: 2024
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45. Clinical Features, Adverse Events and Treatment Outcomes of Multidrug/Rifampicin-resistant Tuberculosis in Children and Adolescents: An Eight-year Retrospective Cohort Study in Bandung, Indonesia.

Author: Nataprawira HM, Gafar F, Sari CA, Alffenaar JC, Marais BJ, Ruslami R, and Menzies D
Abstract: Background: Data on childhood and adolescent multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in Indonesia are lacking. We aimed to assess clinical features, adverse events (AEs) and treatment outcomes of childhood and adolescent MDR/RR-TB., Methods: A retrospective cohort study was performed in children and adolescents aged <18 years treated for MDR/RR-TB at Hasan Sadikin General Hospital in Bandung, Indonesia, between June 2016 and March 2024. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for predictors of all-cause mortality., Results: Among 84 included patients, 69 (82%) were adolescents aged 10-17 years, 54 (64%) were female, 54 (64%) were malnourished and 55 (65%) had culture-confirmed disease. Among 69 (82%) patients with known outcomes, 48 (70%) were successfully treated, 14 (20%) died (including 5 pretreatment deaths) and 7 (10%) were lost to follow-up (LTFU) (including 5 pretreatment LTFU). Predictors of all-cause mortality included shortness of breath on admission [aOR: 6.4, 95% confidence interval (CI): 1.3-49.1], high bacillary burden on Xpert MTB/RIF assay (aOR: 17.0, 95% CI: 1.6-260.5) and the presence of lung cavities on chest radiograph (aOR: 4.8, 95% CI: 1.1-23.3). Among 74 patients who initiated treatment, 39 (53%) had at least one grade 1-2 AE, and 4 (5%) had one grade 3-4 AE each, including hepatotoxicity, QT prolongation, hearing loss and rash/hyperpigmentation., Conclusion: Younger children were underrepresented among those treated for MDR/RR-TB, indicating reduced access to care. Severe AEs were uncommon during MDR/RR-TB treatment. Baseline indicators of extensive disease were associated with all-cause mortality. The high proportion of pre-treatment mortality and LTFU may reflect complex patient pathways limiting access to care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Published: 2024
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46. Germline mutations in a G protein identify signaling cross-talk in T cells.

Author: Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA, Anderson DE, Druey KM, Mandl JN, Isidor B, Ferreira CR, Freeman AF, Ganesan S, Karsak M, Mustillo PJ, Teo J, Zolkipli-Cunningham Z, Chatron N, Lecoquierre F, Oler AJ, Schmid JP, Kuhns DB, Xu X, Hauck F, Al-Herz W, Wagner M, Terhal PA, Muurinen M, Barlogis V, Cruz P, Danielson J, Stewart H, Loid P, Rading S, Keren B, Pfundt R, Zarember KA, Vill K, Potocki L, Olivier KN, Lesca G, Faivre L, Wong M, Puel A, Chou J, Tusseau M, Moutsopoulos NM, Matthews HF, Simons C, Taft RJ, Soldatos A, Masle-Farquhar E, Pittaluga S, Brink R, Fink DL, Kong HH, Kabat J, Kim WS, Bierhals T, Meguro K, Hsu AP, Gu J, Stoddard J, Banos-Pinero B, Slack M, Trivellin G, Mazel B, Soomann M, Li S, Watts VJ, Stratakis CA, Rodriguez-Quevedo MF, Bruel AL, Lipsanen-Nyman M, Saultier P, Jain R, Lehalle D, Torres D, Sullivan KE, Barbarot S, Neu A, Duffourd Y, Similuk M, McWalter K, Blanc P, Bézieau S, Jin T, Geha RS, Casanova JL, Makitie OM, Kubisch C, Edery P, Christodoulou J, Germain RN, Goodnow CC, Sakmar TP, Billadeau DD, Küry S, Katanaev VL, Zhang Y, Lenardo MJ, and Su HC
Subjects: Humans, Cell Movement genetics, Cell Proliferation, Immunity genetics, MAP Kinase Signaling System, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, ras Proteins metabolism, ras Proteins genetics, Signal Transduction, Pedigree, Germ-Line Mutation, GTP-Binding Protein alpha Subunit, Gi2 genetics, ras GTPase-Activating Proteins genetics, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
Abstract: Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.
Published: 2024
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47. Correction to: A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Author: Huynh A, E Gray P, Sullivan A, Mackie J, Guerin A, Rao G, Pathmanandavel K, Della Mina E, Hollway G, Hobbs M, Enthoven K, O'Young P, McManus S, H Wainwright L, Higgins M, Noon F, Wong M, Bastard P, Zhang Q, Casanova JL, Hsiao KC, Pinzon-Charry A, S Ma C, and G Tangye S
Published: 2024
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48. Letter to the Editor.

Author: Riordan G, Dhayade A, and Gupta V
Published: 2024
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49. Association between Congenital Anomalies and Late-Onset Bacterial Infections in Neonates Admitted to Neonatal Intensive Care Units in Australia and New Zealand: A Population-Based Cohort Study.

Author: Chughtai AA, Spotswood N, Strunk T, Parmar T, Schindler T, Popat H, Chow SSW, and Lui K
Abstract: Introduction: Compromised neonatal intensive care unit neonates are at risk of acquiring late-onset infections (late-onset sepsis [LOS]). Neonates born with congenital anomalies (CAs) could have an additional LOS risk., Methods: Utilising the population-based Australian and New Zealand Neonatal Network data from 2007 to 2017, bacterial LOS rates were determined in very preterm (VPT, <32 week), moderately preterm (MPT, 32-36 weeks), and term (FT, 37-41 weeks) neonates with or without CA. Stratified by major surgery, the association between CA and bacterial LOS was evaluated., Results: Of 102,808 neonates, 37.7%, 32.8%, and 29.6% were born VPT, MPT, and FT, respectively. Among these, 3.4% VPT, 7.5% MPT, and 16.2% FT neonates had CA. VPT neonates had the highest LOS rate (11.1%), compared to MPT (1.8%) and FT (1.8%) neonates. LOS rates were higher in CA neonates than those without (8.2% versus 5.1% adjusted relative risk [aRR] 1.67, 95% confidence interval [CI]: 1.45-1.92). Neonates with surgery had a higher LOS rate (14.2%) than neonates without surgery (4.4%, p < 0.001). Among the neonates without surgery, CA neonates had consistently higher LOS rates than those without CA (VPT 14.3% vs. 9.6% [aRR 1.32, 95% CI: 1.11-1.57]; MPT 4% vs. 0.9% [aRR 4.45, 95% CI: 3.23-6.14]; and FT 2% vs. 0.7% [aRR 2.87, 95% CI: 1.97-4.18]). For the neonates with surgery, CAs were not associated with additional LOS risks., Conclusion: Overall, we reported higher rates of LOS in neonates with CA compared to those without CA. Regardless of gestation, CA was associated with an increased LOS risk among non-surgical neonates. Optimisation of infection prevention strategies for CA neonates should be explored. Future studies are needed to evaluate if the infection risk is caused by CA or associated complications., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
Published: 2024
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50. A systematic review protocol: health economic evaluations of immunotherapy and biologics for food allergy management.

Author: Fong AT, Jacob J, Protudjer JLP, Lloyd M, Thyer L, Hsu PS, and Si L
Published: 2024
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