description of the methodological approach

publishersversionpublishe

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Abstract Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.Additional information International Parkinson’s Disease Genomics Consortium (IPDGC) Members A. Noyce13, A. Tucci14, B. Middlehurst1, D. Kia15, M. Tan16, H. Houlden14, H. R. Morris16, H. Plun-Favreau14, P. Holmans17, J. Hardy14, D. Trabzuni14,18, J. Bras19, K. Mok14, K. Kinghorn20, N. Wood15, P. Lewis21, R. Guerreiro14,19, R. Lovering22, L. R’Bibo14, M. Rizig14, V. Escott-Price22,23, V. Chelban14, T. Foltynie6, N. Williams24, A. Brice25, F. Danjou25, S. Lesage25, M. Martinez26, A. Giri27,28, C. Schulte27,28, K. Brockmann27,28, J. Simón-Sánchez27,28, P. Heutink27,28, P. Rizzu28, M. Sharma29, T. Gasser27,28, A. Nicolas2, M. Cookson2, F. Faghri2,30, D. Hernandez2, J. Shulman31,32, L. Robak33, S. Lubbe34, S. Finkbeiner35,36,37, N. Mencacci38, C. Lungu39, S. Scholz40, X. Reed2, H. Leonard2, G. Rouleau7, L. Krohan41, J. van Hilten42, J. Marinus42, A. Adarmes-Gómez43, M. Aguilar44, I. Alvarez44, V. Alvarez45, F. Javier Barrero46, J. Bergareche Yarza47, I. Bernal-Bernal43, M. Blazquez45, M. Bonilla-Toribio Bernal43, M. Boungiorno44, Dolores Buiza-Rueda43, A. Cámara48, M. Carcel44, F. Carrillo43, M. Carrión-Claro43, D. Cerdan49, J. Clarimón50,51, Y. Compta48, M. Diez-Fairen44, O. Dols-Icardo50,51, J. Duarte49, R. l. Duran52, F. Escamilla-Sevilla53, M. Ezquerra48, M. Fernández48, R. Fernández-Santiago48, C. Garcia45, P. García-Ruiz54, P. Gómez-Garre43, M. Gomez Heredia55, I. Gonzalez-Aramburu56, A. Gorostidi Pagola57, J. Hoenicka58, J. Infante51,56, S. Jesús43, A. Jimenez-Escrig59, J. Kulisevsky51,60, M. Labrador-Espinosa43, J. Lopez-Sendon59, A. López de Munain Arregui59, D. Macias43, I. Martínez Torres61, J. Marín51,60, M. Jose Marti48, J. Martínez-Castrillo59, C. Méndez-del-Barrio43, M. Menéndez González43, A. Mínguez53, P. Mir43, E. Mondragon Rezola57, E. Muñoz48, J. Pagonabarraga51,60, P. Pastor44, F. Perez Errazquin55, T. Periñán-Tocino43, J. Ruiz-Martínez57, C. Ruz52, A. Sanchez Rodriguez56, M. Sierra56, E. Suarez-Sanmartin4, C. Tabernero59, J. Pablo Tartari44, C. Tejera-Parrado43, E. Tolosa48, F. Valldeoriola48, L. Vargas-González43, L. Vela62, F. Vives52, A. Zimprich63, L. Pihlstrom64, P. Taba65, K. Majamaa66,67, A. Siitonen66, N. Okubadejo68, O. Ojo68 1 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK 2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA 3Department of Medical and Molecular Genetics, King’s College London School of Basic and Medical Biosciences, London, SE1 9RT, UK 4Clinical Genetics Unit, Guys and St. Thomas’ NHS Foundation Trust, London, SE1 9RT, UK 5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100, Murcia, Spain 6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK 7Montreal Neurological Institute, McGill University, Montréal, QC, Canada 8Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada 9Department of Human Genetics, McGill University, Montréal, QC, Canada 10Data Tecnica International, Glen Echo, MD, 20812, USA 11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA, 6009, Australia 12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150, Australia 13Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, UK 14Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 15UCL Genetics Institute; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 16Department of Clinical Neuroscience, University College London, London, UK 17Biostatistics &amp; Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics &amp; Genomics, Cardiff, UK 18Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia 19UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 20Institute of Healthy Ageing, University College London, London, UK 21University of Reading, Reading, UK 22University College London, London, UK 23MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, UK 24Cardiff University School of Medicine, Cardiff, UK 25Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France 26INSERM UMR 1220; and Paul Sabatier University, Toulouse, France 27Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 28DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany 29Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany 30Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA 31Departments of Neurology, Neuroscience, and Molecular &amp; Human Genetics, Baylor College of Medicine, Houston, TX, USA 32Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA 33Baylor College of Medicine, Houston, TX, USA 34Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 35Departments of Neurology and Physiology, University of California, San Francisco, CA, USA 36Gladstone Institute of Neurological Disease, San Francisco, CA, USA 37Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA) 38 (Northwestern University Feinberg School of Medicine, Chicago, IL, USA) 39 (National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, USA) 40Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA 41Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada 42Department of Neurology, Leiden University Medical Center, Leiden, Netherlands 43Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Seville, Spain 44Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain 45Hospital Universitario Central de Asturias, Oviedo, Spain 46Hospital Universitario Parque Tecnologico de la Salud, Granada, Spain 47Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain 48Hospital Clinic de Barcelona, Barcelona, Spain 49Hospital General de Segovia, Segovia, Spain 50Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 51Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain 52Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain 53Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain 54Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain 55Hospital Universitario Virgen de la Victoria, Malaga, Spain 56Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain 57Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain 58Institut de Recerca Sant Joan de Déu, Barcelona, Spain 59Hospital Universitario Ramón y Cajal Madrid, Madrid, Spain 60Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 61Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain 62Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain 63Department of Neurology, Medical University of Vienna, Vienna, Austria 64Department of Neurology, Oslo University Hospital, Oslo, Norway 65Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia 66Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland 67Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland 68University of Lagos, Yaba, Lagos State, Nigeri

Fibrinogen scaffolds with immunomodulatory properties promote in vivo bone regeneration

The hypothesis behind this work is that fibrinogen (Fg), classically considered a pro-inflammatory protein, can promote bone repair/regeneration. Injury and biomaterial implantation naturally lead to an inflammatory response, which should be under control, but not necessarily minimized. Herein, porous scaffolds entirely constituted of Fg (Fg-3D) were implanted in a femoral rat bone defect and investigated at two important time points, addressing the bone regenerative process and the local and systemic immune responses, both crucial to elucidate the mechanisms of tissue remodelling. Fg-3D led to early infiltration of granulation tissue (6 days post-implantation), followed by bone defect closure, including periosteum repair (8 weeks post-injury). In the acute inflammatory phase (6 days) local gene expression analysis revealed significant increases of pro-inflammatory cytokines IL-6 and IL-8, when compared with non-operated animals. This correlated with modified proportions of systemic immune cell populations, namely increased T cells and decreased B, NK and NIT lymphocytes and myeloid cell, including the Mac 1+ (CD18+/CD11b+) subpopulation. At 8 weeks, Fg-3D led to decreased plasma levels of IL-1 beta and increased TGF-beta 1. Thus, our data supports the hypothesis, establishing a link between bone repair induced by Fg-3D and the immune response. In this sense, Fg-3D scaffolds may be considered immunomodulatory biomaterials. (C) 2016 Elsevier Ltd. All rights reserved

Tempo de latência e características da nomeação de figuras de crianças com transtorno da leitura Latency time and characteristics of picture labelling by children with reading disorders

O objetivo deste estudo foi investigar o tempo de latência e as características da nomeação de figuras em crianças com Transtorno da Leitura e com desenvolvimento típico de leitura, de mesma escolaridade. As amostras foram constituídas por 20 crianças com Transtorno da Leitura (m=8,3 a) e 25 criançassem dificuldades na leitura (m=8,6 a), de ambos os gêneros. O teste de nomeação de figuras foi constituído por 96 figuras, com balanceamento equivalente às palavras escritas: freqüência de ocorrência, extensão e complexidade para o português falado no Brasil. As figuras foram apresentadas na tela de um computador e as crianças foram instruídas a dizer o nome das figuras. O tempo de latência e as respostas foram registradas em um programa criado especialmente para esta pesquisa. As respostas foram analisadas de acordo com os critérios da literatura específica. Não foram observadas diferenças entre crianças com Transtorno da Leitura e seus controles para o tempo de latência. Todavia os resultados apontaram mais respostas corretas para o grupo de leitores e mais erros fonológicos para as crianças com Transtorno da Leitura. Conclui-se que o tempo gasto para a recuperação dos nomes das figuras é semelhante entre as amostras, porém as crianças com Transtorno da Leitura podem exibir déficits na nomeação de figuras, principalmente para selecionar as formas fonológicas dos nomes, resultando em nomeações incorretas.<br>The aim of this study was to verify latency time and the properties for the picture labelling in children with reading disorders and children with typical reading development. The sample was composed of 20 children with reading disorders (age mean=8,3 y) and 25 children without reading disorders (age mean=8,6 y), from both genders. The picture labelling test was made up of 96 pictures, divided into stimuli groups, with equivalent balance to written words: frequency of occurrence of the written word, word extension and complexity for Portuguese spoken in Brazil. The pictures were presented on a computer screen and children were asked to name the pictures. The latency time and the responses were registered in a program designed specially for this study. The responses were analyzed according to criteria of specific literature. No statistical differences were observed between readers and non-readers related to the processing time, however, results pointed to more correct answers in the reader group. Non-readers have more phonological errors than readers. In conclusion, the latency time is similar between the subjects. However non-readers can show difficulties in picture naming, especially as to selection of phonological properties of the picture naming, which result in errors in labelling