ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

BackgroundWhole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts.MethodsWe developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA).ResultsClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes.ConclusionsClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume

The old age and the sport like object of social representations

In the present work we analyzed the social function of the Physical Education and the sport with respect to the elderly people. One is a relation hyped by the social representations that the implied agents own on the old age, the body, the health and the sport, nonfree of stereotypes and prejudices that condition their social practices. It constitutes a social problem and simultaneously a challenge for institutions to eradicate the social practices of exclusion to that they give rise. For it two steps are essential. In the first place to denounce the contents of the social representations on the sport old age and activities physical that favor the social exclusion, especially from the Educative System and mass media. Secondly to promote the average materials and necessary structural conditions for the social change

La vejez y el deporte como objeto de representaciones sociales

In the present work we analyzed the social function of the Physical Education and the sport with respect to the elderly people. One is arelation hyped by the social representations that the implied agents own on the old age, the body, the health and the sport, nonfree of stereotypes andprejudices that condition their social practices. It constitutes a social problem and simultaneously a challenge for institutions to eradicate the socialpractices of exclusion to that they give rise. For it two steps are essential. In the first place to denounce the contents of the social representations onthe sport old age and activities physical that favor the social exclusion, especially from the Educative System and mass media. Secondly to promote theaverage materials and necessary structural conditions for the social changeEn el presente trabajo analizamos la función social de la Educación Física y el deporte respecto a las personas mayores. Se trata de unarelación mediatizada por las representaciones sociales que los agentes implicados poseen sobre la vejez, el cuerpo, la salud y el deporte, no exentas deestereotipos y prejuicios que condicionan sus prácticas sociales. Constituye un problema social y a la vez un reto para las instituciones erradicar lasprácticas sociales de exclusión a que dan lugar. Para ello resultan imprescindibles dos pasos. En primer lugar denunciar los contenidos de las representa-ciones sociales sobre la vejez y las actividades físico-deportivas que favorecen la exclusión social, especialmente desde el Sistema Educativo y los mediosde comunicación. En segundo lugar promover los medios materiales y condiciones estructurales necesarias para el cambio social

Íber : didáctica de las ciencias sociales, geografía e historia

El artículo forma parte de una sección dedicada a investigación y opinión.La historia del deporte como disciplina científica tiene un recorrido relativamente corto. Además ha tenido que enfrentarse a numerosos estereotipos. Su estudio ha tomado como referencia el idealismo de la Grecia Clásica y ha menospreciado las prácticas romanas. Este hecho se ejemplifica a través del análisis de varios textos sobre la materia del siglo XX. Para poner fin a esta situación se aboga por un estudio de la materia más riguroso y científico que ha de basarse en el análisis crítico de fuentes documentales válidas y fiables..CataluñaConsejería de Educación, Formación y Empleo. Servicio de Publicaciones y Estadística; Avda. de la Fama, 15 - 1ª Planta; 30006 Murcia; Tel. +34968279685; Fax +34968279835; [email protected]

Escala de clima social de clase como instrumento de análisis en Educación Física

The purpose of the present work is to show the utility of the the classrom environment scale (CES) as tool to know and to interpret the social existing interactions in the meetings of Physical Education. Concretly, we have applied the scale to four groups-classes of Secondary Obligatory Education. Our lens is to know how the student body perceives the climate of existing classroom in his classes of Physical Education.la finalidad del presente trabajo es mostrar la utilidad de la Escala de Clima Social de Clase (CES) como instrumento para conocer e interpretar las interacciones sociales existentes en las sesiones de Educación Física. Concretamente, hemos aplicado la escala a cuatro grupos-clase de Educación Secundaria Obligatoria. Nuestro objetivo es saber cómo el alumnado percibe el clima de aula existente en sus clases de Educación Física

A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman syndrome (A-MANECE study)

Background: Minocycline is an old tetracycline antibiotic that has shown antiinflammatory and antiapoptotic properties in different neurological disease mouse models. Previous single arm study in humans demonstrated benefits in individuals with Angelman Syndrome (AS); however, its efficacy in patients with Angelman Syndrome has not been assessed in a controlled trial. This was a randomized, double-blind, placebo-controlled, crossover trial in individuals with AS, aged 6 years to 30 years (n = 32, mean age 12 [SD 6·29] years). Participants were randomized to minocycline or placebo for 8 weeks and then switched to the other treatment (a subset of 22 patients) or to receive minocycline for up to 16 weeks (10 patients). After week 16, all patients entered a wash-out 8-week follow-up period. Results: Thirty-six subjects were screened and 34 were randomized. Thirty two subjects (94·1%) completed at least the first period and all of them completed the full trial. Intention-to-treat analysis demonstrated the lack of significantly greater improvements in the primary outcome, mean changes in age equivalent of the development index of the Merrill-Palmer Revised Scale after minocycline compared with placebo (1·90 ± 3·16 and 2·00 ± 3·28, respectively, p = 0·937). Longer treatment duration up to 16 weeks did not result in better treatment outcomes (1·86 ± 3·35 for 8 weeks treatment vs 1·20 ± 5·53 for 16 weeks treatment, p = 0·667). Side effects were not significantly different during minocycline and placebo treatments. No serious adverse events occurred on minocycline. Conclusions: Minocycline treatment for up to 16 weeks in children and young adults with AS resulted in lack of significant improvements in development indexes compared to placebo treatment. Treatment with minocycline appears safe and well tolerated; even if it cannot be completely ruled out that longer trials might be required for a potential minocycline effect to be expressed, available results and lack of knowledge on the actual mechanism of action do not support this hypothesis. Trial registration: European Clinical Trial database (EudraCT 2013-002154-67), registered 16th September 2013; US Clinical trials database (NCT02056665), registered 6th February 2014.Depto. de Psicología Experimental, Procesos Cognitivos y LogopediaFac. de PsicologíaTRUEpu