454,141 research outputs found
CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018)
No full textAn Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrión Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.Peer reviewe
Análise do padrão de consumo dos antimicrobianos no Hospital Universitário da Universidade Federal de Santa Catarina no período de 2000 a 2006
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2008O conhecimento sobre os aspectos relacionados à utilização dos antimicrobianos pode subsidiar a elaboração de políticas de utilização, bem como contribuir para a reorientação das estratégias utilizadas no controle desses agentes. Objetivo: Descrever quantitativamente o padrão de consumo de antimicrobianos no Hospital Universitário da Universidade Federal de Santa Catarina, no período de 2000 a 2006. Método: A pesquisa adotou a metodologia ATC/DDD e seguiu o modelo de estudo descritivo, com coleta de dados retrospectiva no período de 2000 a 2006, sendo os resultados expressos em DDD/100 leitos/dia. Os dados de consumo dos antimicrobianos foram obtidos a partir dos registros de dispensação desses medicamentos, disponibilizados pelo Serviço de Farmácia. Os dados referentes à ocupação hospitalar, foram obtidos por meio do Serviço de Prontuário do Paciente. Os valores correspondentes a DDD (dose diária definida) de cada fármaco foram obtidos por meio do Índice ATC/DDD, versão 2007. A análise das tendências de variação no consumo dos antimicrobianos foi realizada por regressão linear simples, e os valores de P <0,05 foram considerados estatisticamente significantes. Resultados: Os resultados mostraram um aumento de 50% no consumo global dos antimicrobianos, passando de 64,3 DDD/100 leitos/dia, em 2000, para 96,8 DDD/100 leitos/dia, em 2006, correspondendo a uma média de 70,58 DDD/100 leitos/dia no período. Os antimicrobianos mais consumidos corresponderam à classe das penicilinas (30,8%), seguidas por cefalosporinas (25,5%) e quinolonas (11,3%). Estes grupos foram responsáveis por 67% do consumo dos antimicrobianos. As demais classes de antimicrobianos utilizadas foram sulfonamidas e antissépticos urinários (6,9%), antifúngicos (5,8%), nitroimidazólicos (4,9%), aminoglicosídeos (4,1%), lincosamidas (4,1%), glicopeptídeos (2,3%), carbapenêmicos (2,2%), macrolídeos (1,1%), tetraciclinas (0,4%), antivirais (0,3%), anfenicóis (0,1%), polimixinas (0,002%) e monobactâmicos (0,001%). O fármaco mais consumido no período de estudo foi a ceftriaxona (6,25 DDD/100 leitos/dia), seguido por ampicilina + sulbactam (5,04 DDD/100 leitos/dia), benzilpenicilina potássica (4,14 DDD/100 leitos/dia), cefazolina (3,78 DDD/100 leitos/dia) e metronidazol de uso parenteral (3,20 DDD/100 leitos/dia). A análise por regressão linear simples mostrou um grupo de 12 fármacos com tendência a aumento no uso e um outro grupo de 12 agentes com tendência à redução de consumo. Conclusões: O consumo de antimicrobianos apresentou oscilações importantes e aumentou expressivamente no período estudado. Diante da importância do uso racional desses agentes, há necessidade de uma reorientação das estratégias adotadas para o controle desses medicamentos, bem como da realização de estudos complementares que possam orientar a implementação de ações voltadas ao monitoramento contínuo dos antimicrobianos no hospital
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
No full textWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability
The UN-SUSTAINABLE Match in HCV Recipients. Evidences from the Italian D-MELD Study on Balancing Donor-Recipient Risk Factors
No full textThe UN-SUSTAINABLE Match in HCV Recipients. Evidences from the Italian D-MELD Study on Balancing Donor-Recipient Risk Factor
Estudo da reação da vitamina b12s com ddd
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Florianópolis, 1978
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
No full textBackgroundPediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.MethodsWe conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.ResultsA total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent–offspring trio and 2.5 variants per singleton proband. With the use of clinical and computational approaches to variant classification, a diagnosis was made in approximately 41% of probands (5502 of 13,449), of whom 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent–offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks’ gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).ConclusionsAmong probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.
De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder
No full textMany genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease gene
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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