Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Organização Administrativa de uma Escola Estudo de caso – Escola “Amor de Deus”

Este trabalho enquadra-se no âmbito da memória de Licenciatura em Ciências da Educação e Praxis Educativa – Vertente Administração Escolar e Gestão Pedagógica. Neste sentido propomos estudar a Organização Administrativa da “Escola Amor de Deus” tendo como objectivo final conhecer melhor a sua organização administrativa e o funcionamento da mesma. A escola “Amor de Deus” é a primeira escola da ilha de Santiago e de Cabo Verde que funciona desde o berçário ao ensino secundário. Para além disso, é uma escola com alto grau de organização visto que há uma preparação moral a nível geral de todos os alunos professores e funcionários. Em termos de funcionamento é uma Escola Pública de Gestão Privada, ou seja, é uma Escola Mista, por um lado, porque funciona como as outras escolas, quer a nível do Ensino Secundário quer da Educação Pré-escolar, todos os programas provêm do MEES, por outro lado, porque todos os professores são remunerados pelo próprio Ministério da Educação. Os funcionários são pagos pela Congregação das Irmãs do “Amor de Deus” e todas as despesas da referida escola são da responsabilidade da mesma. Enquanto que nas escolas Públicas as receitas das propinas são, de um modo geral, encaminhadas para o MEES, na Escola “Amor de Deus” as receitas pertencem à Congregação. Foram feitos alguns trabalhos de pesquisa nomeadamente a aplicação de inquéritos por questionários aos professores e alunos, entrevista à Directora da Escola e ao Subdirector Administrativo e Financeiro. No que se refere aos inquéritos por questionários, trinta e oito professores deram os seus contributos, sendo seis do Ensino Básico Integrado e trinta e dois do Ensino Secundário, Noventa e três alunos responderam aos inquéritos por questionário. Com efeito, os resultados obtidos através da análise e cruzamento dos dados recolhidos durante a investigação permitiram – nos concluir que a Organização Administrativa da Escola “ Amor de Deus” está a atingir o seu máximo na medida em que consideramos que esta escola é uma das mais novas, ou seja com apenas 6 anos de existência.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Directional dominance on stature and cognition in diverse human populations.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Attitudes of second year diploma nurses in three community colleges toward the use of computers in the nursing role /

The effectiveness of various kinds of computer programs is of concern to nurse-educators. Using a 3x3 experimental design, ninety second year diploma student nurses were randomly selected from a total population at three community colleges in Ontario. Data were collected via a 20-item valid and reliable Likert-type questionnaire developed by the nursing profession to measure perceptions of nurses about computers in the nursing role. The groups were pretested and posttested at the beginning and end of one semester. Subjects attending College A group received a computer literacy course which comprised word processing with technology awareness. College B students were exposed to computer-aided instruction primarily in nursing simulations intermittently throughout the semester. College C subjects maintained their regular curriculum with no computer involvement. The student's t-test (two-tailed) was employed to assess the attitude scores data and a one-way analysis of variance was performed on the attitude scores. Posttest analysis revealed that there was a significant difference (p<.05) between attitude scores on the use of computers in the nursing role between College A and C. No significant differences (p>.05) were seen between College B and A in posttesting. Suggestions for continued computer education of diploma student nurses are provided.

Efectividad del tratamiento con neurofeedback en trastornos del estado del ánimo, ansiedad y fibromialgia: una revisión de literatura

El neurofeedback es una técnica no invasiva en la que se pretende corregir, mediante condicionamiento operante, ondas cerebrales que se encuentren alteradas en el electroencefalograma. Desde 1967, se han conducido numerosas investigaciones relacionadas con los efectos de la técnica en el tratamiento de alteraciones psicológicas. Sin embargo, a la fecha no existen revisiones sistemáticas que reúnan los temas que serán aquí tratados. El aporte de este trabajo es la revisión de 56 artículos, publicados entre los años 1995 y 2013 y la evaluación metodológica de 29 estudios incluidos en la revisión. La búsqueda fue acotada a la efectividad del neurofeedback en el tratamiento de depresión, ansiedad, trastorno obsesivo compulsivo (TOC), ira y fibromialgia. Los hallazgos demuestran que el neurofeedback ha tenido resultados positivos en el tratamiento de estos trastornos, sin embargo, es una técnica que aún está en desarrollo, con unas bases teóricas no muy bien establecidas y cuyos resultados necesitan de diseños metodológicamente más sólidos que ratifiquen su validez.

Internacionalización de operadores logísticos casos exitosos: SERVIENTREGA FEDEX DEUTSCHE POST - DHL

Este trabajo muestra la evolución de la internacionalización de las empresas del sector Operadores Logísticos a partir de una muestra suficientemente amplia que permita deducir similitudes dentro de los procesos que llevaron a cabo al realizarlos. Para lograr este objetivo se tomó como muestra representativa las empresas de operadores logísticos en contextos diferentes; específicamente se analizaron las compañías Servientrega, FedEx, Deutsche Post-DHL. Se consideró que estas firmas son ejemplos claros del sector por ser los líderes en sus países y mantener el mercado cautivo a lo largo del tiempo. Gran parte de la relevancia del estudio se desprende de los diferentes entornos en que las empresas desarrollan sus actividades; con lo anterior se quiere decir que no deberían mostrar la misma evolución, el crecimiento y desarrollo de un operador logístico en el caso alemán, ni en el estadounidense y mucho menos en el caso colombiano. Sin embargo, como se demostrará a lo largo de este working paper se pueden hallar procesos similares demostrando que los casos empíricos muestran congruencia con la literatura de teorías de internacionalización. El resultado del estudio es una ruta de exportación a seguir para futuros operadores logísticos. De tal forma, se podría tomar este working paper como una guía de navegación para diferentes empresas nacientes en el sector a lo largo del mundo, toda vez que están por encima de los diferentes ámbitos locales.