Meta-analysis of gene-level associations for rare variants based on single-variant statistics.

Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

Dissection of the complex phenotype in cuticular mutants of Arabidopsis reveals a role of SERRATE as a mediator.

Mutations in LACERATA (LCR), FIDDLEHEAD (FDH), and BODYGUARD (BDG) cause a complex developmental syndrome that is consistent with an important role for these Arabidopsis genes in cuticle biogenesis. The genesis of their pleiotropic phenotypes is, however, poorly understood. We provide evidence that neither distorted depositions of cutin, nor deficiencies in the chemical composition of cuticular lipids, account for these features, instead suggesting that the mutants alleviate the functional disorder of the cuticle by reinforcing their defenses. To better understand how plants adapt to these mutations, we performed a genome-wide gene expression analysis. We found that apparent compensatory transcriptional responses in these mutants involve the induction of wax, cutin, cell wall, and defense genes. To gain greater insight into the mechanism by which cuticular mutations trigger this response in the plants, we performed an overlap meta-analysis, which is termed MASTA (MicroArray overlap Search Tool and Analysis), of differentially expressed genes. This suggested that different cell integrity pathways are recruited in cesA cellulose synthase and cuticular mutants. Using MASTA for an in silico suppressor/enhancer screen, we identified SERRATE (SE), which encodes a protein of RNA-processing multi-protein complexes, as a likely enhancer. In confirmation of this notion, the se lcr and se bdg double mutants eradicate severe leaf deformations as well as the organ fusions that are typical of lcr and bdg and other cuticular mutants. Also, lcr does not confer resistance to Botrytis cinerea in a se mutant background. We propose that there is a role for SERRATE-mediated RNA signaling in the cuticle integrity pathway.

Effectiveness of chronic obstructive pulmonary disease-management programs: systematic review and meta-analysis

BACKGROUND: Disease-management programs may enhance the quality of care provided to patients with chronic diseases, such as chronic obstructive pulmonary disease (COPD). The aim of this systematic review was to assess the effectiveness of COPD disease-management programs. METHODS: We conducted a computerized search of MEDLINE, EMBASE, CINAHL, PsychINFO, and the Cochrane Library (CENTRAL) for studies evaluating interventions meeting our operational definition of disease management: patient education, 2 or more different intervention components, 2 or more health care professionals actively involved in patients' care, and intervention lasting 12 months or more. Programs conducted in hospital only and those targeting patients receiving palliative care were excluded. Two reviewers evaluated 12,749 titles and fully reviewed 139 articles; among these, data from 13 studies were included and extracted. Clinical outcomes considered were all-cause mortality, lung function, exercise capacity (walking distance), health-related quality of life, symptoms, COPD exacerbations, and health care use. A meta-analysis of exercise capacity and all-cause mortality was performed using random-effects models. RESULTS: The studies included were 9 randomized controlled trials, 1 controlled trial, and 3 uncontrolled before-after trials. Results indicate that the disease-management programs studied significantly improved exercise capacity (32.2 m, 95% confidence interval [CI], 4.1-60.3), decreased risk of hospitalization, and moderately improved health-related quality of life. All-cause mortality did not differ between groups (pooled odds ratio 0.84, 95% CI, 0.54-1.40). CONCLUSION: COPD disease-management programs modestly improved exercise capacity, health-related quality of life, and hospital admissions, but not all-cause mortality. Future studies should explore the specific elements or characteristics of these programs that bring the greatest benefit.

Diagnostic performance of &supl;⁸F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a systematic review and meta-analysis.

PURPOSE: The aim of this study was to conduct a systematic review and perform a meta-analysis on the diagnostic performances of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) for giant cell arteritis (GCA), with or without polymyalgia rheumatica (PMR). METHODS: MEDLINE, Embase and the Cochrane Library were searched for articles in English that evaluated FDG PET in GCA or PMR. All complete studies were reviewed and qualitatively analysed. Studies that fulfilled the three following criteria were included in a meta-analysis: (1) FDG PET used as a diagnostic tool for GCA and PMR; (2) American College of Rheumatology and Healey criteria used as the reference standard for the diagnosis of GCA and PMR, respectively; and (3) the use of a control group. RESULTS: We found 14 complete articles. A smooth linear or long segmental pattern of FDG uptake in the aorta and its main branches seems to be a characteristic pattern of GCA. Vessel uptake that was superior to liver uptake was considered an efficient marker for vasculitis. The meta-analysis of six selected studies (101 vasculitis and 182 controls) provided the following results: sensitivity 0.80 [95% confidence interval (CI) 0.63-0.91], specificity 0.89 (95% CI 0.78-0.94), positive predictive value 0.85 (95% CI 0.62-0.95), negative predictive value 0.88 (95% CI 0.72-0.95), positive likelihood ratio 6.73 (95% CI 3.55-12.77), negative likelihood ratio 0.25 (95% CI 0.13-0.46) and accuracy 0.84 (95% CI 0.76-0.90). CONCLUSION: We found overall valuable diagnostic performances for FDG PET against reference criteria. Standardized FDG uptake criteria are needed to optimize these diagnostic performances.

Women survivors of intimate partner violence: the difficult transition to independence

Objective To understand the trajectories that women go through from entering into to leaving relationships involving intimate partner violence (IPV), and identify the stages of the transition process. Method We utilized a constructivist paradigm based on grounded theory. We ensured that the ethical guidelines of the World Health Organization for research on domestic violence were followed. The analysis focused on narratives of 28 women survivors of IPV, obtained from in-depth interviews. Results The results showed that the trajectories experienced by women were marked by gender issues, (self) silencing, hope and suffering, which continued after the end of the IPV. Conclusion The transition process consists of four stages: entry - falls in love and becomes trapped; maintenance - silences own self, consents and remains in the relationship; decides to leave - faces the problems and struggles to be rescued; (re) balance - (re) finds herself with a new life. This (long) process was developed by wanting (and being able to have) self-determination.

Facilitators of the transition process for the self-care of the person with stoma: subsidies for Nursing

OBJECTIVE To know the facilitating factors of the transition process from dependency to the self-care of people with a stoma. METHOD This is a descriptive study of qualitative approach, including 27 people with permanent stomas due to cancer. The data were collected through semi-structured interviews and submitted to content analysis based on the Transition Theory as theoretical reference. RESULTS The self-care facilitators related to the person were the positive significance of ostomy; the preparation for this experience already in the preoperative period; emotional stability; faith; religiousness; and a sense of normalcy acquired from a next image similar to the previous one. The facilitators related to the community were the following: receiving equipment for free from the government; support from family and the multidisciplinary team, especially the nurses; and having contact with other people with stomata. CONCLUSION The results allow that nurses develop strategies to help people with stomata to resume their self-care.

O Processo de Raciocínio na Teoria dos Constrangimentos Aplicado numa Instituição de Ensino Superior

A Teoria dos Constrangimentos (TOC) ou das Restrições tem-se mostrado uma valiosa ferramenta de gestão, auxiliando na identificação dos constrangimentos que limitem a capacidade das empresas na prossecução da sua meta. Assim, para as restrições não físicas, a TOC desenvolveu o Processo de Raciocínio que é composto por ferramentas de análise lógica que dão subsídios para o diagnóstico de problemas bem como a formulação de soluções e planos de acção para implementá-las. Neste contexto, este trabalho se propõe a determinar a adequação do Processo de Raciocínio da Teoria dos Constrangimentos numa Instituição de Ensino Superior (IES) como forma de diagnosticar os problemas e propor soluções capazes de permitir a empresa uma melhoria contínua do seu desempenho. Serão avaliadas as ferramentas que compõem o Processo de Raciocínio, que são: Árvore de Realidade Actual, Diagrama de Dispersão de nuvens, Árvore de Realidade Futura, Árvore de Pré-Requisitos e Árvore de Transição. O trabalho inicia-se com uma pesquisa bibliográfica seguida de uma pesquisa de campo e finalizando com uma aplicação do PR numa IES localizada na ilha de São Vicente. A colecta de informações para a análise processou-se mediante a aplicação de um questionário fechado aos discentes e funcionários, questionário aberto aos docentes e entrevista estruturada aos dirigentes, elaborados em coerência com os objectivos que este estudo pretende atingir. Os resultados da aplicação do método aqui apresentado permitiram chegar as conclusões apontadas no capítulo final deste trabalho The Theory of Constraints (TOC) or Restriction Theory has proved to be a valuable management tool, assisting in the identification of constraints that restrict the ability of companies in the pursuit of its goals. Therefore, for the nonphysical constraints, TOC developed the Thinking Process (TP) that consists of logical analysis tools that provide a basis for diagnosing problems and formulating solutions and action plans to implement them. This study aims, thus, to determine the suitability of the use of the Thinking Process of the Theory of Constraints in a Higher Education Institution (HEI) as a way to diagnose problems and propose solutions that enable the firm to continually improve their performance. We will evaluate the tools that make up the TP, which are: Current Reality Tree, Evaporating Cloud Diagram, Future Reality Tree, Prerequisites Tree and Transition Tree. The work starts with a literature review, followed by a field search, and finishes with an application of the reasoning process in a higher education institution, located in São Vicente. The collection of the data for the analysis was processed through the application of a closed questionnaire to students and staff, opened questionnaire to teachers and interviews to management, drafted in line with the objectives that this study aims to reach. The results of the application of the method presented here, allowed us to reach the conclusions drawn in the final chapter of this work.

Prevalence of infection in kidney transplantation from living versus deceased donor: systematic review and meta-analysis

OBJECTIVE To verify if the type of donor is a risk factor for infection in kidney transplant recipients. METHODS Systematic Review of Literature with Meta-analysis with searches conducted in the databases MEDLINE, LILACS, Embase, Cochrane, Web of Science, SciELO and CINAHL. RESULTS We selected 198 studies and included four observational studies describing infections among patients distinguishing the type of donor. Through meta-analysis, it was shown that in patients undergoing deceased donor transplant, the outcome infection was 2.65 higher, than those who received an organ from a living donor. CONCLUSION The study showed that deceased kidney donor recipients are at an increased risk for developing infections and so the need for establishing and enforcing protocols from proper management of ischemic time to the prevention and control of infection in this population emerges.

Hypertension prevalence among indigenous populations in Brazil: a systematic review with meta-analysis

Abstract OBJECTIVE Evaluating the evidence of hypertension prevalence among indigenous populations in Brazil through a systematic review and meta-analysis. METHODS A search was performed by two reviewers, with no restriction of date or language in the databases of PubMed, LILACS, SciELO, Virtual Health Library and Capes Journal Portal. Also, a meta-regression model was designed in which the last collection year of each study was used as a moderating variable. RESULTS 23 articles were included in the review. No hypertension was found in indigenous populations in 10 studies, and its prevalence was increasing and varied, reaching levels of up to 29.7%. Combined hypertension prevalence in Indigenous from the period of 1970 to 2014 was 6.2% (95% CI, 3.1% - 10.3%). In the regression, the value of the odds ratio was 1.12 (95% CI, 1.07 - 1.18; p <0.0001), indicating a 12% increase every year in the probability of an indigenous person presenting hypertension. CONCLUSION There has been a constant increase in prevalence despite the absence of hypertension in about half of the studies, probably due to changes in cultural, economic and lifestyle habits, resulting from indigenous interaction with non-indigenous society.

Transition from pediatric to adult health care: expectations of adolescents with chronic disorders and their parents.

The aim of this study was to assess the expectations of adolescents with chronic disorders with regard to transition from pediatric to adult health care and to compare them with the expectations of their parents. A cross-sectional study was carried out including 283 adolescents with chronic disorders, aged 14-25 years (median age, 16.0 years), and not yet transferred to adult health care, and their 318 parents from two university children's hospitals. The majority of adolescents and parents (64%/70%) perceived the ages of 18-19 years and older as the best time to transfer to adult health care. Chronological age and feeling too old to see a pediatrician were reported as the most important decision factors for the transfer while the severity of the disease was not considered important. The most relevant barriers were feeling at ease with the pediatrician (45%/38%), anxiety (20%/24%), and lack of information about the adult specialist and health care (18%/27%). Of the 51% of adolescents with whom the pediatric specialist had spoken about the transfer, 53% of adolescents and 69% of parents preferred a joint transfer meeting with the pediatric and adult specialist, and 24% of these adolescents declared that their health professional had offered this option. In summary, the age preference for adolescents with chronic disorders and their parents to transfer to adult health care was higher than the upper age limits for admission to pediatric health care in many European countries. Anxiety and a lack of information of both adolescents and their parents were among the most important barriers for a smooth and timely transfer according to adolescents and parents.

Determinants of linear judgment: A meta-analysis of lens model studies

The mathematical representation of Brunswik s lens model has been usedextensively to study human judgment and provides a unique opportunity to conduct ameta-analysis of studies that covers roughly five decades. Specifically, we analyzestatistics of the lens model equation (Tucker, 1964) associated with 259 different taskenvironments obtained from 78 papers. In short, we find on average fairly high levelsof judgmental achievement and note that people can achieve similar levels of cognitiveperformance in both noisy and predictable environments. Although overall performancevaries little between laboratory and field studies, both differ in terms of components ofperformance and types of environments (numbers of cues and redundancy). An analysisof learning studies reveals that the most effective form of feedback is information aboutthe task. We also analyze empirically when bootstrapping is more likely to occur. Weconclude by indicating shortcomings of the kinds of studies conducted to date, limitationsin the lens model methodology, and possibilities for future research.

Transition probabilities and duration analysis among disability states: Some evidence from Spanish data

In this paper we study the disability transition probabilities (as well as the mortalityprobabilities) due to concurrent factors to age such as income, gender and education. Althoughit is well known that ageing and socioeconomic status influence the probability ofcausing functional disorders, surprisingly little attention has been paid to the combined effectof those factors along the individuals' life and how this affects the transition from one degreeof disability to another. The assumption that tomorrow's disability state is only a functionof the today's state is very strong, since disability is a complex variable that depends onseveral other elements than time. This paper contributes into the field in two ways: (1) byattending the distinction between the initial disability level and the process that leads tohis course (2) by addressing whether and how education, age and income differentially affectthe disability transitions. Using a Markov chain discrete model and a survival analysis, weestimate the probability by year and individual characteristics that changes the state of disabilityand the duration that it takes its progression in each case. We find that people withan initial state of disability have a higher propensity to change and take less time to transitfrom different stages. Men do that more frequently than women. Education and incomehave negative effects on transition. Moreover, we consider the disability benefits associatedto those changes along different stages of disability and therefore we offer some clues onthe potential savings of preventive actions that may delay or avoid those transitions. Onpure cost considerations, preventive programs for improvement show higher benefits thanthose for preventing deterioration, and in general terms, those focussing individuals below65 should go first. Finally the trend of disability in Spain seems not to change among yearsand regional differences are not found.

IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25.

IL-2 is crucial to T cell homeostasis, especially of CD4(+) T regulatory cells and memory CD8(+) cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor alpha (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.