ACALASIA NA DOENÇA DE CHAGAS É DIFERENTE DE ACALASIA IDIOPÁTICA? EXPERIÊNCIA DO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE

Objetive: The objective of this study is to evaluate the differences between achalasia in Chagas’ disease and idiopathic achalasia in patients admitted to the Hospital de Clínicas de Porto Alegre, by analyzing epidemiologic, clinic, radiologic and manometric findings.Methods: Patients referred to the Hospital de Clinicas de Porto Alegre between November 1996 and December 2001 with suspicion of achalasia, later confirmed by esophageal manometry, were included in the study. In addition to manometric and radiologic findings, patients were assessed for age, sex, symptomsand symptomatic period.Results: Among 51 patients, nine (18%) presented positive serology for Chagas’ disease and 42 (82%) presented negative serology. The latter were considered carriers of idiopathic achalasia. The mean age of patients with achalasia in Chagas’ disease was 62 ± 15 years, while the mean age in the idiopathic group was 43 ± 18 years (P < 0.02). The symptomatic period for patients with achalasia in Chagas’ disease was 74 ± 47 months, and in the idiopathic group, 49 ± 35 months (P < 0.05). Dysphagia, regurgitation, thoracic pain and weight loss, values at the lower esophageal sphincter (basal pressure, post-deglutitive relaxation pressure/duration and total length) and at the esophageal body (amplitude and duration of the post-deglutitive waves) were similar in both groups.Conclusions: The only statistically significant differences found between the two groups were age and length of the symptomatic period, significantly greater in patients with achalasia in Chagas’ disease. These data suggest a greater resistance to the symptoms in older patients.Objetivo: O presente trabalho tem como objetivo avaliar as diferenças entre a acalasia chagásica e a idiopática em pacientes do Hospital de Clínicas de Porto Alegre, através da análise de achados epidemiológicos, clínicos, radiológicos e manométricos.Métodos: Foram estudados pacientes encaminhados ao Hospital de Clínicas de Porto Alegre, entre novembro de 1996 e dezembro de 2001, com suspeita de acalasia, posteriormente, confirmada por manometria esofágica. Além das características manométricas e radiológicas, os pacientes foram avaliados quanto a idade, sexo, sintomas e tempo de evolução.Resultados: Entre 51 pacientes, nove (18%) tiveram sorologia positiva para doença de Chagas e 42 (82%) sorologia negativa. Indivíduos com sorologia negativa foram considerados portadores de acalasia idiopática. Pacientes com acalasia chagásica tinham média de idade de 62 ± 15 anos e os com idiopática 43 ± 18 anos (P < 0,02). O período de evolução dos sintomas em pacientes com acalasia chagásica foi de 74 ± 47 meses e nos idiopáticos 49 ± 35 meses (P < 0,05). Disfagia, regurgitação, dor torácica e emagrecimento, valores do esfíncter esofágico inferior (pressão basal, pressão e duração de relaxamento pós-deglutição e comprimento total) e do corpo esofágico (amplitude e duração das ondas pós-deglutição) foram similares em ambos os grupos.Conclusões: As únicas diferenças estatisticamente significativas encontradas entre os dois grupos foram a média de idade e o período de evolução dos sintomas, maiores nos pacientes chagásicos. Esses dados permitem especular sobre uma maior tolerância aos sintomas nos pacientes com idade mais avançada

ENIGMA-anxiety working group : Rationale for and organization of large-scale neuroimaging studies of anxiety disorders

Altres ajuts: Anxiety Disorders Research Network European College of Neuropsychopharmacology; Claude Leon Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 44541416-TRR58); EU7th Frame Work Marie Curie Actions International Staff Exchange Scheme grant 'European and South African Research Network in Anxiety Disorders' (EUSARNAD); Geestkracht programme of the Netherlands Organization for Health Research and Development (ZonMw, 10-000-1002); Intramural Research Training Award (IRTA) program within the National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, MH002781); National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, ZIA-MH-002782); SA Medical Research Council; U.S. National Institutes of Health grants (P01 AG026572, P01 AG055367, P41 EB015922, R01 AG060610, R56 AG058854, RF1 AG051710, U54 EB020403).Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the enigma-anxiety working group

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology

ACALASIA NA DOENÇA DE CHAGAS É DIFERENTE DE ACALASIA IDIOPÁTICA? EXPERIÊNCIA DO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE

Objetive: The objective of this study is to evaluate the differences between achalasia in Chagas’ disease and idiopathic achalasia in patients admitted to the Hospital de Clínicas de Porto Alegre, by analyzing epidemiologic, clinic, radiologic and manometric findings.Methods: Patients referred to the Hospital de Clinicas de Porto Alegre between November 1996 and December 2001 with suspicion of achalasia, later confirmed by esophageal manometry, were included in the study. In addition to manometric and radiologic findings, patients were assessed for age, sex, symptomsand symptomatic period.Results: Among 51 patients, nine (18%) presented positive serology for Chagas’ disease and 42 (82%) presented negative serology. The latter were considered carriers of idiopathic achalasia. The mean age of patients with achalasia in Chagas’ disease was 62 ± 15 years, while the mean age in the idiopathic group was 43 ± 18 years (P &lt; 0.02). The symptomatic period for patients with achalasia in Chagas’ disease was 74 ± 47 months, and in the idiopathic group, 49 ± 35 months (P &lt; 0.05). Dysphagia, regurgitation, thoracic pain and weight loss, values at the lower esophageal sphincter (basal pressure, post-deglutitive relaxation pressure/duration and total length) and at the esophageal body (amplitude and duration of the post-deglutitive waves) were similar in both groups.Conclusions: The only statistically significant differences found between the two groups were age and length of the symptomatic period, significantly greater in patients with achalasia in Chagas’ disease. These data suggest a greater resistance to the symptoms in older patients.Objetivo: O presente trabalho tem como objetivo avaliar as diferenças entre a acalasia chagásica e a idiopática em pacientes do Hospital de Clínicas de Porto Alegre, através da análise de achados epidemiológicos, clínicos, radiológicos e manométricos.Métodos: Foram estudados pacientes encaminhados ao Hospital de Clínicas de Porto Alegre, entre novembro de 1996 e dezembro de 2001, com suspeita de acalasia, posteriormente, confirmada por manometria esofágica. Além das características manométricas e radiológicas, os pacientes foram avaliados quanto a idade, sexo, sintomas e tempo de evolução.Resultados: Entre 51 pacientes, nove (18%) tiveram sorologia positiva para doença de Chagas e 42 (82%) sorologia negativa. Indivíduos com sorologia negativa foram considerados portadores de acalasia idiopática. Pacientes com acalasia chagásica tinham média de idade de 62 ± 15 anos e os com idiopática 43 ± 18 anos (P &lt; 0,02). O período de evolução dos sintomas em pacientes com acalasia chagásica foi de 74 ± 47 meses e nos idiopáticos 49 ± 35 meses (P &lt; 0,05). Disfagia, regurgitação, dor torácica e emagrecimento, valores do esfíncter esofágico inferior (pressão basal, pressão e duração de relaxamento pós-deglutição e comprimento total) e do corpo esofágico (amplitude e duração das ondas pós-deglutição) foram similares em ambos os grupos.Conclusões: As únicas diferenças estatisticamente significativas encontradas entre os dois grupos foram a média de idade e o período de evolução dos sintomas, maiores nos pacientes chagásicos. Esses dados permitem especular sobre uma maior tolerância aos sintomas nos pacientes com idade mais avançada

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process

methods in : The experience of the generalized anxiety disorder working group

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses. This report summarizes the background information and rationale for the various methodological decisions made by the ENIGMA-GAD group. The aim of this work is to help guide other research groups working with large brain imaging data set