Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background<p></p> Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.<p></p> Methods and Results<p></p> We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).<p></p> Conclusion<p></p> Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.

Centerscope

Centerscope, formerly Scope, was published by the Boston University Medical Center "to communicate the concern of the Medical Center for the development and maintenance of improved health care in contemporary society.

Forecasting the spread of raccoon rabies using a purpose-specific group decisionmaking process

The Centers for Disease Control (CDC) and USDA Wildlife Services (WS) have been involved in an oral rabies vaccination (ORV) program for raccoons (Procyon lotor) that has slowed the westward spread of raccoon rabies. The objective of this study was to forecast the spread of the disease if an ORV zone was not maintained. A group decision-making process was designed to address the forecasting problem and was implemented using a group of 15 experts and 4 support personnel at a meeting at the USDA National Wildlife Research Center. Ten expansion regions were constructed that described the spread of disease at 2-year intervals. This forecast may provide for more accurate cost-benefit analysis of the ORV barrier

Transmission of HIV-1 infection in sub-Saharan Africa and effect of elimination of unsafe injections

During the past year, a group has argued that unsafe injections are a major if not the main mode of HIV-1 transmission\ud in sub-Saharan Africa. We review the main arguments used to question the epidemiological interpretations on the lead\ud role of unsafe sex in HIV-1 transmission, and conclude there is no compelling evidence that unsafe injections are a\ud predominant mode of HIV-1 transmission in sub-Saharan Africa. Conversely, though there is a clear need to eliminate\ud all unsafe injections, epidemiological evidence indicates that sexual transmission continues to be by far the major\ud mode of spread of HIV-1 in the region. Increased efforts are needed to reduce sexual transmission of HIV-1

Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13–dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Unhappy patients are not alike: Content analysis of the negative comments from China's good doctor website

Background: With the rise in popularity of Web 2.0 technologies, the sharing of patient experiences about physicians on online forums and medical websites has become a common practice. However, negative comments posted by patients are considered to be more influential by other patients and physicians than those that are satisfactory. Objective: The aim of this study was to analyze negative comments posted online about physicians and to identify possible solutions to improve patient satisfaction, as well as their relationship with physicians. Methods: A Java-based program was developed to collect patient comments on the Good Doctor website, one of the most popular online health communities in China. A total of 3012 negative comments concerning 1029 physicians (mean 2.93 [SD 4.14]) from 5 highly ranked hospitals in Beijing were extracted for content analysis. An initial coding framework was constructed with 2 research assistants involved in the codification. Results: Analysis, based on the collected 3012 negative comments, revealed that unhappy patients are not alike and that their complaints cover a wide range of issues experienced throughout the whole process of medical consultation. Among them, physicians in Obstetrics and Gynecology (606/3012, 20.12%; P=.001) and Internal Medicine (487/3012, 16.17%; P=.80) received the most negative comments. For negative comments per physician, Dermatology and Sexually Transmitted Diseases (mean 5.72, P<.001) and Andrology (mean 5, P=.02) ranked the highest. Complaints relating to insufficient medical consultation duration (577/3012, 19.16%), physician impatience (527/3012, 17.50%), and perceived poor therapeutic effect (370/3012, 12.28%) received the highest number of negative comments. Specific groups of people, such as those accompanying older patients or children, traveling patients, or very important person registrants, were shown to demonstrate little tolerance for poor medical service. Conclusions: Analysis of online patient complaints provides an innovative approach to understand factors associated with patient dissatisfaction. The outcomes of this study could be of benefit to hospitals or physicians seeking to improve their delivery of patient-centered services. Patients are expected to be more understanding of overloaded physicians' workloads, which are impacted by China's stretched medical resources, as efforts are made to build more harmonious physician-patient relationships.National Natural Science Foundation of China; Hubei Social Science Foundation; Fundamental Research Funds for the Central Universitie

'Tough'-constructions and their derivation

This article addresses the syntax of the notorious 'tough' (-movement) construction (TC) in English. TCs exhibit a range of apparently contradictory empirical properties suggesting that their derivation involves the application of both A-movement and A'-movement operations. Given that within previous Principles and Parameters models TCs have remained “unexplained and in principle unexplainable” (Holmberg 2000: 839) due to incompatibility with constraints on theta-assignment, locality, and Case, this article argues that the phase-based implementation of the Minimalist program (Chomsky 2000, 2001, 2004) permits a reanalysis of null wh-operators capable of circumventing the previous theoretical difficulties. Essentially, 'tough'-movement consists of A-moving a constituent out of a “complex” null operator which has already undergone A'-movement, a “smuggling” construction in the terms of Collins (2005a,b