Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

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

Introduction: A Journal of John Forbes, Part 2: The Continuation of a Journal of Talks with the Four Nations Assembled at Hickory Ground, May & June 1803

Near the end of May 1803, William Augustus Bowles, the dashing adventurer and agent provocateur, whose schemes had ruffled the Creek Country and Gulf Coast for two decades, stood with arms bound on a small island in the Tallapoosa River.1 Shortly, newly-forged handcuffs replaced the rope and represented a subtle and effective symbol of the outlaw\u27s transfer of custody from Indian to European control. Once in Spanish hands, Bowles floated peacefully away from the center of Creek power toward his ultimate demise in Havana\u27s El Morro prison in December 1805. The story of Bowles\u27s misadventures in the tumultuous post-Revolutionary South has been told and re-told, and still garners significant attention.2 Inevitably described as handsome and charming, Bowles\u27 actions have been cast as adventures, and his conspiracies to undermine both Spanish authority and the commercial hegemony of Panton, Leslie and Company have been romanticized and analyzed since the publication of his own memoir in 1791

Negotiating the area between: exploration of an upper creek settlement in the lower Black Warrior river valley

During the 1930s, Dr. Walter B. Jones of the University of Alabama uncovered evidence at the Haney site (1Tu52), near the town of Moundville, Alabama, which indicated an unexpected Native settlement in the lower Black Warrior River valley during the historic period. The ethnohistorical documentation as well as the archaeological record for that area produced no other signs of Native settlement in the area, with the lower Black Warrior river valley serving instead as a violently contested buffer zone between the Choctaws and Creeks. Though subsequent researchers have attempted to locate and investigate this anomaly, mislabeled site files made these attempts futile. Fieldwork and archival research in the fall of 2010 resulted in the relocation and further investigation of the site, confirming the historic Native presence in the area. This confirmation begged the question why would a group of historic Natives settle in this violently contested area? Employing a landscape perspective, this thesis aims to illuminate this anomaly by placing the site and the activities that took place there within the ethnohistorical framework in order to determine possible agendas for settlement in this dangerous and liminal area. (Published By University of Alabama Libraries

Engaging teenagers in improving their health behaviours and increasing their interest in science (Evaluation of LifeLab Southampton): study protocol for a cluster randomized controlled trial

BackgroundLifestyle and health behaviours are strongly linked to non-communicable disease risk, but modifying them is challenging. There is an increasing recognition that adolescence is an important time when lifestyle and health behaviours become embedded. Improving these in adolescents is important not only for their own health but also for that of their future children. LifeLab Southampton has been developed as a purpose-built classroom and laboratory in University Hospital Southampton. Secondary school students visit LifeLab to learn how childhood, adolescent and parental nutrition influences health, understand the impact of their lifestyle on their cardiovascular and metabolic health, and to inspire them with the excitement of research and future career possibilities in science. The LifeLab visit is part of a programme of work linked to the English National Curriculum. Pilot work has indicated that attitudes towards health can be changed by such LifeLab sessions. MethodsA cluster randomised controlled trial is being conducted to evaluate the effectiveness of the LifeLab intervention, the primary outcome being a measurement of the change in nutrition, health and lifestyle literacy from before to after the LifeLab intervention. The LifeLab intervention comprises: professional development for the teachers involved, preparatory-lessons for the school students, delivered in school, a hands-on practical day at LifeLab including a ‘Meet the Scientist’ session, post-visit lessons delivered in school and the opportunity to participate in the annual LifeLab Schools’ Conference. This study aims to recruit approximately 2,500 secondary school students aged 13-14 years from 32 schools (the clusters) from Southampton and neighbouring areas. Participating schools will be randomised to control or intervention groups. The intervention will be run over two academic school years, with baseline questionnaire data collected from students at participating schools at the start of the academic year and follow- up questionnaire data collected approximately 12 months later.Evaluation of LifeLab is a cluster randomised controlled trial (ISRCTN71951436, registered 25th March 2015), funded by the British Heart Foundation (PG/14/33/30827)

Impact of Selection Bias on Estimation of Subsequent Event Risk

Background - Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results - We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias. Conclusions - In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal

Impact of Selection Bias on Estimation of Subsequent Event Risk

Background - Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results - We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias. Conclusions - In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal

'The Indians of every denomination were free, and independent of us’: White Southern Explorations of Indigenous Slavery, Freedom, and Society, 1772-1830

In arguing against Indian slavery, plaintiff’s attorneys in the 1772 Virginia General Court case Robin v Hardaway faced a dilemma: how could they condemn enslavement while mollifying public conviction that Indigenous “savagery” made them dangerous to community stability? Their solution, rooted in a nearly two-century discourse of slavery and freedom, was to insist that Indians derived from independent polities (unlike other enslaved communities). As such, they were both inherently free and outside the evolving Anglo-American body politic, and whites could legitimately deprive them of property, happiness, and safety. Subsequent Virginia freedom cases contributed to the discourse employed in Robin, as did early-nineteenth-century US Supreme Court decisions. It came to underpin civilization policies as well as removal, once older understandings of Anglo-American “civility” became untenable to Southern whites