Whole exome sequence analysis reveals a homozygous mutation in PNPLA2 as the cause of severe dilated cardiomyopathy secondary to neutral lipid storage disease.

Accepted manuscript 12 month embargo, pre-print immediately

Poverty, Deprivation, and Mortality Risk among Women with HIV in the United States

Background: Prior studies suggest neighborhood poverty and deprivation are associated with adverse health outcomes including death, but evidence is limited among persons with HIV, particularly women. We estimated changes in mortality risk from improvement in three measures of area-level socioeconomic context among participants of the Women's Interagency HIV Study. Methods: Starting in October 2013, we linked geocoded residential census block groups to the 2015 Area Deprivation Index (ADI) and two 2012-2016 American Community Survey poverty variables, categorized into national tertiles. We used parametric g-computation to estimate, through March 2018, impacts on mortality of improving each income or poverty measure by one and two tertiles maximum versus no improvement. Results: Of 1596 women with HIV (median age 49), 91 (5.7%) were lost to follow-up and 83 (5.2%) died. Most women (62%) lived in a block group in the tertile with the highest proportions of individuals with income:poverty <1; 13% lived in areas in the tertile with the lowest proportions. Mortality risk differences comparing a one-tertile improvement (for those in the two highest poverty tertiles) in income:poverty <1 versus no improvement increased over time; the risk difference was -2.2% (95% confidence interval [CI] = -3.7, -0.64) at 4 years. Estimates from family income below poverty level (-1.0%; 95% CI = -2.7, 0.62) and ADI (-1.5%; 95% CI = -2.8, -0.21) exposures were similar. Conclusions: Consistent results from three distinct measures of area-level socioeconomic environment support the hypothesis that interventions to ameliorate neighborhood poverty or deprivation reduce mortality risk for US women with HIV. See video abstract at, http://links.lww.com/EDE/B863

Predictors of mortality by sex and race in heart failure with preserved ejection fraction: Aric community surveillance study

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure hospitalizations, with limited data on predictors of mortality by sex and race. We evaluated for differences in predictors of all-cause mortality by sex and race among hospitalized patients with HFpEF in the ARIC (Atherosclerosis Risk in Communities) Community Surveillance Study. METHODS AND RESULTS: Adjudicated HFpEF hospitalization events from 2005 to 2013 were analyzed from the ARIC Community Surveillance Study, comprising 4 US communities. Comparisons between clinical characteristics and mortality at 1 year were made by sex and race. Of 4335 adjudicated acute decompensated heart failure cases, 1892 cases (weighted n=8987) were categorized as HFpEF. Men had an increased risk of 1-year mortality compared with women in adjusted analysis (hazard ratio [HR], 1.27; 95% CI, 1.06–1.52 [P=0.01]). Black participants had lower mortality compared with White participants in unadjusted and adjusted analyses (HR, 0.79; 95% CI, 0.64–0.97 [P=0.02]). Age, heart rate, worsening renal function, and low hemoglobin were associated with increased mortality in all subgroups. Higher body mass index was associated with improved survival in men, with borderline interaction by sex. Higher blood pressure was associated with improved survival among all groups, with significant interaction by race. CONCLUSIONS: In a diverse HFpEF population, men had worse survival compared with women, and Black participants had improved survival compared with White participants. Age, heart rate, and worsening renal function were associated with increased mortality across all subgroups; high blood pressure was associated with decreased mortality with interaction by race. These insights into sex-and race-based differences in predictors of mortality may help strategize targeted management of HFpEF

G-computation for policy-relevant effects of interventions on time-to-event outcomes

Background: Parametric g-computation is an analytic technique that can be used to estimate the effects of exposures, treatments and interventions; it relies on a different set of assumptions than more commonly used inverse probability weighted estimators. Whereas prior work has demonstrated implementations for binary exposures and continuous outcomes, use of parametric g-computation has been limited due to difficulty in implementation in more typical complex scenarios. Methods: We provide an easy-to-implement algorithm for parametric g-computation in the setting of a dynamic baseline intervention of a baseline exposure and a time-to-event outcome. To demonstrate the use of our algorithm, we apply it to estimate the effects of interventions to reduce area deprivation on the cumulative incidence of sexually transmitted infections (STIs: Gonorrhea, chlamydia or trichomoniasis) among women living with HIV in the Women's Interagency HIV Study. Results: We found that reducing area deprivation by a maximum of 1 tertile for all women would lead to a 2.7% [95% confidence interval (CI): 0.1%, 4.3%] reduction in 4-year STI incidence, and reducing deprivation by a maximum of 2 tertiles would lead to a 4.3% (95% CI: 1.9%, 6.4%) reduction. Conclusions: As analytic methods such as parametric g-computation become more accessible, epidemiologists will be able to estimate policy-relevant effects of interventions to better inform clinical and public health practice and policy

A global database of lake surface temperatures collected by in situ and satellite methods from 1985–2009

Peer reviewe

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.Puya Gharahkhani … Robert Casson … et al. [and The NEIGHBORHOOD consortium]

Rapid and highly variable warming of lake surface waters around the globe

In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade−1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors—from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade−1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade−1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes.Peer reviewe

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.Peer reviewe