A Pilot Study Identifying Statin Nonadherence With Visit-to-Visit Variability of Low-Density Lipoprotein Cholesterol

Nonadherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication nonadherence. The visit-to-visit variability (VVV) of low-density lipoprotein (LDL) cholesterol might represent an opportunity to identify statin nonadherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center Health Plan, seen at either the Boston Medical Center or its affiliated community health centers, who were taking statins and had ≥3 LDL cholesterol measurements from 2008 to 2011. The LDL cholesterol VVV (defined by the within-patient SD) was categorized into quintiles. Multivariate logistic regression models were generated with statin nonadherence (defined by the standard 80% pharmacy refill-based medication possession ratio threshold) as the dependent variable. The proportion of statin nonadherence increased across the quintiles of LDL cholesterol VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL cholesterol VVV had a strong positive association with statin nonadherence, with an adjusted odds ratio of 3.4 (95% confidence interval 1.7 to 7.1) in the highest versus lowest quintile of LDL cholesterol VVV. The age- and gender-adjusted model had poor discrimination (C-statistic 0.62, 95% confidence interval 0.57 to 0.67), but the final adjusted model (age, gender, race, mean LDL cholesterol) demonstrated good discrimination (C-statistic 0.75, 95% confidence interval 0.71 to 0.79) between the adherent and nonadherent patients. In conclusion, the VVV of LDL cholesterol demonstrated a strong association with statin nonadherence in a clinic setting. Furthermore, a VVV of LDL cholesterol-based model had good discrimination characteristics for statin nonadherence. Research is needed to validate and generalize these findings to other populations and biomarkers

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Representation of precipitation and top-of-atmosphere radiation in a multi-model convection-permitting ensemble for the Lake Victoria Basin (East-Africa)

The CORDEX Flagship Pilot Study ELVIC (climate Extremes in the Lake VICtoria basin) was recently established to investigate how extreme weather events will evolve in this region of the world and to provide improved information for the climate impact community. Here we assess the added value of the convection-permitting scale simulations on the representation of moist convective systems over and around Lake Victoria. With this aim, 10 year present-day model simulations were carried out with five regional climate models at both PARameterized (PAR) scales (12–25 km) and Convection-Permitting (CP) scales (2.5–4.5 km), with COSMO-CLM, RegCM, AROME, WRF and UKMO. Most substantial systematic improvements were found in metrics related to deep convection. For example, the timing of the daily maximum in precipitation is systematically delayed in CP compared to PAR models, thereby improving the agreement with observations. The large overestimation in the total number of rainy events is alleviated in the CP models. Systematic improvements were found in the diurnal cycle in Top-Of-Atmosphere (TOA) radiation and in some metrics for precipitation intensity. No unanimous improvement nor deterioration was found in the representation of the spatial distribution of total rainfall and the seasonal cycle when going to the CP scale. Furthermore, some substantial biases in TOA upward radiative fluxes remain. Generally our analysis indicates that the representation of the convective systems is strongly improved in CP compared to PAR models, giving confidence that the models are valuable tools for studying how extreme precipitation events may evolve in the future in the Lake Victoria basin and its surroundings

Myocardial infarction and stroke associated with diuretic based two drug antihypertensive regimens: population based case-control study

Objective To examine the association of myocardial infarction and stroke incidence with several commonly used two drug antihypertensive treatment regimens

"'Asianness Under Construction:' The Contours and Negotiation of Panethnic Identity/Culture among Interethnically Married Asian Americans."

Based on life-history interviews of interethnically married U.S.-raised Asians, this article examines the meaning and dynamics of Asian American interethnic marriages, and what they reveal about the complex incorporative process of this “in-between” racial minority group into the U.S.. In particular, this article explores the connection between Asian American interethnic marriage and pan-Asian consciousness/identity, both in terms of how panethnicity shapes romantic/ marital desires of individuals and how pan-Asian culture and identity is invented and negotiated in the process of family-making. My findings indicate that while strong pan-Asian consciousness/ identity underlies the connection among intermarried couples, these unions are not simply a defensive effort to “preserve” Asian-ethnic identity and cultur against a society that still racializes Asian Americans, but a tentative and often unpremeditated effort to navigate a path toward integration into the society through an ethnically based, albeit hybrid and reconstructed identity and culture, that helps the respondents retain the integrity of “Asianness.

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using $\sim$2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant $(p<5 \times 10^{-8})$ or suggestive associations $(p<4 \times 10^{-7})$ were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding $(p<4 \times 10^{-7})$. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels

Multi-Ethnic Analysis of Lipid-Associated Loci: The NHLBI CARe Project

Background: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. Methodology/Principal Findings: We tested a set of $\sim$50,000 polymorphisms from $\sim$2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. Conclusions/Significance: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans

Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

10.1371/journal.pone.0054232PLoS ONE82

The association between lithium use and neurocognitive performance in patients with bipolar disorder

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1–5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.acceptedVersio

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined