Mild Neurocognitive Disorder, Social Engagement, and Falls Among Older Primary Care Patients.

OBJECTIVES: (1) To estimate the association between social engagement (SE) and falls; (2) To examine the relation between mild neurocognitive disorder (MNCD) and falls by different levels of SE. DESIGN: We performed a secondary data analysis using prospective cohort study design. SETTING: Primary care. PARTICIPANTS: A total of 425 older adult primary care patients at risk for mobility decline (N=425). As previously reported, at baseline, 42% of participants exhibit MNCD. MAIN OUTCOME MEASURES: The outcome variable was the number of falls during 2 years of follow-up. Exposure variables at baseline included (1) MNCD identified using a cut-off of 1.5 SD below the age-adjusted mean on at least 2 measures within a cognitive performance battery and (2) SE, which was assessed using the social component of the Late-Life Function and Disability Instrument. High SE was defined as having a score ≥ median value (≥49 out of 100). All models were adjusted for age, sex, education, marital status, comorbidities, and pain status. RESULTS: Over 2 years of follow-up, 48% of participants fell at least once. MNCD was associated with a higher rate of falls, adjusting for the covariates (Incidence Rate Ratio=1.6, 95% confidence interval: 1.1-2.3). There was no significant association between MNCD and the rate of falls among people with high SE. In participants with low SE (having a score less than 49.5 out 100), MNCD was associated with a higher rate of falls as compared with participants with no neurocognitive disorder (No-NCD). CONCLUSIONS: Among participants with low SE, MNCD was associated with a higher rate of falls, but not among participants with high SE. The findings suggest that high SE may be protective against falls among older primary care patients with MNCD.

Scalable relevance ranking algorithm via semantic similarity assessment improves efficiency of medical chart review.

OBJECTIVE: Accurately assigning phenotype information to individual patients via computational phenotyping using Electronic Health Records (EHRs) has been seen as the first step towards enabling EHRs for precision medicine research. Chart review labels annotated by clinical experts, also known as "gold standard" labels, are essential for the development and validation of computational phenotyping algorithms. However, given the complexity of EHR systems, the process of chart review is both labor intensive and time consuming. We propose a fully automated algorithm, referred to as pGUESS, to rank EHR notes according to their relevance to a given phenotype. By identifying the most relevant notes, pGUESS can greatly improve the efficiency and accuracy of chart reviews. METHOD: pGUESS uses prior guided semantic similarity to measure the informativeness of a clinical note to a given phenotype. We first select candidate clinical concepts from a pool of comprehensive medical concepts using public knowledge sources and then derive the semantic embedding vector (SEV) for a reference article (SEVref) and each note (SEVnote). The algorithm scores the relevance of a note as the cosine similarity between SEVnote and SEVref. RESULTS: The algorithm was validated against four sets of 200 notes that were manually annotated by clinical experts to assess their informativeness to one of three disease phenotypes. pGUESS algorithm substantially outperforms existing unsupervised approaches for classifying the relevance status with respect to both accuracy and scalability across phenotypes. Averaging over the three phenotypes, the rank correlation between the algorithm ranking and gold standard label was 0.64 for pGUESS, but only 0.47 and 0.35 for the next two best performing algorithms. pGUESS is also much more computationally scalable compared to existing algorithms. CONCLUSION: pGUESS algorithm can substantially reduce the burden of chart review and holds potential in improving the efficiency and accuracy of human annotation.

Body Mass Index, Diabetes and Intrahepatic Cholangiocarcinoma Risk: The Liver Cancer Pooling Project and Meta-analysis.

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Long-term multivitamin supplementation and cognitive function in men: a randomized trial.

BACKGROUND: Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons. OBJECTIVE: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life. DESIGN: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II. PATIENTS: 5947 male physicians aged 65 years or older. INTERVENTION: Daily multivitamin or placebo. MEASUREMENTS: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease. RESULTS: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU]). LIMITATION: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin. CONCLUSION: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits. PRIMARY FUNDING SOURCE: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.

The genetics of functional disability in schizophrenia and bipolar illness: Methods and initial results for VA cooperative study #572.

Given the prominence of cognitive impairments and disability associated with schizophrenia and bipolar disorder, substantial interest has arisen in identifying determinants of the diseases and their features. Genetic variation has been linked to skills that underlie disability ("functional capacity" or FC), highlighting need for understanding of these relationships. We describe the design and methods of a large, multisite, observational study focusing on the genetics of functional disability in schizophrenia and bipolar disorder, presenting initial data on recruitment, and characterization of the sample. Known as Veterans Affairs (VA) Cooperative Studies Program (CSP)#572, this study is recruiting, diagnosing, and assessing U.S. Veterans with either schizophrenia or bipolar I disorder. Assessments include neuropsychological (NP) testing, FC, suicidality, and co-morbid conditions such as posttraumatic stress disorder (PTSD). A sample of "psychiatrically healthy" Veterans from another project serves as a comparison group. An interim total of 8,140 participants (42.1% schizophrenia) have been recruited and assessed as of September 30, 2013, with 9 months of enrollment remaining and with a target sample size of 9,500. Veterans with schizophrenia were more likely to never have married, whereas lifetime PTSD and suicidality were more common in the bipolar veterans. Performance on the FC measures and NP tests was consistent with previous results, with mean t-scores of 35 (-1.5 SD) for schizophrenia and 41 (-0.9 SD) for the bipolar Veterans. This large population is representative of previous studies in terms of patient performance and co-morbidities. Subsequent genomic analyses will examine the genomic correlates of performance-based measures. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Comparison of methods for building polygenic scores for diverse populations.

Polygenic scores (PGSs) are a promising tool for estimating individual-level genetic risk of disease based on the results of genome-wide association studies (GWASs). However, their promise has yet to be fully realized because most currently available PGSs were built with genetic data from predominantly European-ancestry populations, and PGS performance declines when scores are applied to target populations different from the populations from which they were derived. Thus, there is a great need to improve PGS performance in currently under-studied populations. In this work we leverage data from two large and diverse cohorts the Million Veterans Program (MVP) and All of Us (AoU), providing us the unique opportunity to compare methods for building PGSs for multi-ancestry populations across multiple traits. We build PGSs for five continuous traits and five binary traits using both multi-ancestry and single-ancestry approaches with popular Bayesian PGS methods and both MVP META GWAS results and population-specific GWAS results from the respective African, European, and Hispanic MVP populations. We evaluate these scores in three AoU populations genetically similar to the respective African, Admixed American, and European 1000 Genomes Project superpopulations. Using correlation-based tests, we make formal comparisons of the PGS performance across the multiple AoU populations. We conclude that approaches that combine GWAS data from multiple populations produce PGSs that perform better than approaches that utilize smaller single-population GWAS results matched to the target population, and specifically that multi-ancestry scores built with PRS-CSx outperform the other approaches in the three AoU populations.

Distal Pancreatic Necrosis After Splenic Angioembolization.

Pancreatic ischemia with necrosis is an extremely rare complication of splenic angioembolization (SAE). A 48-year-old male with a grade IV blunt splenic injury underwent angiography which demonstrated no active bleeding or pseudoaneurysm. Proximal SAE was performed. One week later, he developed severe sepsis. Repeat CT imaging showed nonperfusion of the distal pancreas, and laparotomy found necrosis of approximately 40% of the pancreas. Distal pancreatectomy and splenectomy were performed. He endured a prolonged hospital course with multiple complications. Clinicians should have a high index of suspicion for ischemic complications after SAE when sepsis develops.

Data resource profile: nutrition data in the VA million veteran program.

Introduction: The Department of Veterans Affairs (VA) Million Veteran Program (MVP) nutrition data is derived from dietary food/beverage intake information collected through a semiquantitative food frequency questionnaire (SFFQ). Methods: Estimates of dietary energy, nutrient, and non-nutritive food components intakes data were derived from an extensively validated SFFQ, which assessed the habitual frequency of consumption of 61 food items, added sugar, fried food frequency, and 21 nutritional supplements over the 12 months preceding questionnaire administration. Results: Complete nutrition data was available for 353,418 MVP participants as of 30th September 2021. Overall, 91.5% of MVP participants with nutrition data were male with an average age of 65.7 years at enrollment. Participants who completed the SFFQ were primarily White (82.5%), and Blacks accounted for 13.2% of the responders. Mean ± SD energy intake for 353, 418 MVP participants was 1428 ± 616 kcal/day, which was 1434 ± 617 kcal/day for males and 1364 ± 601 kcal/day for females. Energy intake and information on 322 nutrients and non-nutritive food components is available through contact with MVP for research collaborations at www.research.va.gov/mvp. Conclusions: The energy and nutrient data derived from MVP SFFQ are an invaluable resource for Veteran health and research. In conjunction with the MVP Lifestyle Survey, electronic health records, and genomic data, MVP nutrition data may be used to assess nutritional status and related risk factors, disease prevalence, and determinants of health that can provide scientific support for the development of evidence-based public health policy and health promotion programs and services for Veterans and general population.

Negative Splenic Angiography in Blunt Trauma: Does Embolization Affect Splenic Salvage?

Angioembolization in blunt splenic trauma is used to maximize splenic preservation. Superiority of prophylactic embolization over expectant management in patients with a negative splenic angiography (SA) is debated. We hypothesized that embolization in negative SA would be associated with splenic salvage. Of 83 patients undergoing SA, 30 (36%) had a negative SA. Embolization was performed in 23 (77%). Grade of injury, contrast extravasation (CE) on computed tomography (CT) or embolization were not associated with splenectomy. In 20 patients with either a high-grade injury or CE on CT, 17 (85%) underwent embolization with a failure rate of 24%. In the remaining 10 without high-risk features, 6 underwent embolization with a 0% splenectomy rate. Despite embolization, the failure rate of nonoperative management (NOM) remains significant in those with high-grade injury or CE on CT. A low threshold for early splenectomy after prophylactic embolization is needed.

Social Characteristics, Health, and Mortality Among Male Centenarians Using Veterans Affairs (VA) Health Care.

We studied male centenarian Veterans using VA health care to understand the impact of social characteristics on their annual mortality rate, adjusting for prevalent health conditions. This longitudinal study used VA Electronic Health Record data from 1997 to 2012 (n = 1,858). Covariates included age, race, marital status, and periods of military service. The mean age was 100.4 ± 1.4 years, 76% were white, and 49% were married. The average annual mortality rate was 32 per 100 person-years. The annual mortality rate was stable and not affected by race but did vary by marital status. Divorced or separated centenarians had a 21% higher rate of death than married centenarians. A diagnosis of dementia or of congestive heart failure each increased the mortality risk by 37%. Providers should consider prevalent health conditions, as well as marital status, in managing care of centenarian Veterans.

Premature Discontinuation of Dual Antiplatelet Therapy After Coronary Stenting in Veterans: Characteristics and Long-Term Outcomes.

Background Premature discontinuation of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention is related to higher short-term risks of adverse outcomes. Whether these risks persist in the long-term is uncertain. Methods and Results We assessed all patients having percutaneous coronary intervention with coronary second- or first-generation drug-eluting stents in the Veterans Affairs healthcare system between 2006 and 2012 who were free of major ischemic or bleeding events in the first 12 months. The characteristics of patients who stopped DAPT prematurely (1-9 months duration), compared with >9 to 12 months, or extended duration (>12 months) were assessed by odds ratios (ORs) from multivariable logistic models. The risk of adverse clinical outcomes over a mean 5.1 years in patients who stopped DAPT prematurely was assessed by hazard ratios (HRs) and 95% CIs from Cox regression models. A total of 14 239 had second-generation drug-eluting stents, and 8583 had first-generation drug-eluting stents. Premature discontinuation of DAPT was more likely in Black patients (OR, 1.54; 95% CI, 1.40-1.68), patients with greater frailty (OR, 1.04; 95% CI, 1.03-1.05), and patients with higher low-density lipoprotein cholesterol, and less likely in patients on statins (OR, 0.87; 95% CI, 0.80-0.95). Patients who stopped DAPT prematurely had higher long-term risks of death (second-generation drug-eluting stents: HR, 1.35; 95% CI, 1.19-1.56), myocardial infarction (second-generation drug-eluting stents: HR, 1.46; 95% CI, 1.22-1.74), and repeated coronary revascularization (second-generation drug-eluting stents: HR, 1.24; 95% CI, 1.08-1.41). Conclusions Patients who stop DAPT prematurely have features that reflect greater frailty, poorer medication use, and other social factors. They continue to have higher risks of major adverse outcomes over the long-term and may require more intensive surveillance many years after percutaneous coronary intervention.

PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.

BACKGROUND: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. METHODS: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. RESULTS: Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04). CONCLUSIONS: Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.

Genomics of posttraumatic stress disorder in veterans: Methods and rationale for Veterans Affairs Cooperative Study #575B.

OBJECTIVES: Heritability in the risk for developing posttraumatic stress disorder (PTSD) has been established, but most genome-wide association studies (GWASs) of PTSD involve relatively small sample sizes and limited identification of associated genetic loci. This report describes the methodology of a Veterans Affairs (VA) Cooperative Studies Program GWAS of PTSD among combat-exposed U.S. veterans. METHODS: Probable cases (with PTSD) and probable controls (without PTSD) were identified from among veterans enrolled in the VA Million Veteran Program (MVP) with an algorithm developed using questionnaire responses and electronic health record information. This algorithm, based on a statistical model, relied on medical chart reviews as a reference standard and was refined using telephone interviews. Subsequently, to evaluate the impact of probabilistic phenotyping on statistical power, the threshold probability for case-control selection was varied in simulations. RESULTS: As of September 2018, >695,000 veterans have enrolled in MVP. For current analyses, genotyping data were available for >353,000 participants, including >83,000 combat-exposed veterans. A threshold probability of 0.7 for case and control designation yielded an interim >16,000 cases and >33,000 controls. CONCLUSIONS: A formal methodological approach was used to identify cases and controls for subsequent GWAS analyses to identify genetic risk loci for PTSD.

Relationship between intra-operative vein graft treatment with DuraGraft® or saline and clinical outcomes after coronary artery bypass grafting.

BACKGROUND: Saphenous vein grafts (SVGs) remain the most often used conduits for coronary bypass grafting (CABG). Progressive intimal hyperplasia contributes to vein-graft disease and vein-graft failure (VGF). We compared the impact of intraoperative preservation of SVGs in a storage solution (DuraGraft®) versus heparinized saline on VGF-related outcomes after CABG. METHODS: From 1996 to 2004, 2436 patients underwent isolated CABG with ≥ 1 SVG. SVGs were consecutively treated with DuraGraft in 1036 patients (2001-2004) and heparinized saline in 1400 patients (1996-1999). Short- (< 30 days) and long-term (≥ 1000 days) outcomes were assessed using repeat revascularization (primary end point), and major adverse cardiac events (MACE) consisting of the composite of death, nonfatal myocardial infarction, or repeat revascularization. RESULTS: Mean follow-up in the DuraGraft group was 8.5 ± 4.2 years and 9.9 ± 5.6 years in controls. Short-term event rates were low and generally did not differ between groups. DuraGraft was associated with a 45% lower occurrence of nonfatal myocardial infarction after 1000 days (hazard ratio 0.55, 95% CI 0.41-0.74; P < 0.0001). There was 35% and 19% lower long-term risk for revascularization (HR 0.65, 95% CI 0.44-0.97; P = 0.037) and MACE (HR 0.81, 95% CI 0.70-0.94; P = 0.0051), respectively, after DuraGraft. Mortality was comparable between both groups at 1, 5, and 10 years. There was no statistically significant association between DuraGraft exposure and time to death starting at 30 or 1000 days (HR 0.91, 95% CI 0.76-1.09; P = 0.29). CONCLUSION: In this study, intraoperative treatment of SVGs with DuraGraft was associated with a lower risk of long-term adverse events suggesting that efficient intraoperative SVG treatment may reduce VGF-related complications post-CABG. These data warrant randomized clinical trials to validate these findings.

A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts.

The Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (ß = 0.45, p = 3.48x10-22), and using a significance level of p = 0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR = 2.17, 95% CI: 1.79-2.63, p = 2.70x10-15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

A prospective study of the APOA1 XmnI and APOC3 SstI polymorphisms in the APOA1/C3/A4 gene cluster and risk of incident myocardial infarction in men.

BACKGROUND: Apolipoproteins AI/CIII/AIV play important roles in the metabolism of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol. However, whether genetic variations in the APOA1/C3/A4 gene cluster are associated with the risk of myocardial infarction (MI) remains uncertain and prospective data are sparse. METHODS: In a prospective nested case-control study of 385 incident cases of MI and 373 age- and smoking-matched controls from the Physicians' Health Study, we examined the relationship between 2 common single nucleotide polymorphisms (APOA1 XmnI and APOC3 SstI) in the APOA1/C3/A4 gene cluster and haplotypes defined by these SNPs and risk of incident MI. RESULTS: No significant differences in allele or genotype frequency for the APOA1 XmnI and APOC3 SstI polymorphisms were detected between cases and controls. After adjusting for non-lipid coronary risk factors, the relative risks for incident MI were 1.00 (95% CI 0.68-1.47) for men carrying the X2 allele compared with those homozygous for the X1 allele in the APOA1 XmnI site and 1.07 (95% CI 0.69-1.64) for men carrying the S2 versus those homozygous for the S1 allele in the APOC3 SstI site. Moreover, we did not observe any effect modification by HDL or TG levels for the associations of these APOA1 and APOC3 genotypes with MI risk. There were significant differences in TG levels among men carrying different haplotypes (P=0.01) and men carrying the X1-S2 haplotype had higher levels of TG than those carrying the X2-S1 haplotype (202 mg/dl versus 157 mg/dl, P=0.03); however, haplotype frequencies defined by these two polymorphisms did not differ significantly between cases and controls. CONCLUSION: In this prospective study of apparently healthy middle-aged US men, carriers of the X1-S2 haplotype in the APOA1 XmnI and APOC3 SstI variants across the APOA1/C3/A4 gene cluster had higher TG levels, but there was no evidence for significant associations between these two common variants or haplotypes defined by them and risk of incident MI in this cohort.

Prolonged clopidogrel use after bare metal and drug-eluting stent placement: the Veterans Administration drug-eluting stent study.

BACKGROUND: Current guidelines recommend combining clopidogrel with aspirin for up to 1 year after coronary stenting, but the value of clopidogrel beyond this time is uncertain. METHODS AND RESULTS: We evaluated all patients in the Veterans Administration healthcare system receiving either drug-eluting or bare metal stents from 2002 to 2006. The Veterans Administration National Patient Care and Pharmacy databases were used to extract patient characteristics, duration of clopidogrel use, and outcomes for up to 4 years after the index procedure. We used Cox proportional hazards to estimate hazard ratios for death, myocardial infarction, revascularization, and bleeding from a 12-month landmark after stenting that excluded patients with events within the first 12 months. Of 42,254 patients, 29,175 met the study inclusion criteria. Compared with ≤12 months of clopidogrel, prolonged clopidogrel (>12 months) was associated with a lower adjusted risk of death for both drug-eluting stents (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.61, 0.82; P<0.01) and bare metal stents (HR, 0.85; 95% CI, 0.76, 0.96; P=0.01) as well as for death and myocardial infarction but was unrelated to stroke or major bleeding. The effect of prolonged clopidogrel on death or myocardial infarction was significantly greater among patients receiving drug-eluting (HR, 0.70; 95% CI, 0.64, 0.84) compared with bare metal stents (HR, 0.88; 95% CI, 0.79, 0.98; interaction P=0.024). CONCLUSIONS: Patients receiving clopidogrel beyond 12 months had a lower risk of death or myocardial infarction compared patients receiving clopidogrel ≤12 months. The risk reduction was greater for drug-eluting stents. These data support longer durations of dual antiplatelet therapy for patients receiving a stent, particularly for those receiving a drug-eluting stent.

Uric acid and the development of hypertension: the normative aging study.

Experimental evidence supports a causative role for uric acid in the pathogenesis of hypertension. Prospective studies have variably adjusted for relevant confounders and have been of relatively limited duration. We prospectively examined the relationship between uric acid level and the development of hypertension in the Normative Aging Study, a longitudinal cohort of healthy adult men. Of the 2280 initial men in the Normative Aging Study, 2062 had available information for inclusion in the analysis. Cox proportional hazards model was used to examine the relationship between baseline serum uric acid level and the development of hypertension adjusting for age, body mass index, abdominal circumference, smoking, alcohol, plasma triglycerides, total cholesterol, and plasma glucose. A total of 892 men developed hypertension over a mean of 21.5 years of follow-up. Serum uric acid level independently predicted the development of hypertension in age-adjusted (relative risk [RR]: 1.10; 95% CI: 1.06 to 1.15: P<0.001) and multivariable (RR: 1.05; 95% CI: 1.01 to 1.10; P=0.02) models. Among 1277 men at risk for the development of hypertension at the time of their first serum creatinine measurement, 508 (39.8%) developed hypertension over a mean of 10.3+/-5.5 years of follow-up. Additionally adjusting for calculated glomerular filtration rate in this subset, serum uric acid remained associated with the development of hypertension (RR: 1.06; 95% CI: 1.01 to 1.12; P=0.03). The baseline serum uric acid level is a durable marker of risk for the development of hypertension. The association is independent of elements of the metabolic syndrome, alcohol intake, and renal function.