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1.  Sequence Analysis of In Vivo Defective Interfering-Like RNA of Influenza A H1N1 Pandemic Virus 
Journal of Virology  2013;87(14):8064-8074.
Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.
doi:10.1128/JVI.00240-13
PMCID: PMC3700204  PMID: 23678180
2.  Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer 
Background
Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.
Methods
We combined data from two case–cohort studies based in the Women’s Health Initiative- Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.
Results
A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2–76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9–68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6–273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8–161.1) for BMI when restricted to estrogen receptor positive (ER+) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8–284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER+ breast cancers.
Conclusions
The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.
Impact
The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
doi:10.1158/1055-9965.EPI-12-0310
PMCID: PMC3858186  PMID: 22564867
3.  Preference for wine is associated with lower hip fracture incidence in post-menopausal women 
BMC Women's Health  2013;13:36.
Background
Past studies of relationships between alcohol and hip fracture have generally focused on total alcohol consumed and not type of alcohol. Different types of alcohol consist of varying components which may affect risk of hip fracture differentially. This study seeks to examine the relationship between alcohol consumption, with a focus on type of alcohol consumed (e.g. beer, wine, or hard liquor) and hip fracture risk in post-menopausal women.
Methods
The longitudinal cohort consisted of U.S. post-menopausal women aged 50–79 years enrolled between 1993–1998 in the Women’s Health Initiative Clinical Trials and Observational Study (N=115,655).
Results
Women were categorized as non-drinkers, past drinkers, infrequent drinkers and drinkers by preference of alcohol type (i.e. those who preferred wine, beer, hard liquor, or who had no strong preference). Mean alcohol consumption among current drinkers was 3.3 servings per week; this was similar among those who preferred wine, beer and liquor. After adjustment for potential confounders, alcohol preference was strongly correlated with hip fracture risk (p = 0.0167); in particular, women who preferred wine were at lower risk than non-drinkers (OR=0.78; 95% CI 0.64-0.95), past drinkers (OR=0.85; 95% CI 0.72-1.00), infrequent drinkers (OR=0.73; 95% CI 0.61-0.88), hard liquor drinkers (OR=0.87; 95% CI 0.71-1.06), beer drinkers (OR=0.72; 95% CI 0.55-0.95) and those with no strong preference (OR=0.89; 95% CI 0.89; 95% CI 0.73-1.10).
Conclusions
Preference of alcohol type was associated with hip fracture; women who preferentially consumed wine had a lower risk of hip fracture compared to non-drinkers, past drinkers, and those with other alcohol preferences.
doi:10.1186/1472-6874-13-36
PMCID: PMC3848688  PMID: 24053784
Alcohol; Wine; Hip fracture; Osteoporosis; Women’s Health Initiative
4.  Human immunodeficiency virus, hepatitis C, and inflammatory biomarkers in individuals with alcohol problems: a cross-sectional study 
BMC Infectious Diseases  2013;13:399.
Background
Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers.
Methods
We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use.
Results
Detectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05–5.89) and detectable HCV RNA alone (2.95; 1.08–8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90–31.97) and TNF-α (7.70; 1.42–41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84).
Conclusions
Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.
doi:10.1186/1471-2334-13-399
PMCID: PMC3848623  PMID: 23987993
HIV; HCV; Inflammation; Alcohol; Liver; Comorbidity
5.  HIV Status, Burden of Comorbid Disease, and Biomarkers of Inflammation, Altered Coagulation, and Monocyte Activation 
We investigated the association between human immunodeficiency virus (HIV) and prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation in a cohort of HIV-infected and uninfected veterans who had a comparable burden of comorbid conditions.
Background. Biomarkers of inflammation, altered coagulation, and monocyte activation are associated with mortality and cardiovascular disease (CVD) in the general population and among human immunodeficiency virus (HIV)–infected people. We compared biomarkers for inflammation, altered coagulation, and monocyte activation between HIV-infected and uninfected people in the Veterans Aging Cohort Study (VACS).
Methods. Biomarkers of inflammation (interleukin-6 [IL-6]), altered coagulation (d-dimer), and monocyte activation (soluble CD14 [sCD14]) were measured in blood samples from 1525 HIV-infected and 843 uninfected VACS participants. Logistic regression was used to determine the association between HIV infection and prevalence of elevated (>75th percentile) biomarkers, adjusting for confounding comorbidities.
Results. HIV-infected veterans had less prevalent CVD, hypertension, diabetes, obesity, hazardous drinking, and renal disease, but more dyslipidemia, hepatitis C, and current smoking than uninfected veterans. Compared to uninfected veterans, HIV-infected veterans with HIV-1 RNA ≥500 copies/mL or CD4 count <200 cells/µL had a significantly higher prevalence of elevated IL-6 (odds ratio [OR], 1.54; 95% confidence interval [CI],1.14–2.09; OR, 2.25; 95% CI, 1.60–3.16, respectively) and d-dimer (OR, 1.97; 95% CI, 1.44–2.71, OR, 1.68; 95% CI, 1.22–2.32, respectively) after adjusting for comorbidities. HIV-infected veterans with a CD4 cell count <200 cells/µL had significantly higher prevalence of elevated sCD14 compared to uninfected veterans (OR, 2.60; 95% CI, 1.64–4.14). These associations still persisted after restricting the analysis to veterans without known confounding comorbid conditions.
Conclusions. These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.
doi:10.1093/cid/cis406
PMCID: PMC3493182  PMID: 22534147
6.  Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease 
Archives of internal medicine  2011;171(8):737-743.
Background
Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association.
Methods
To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007.
Results
There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity–adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI],6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk ofHF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P< .001 for comparison between high and low HIV-1 RNA groups).
Conclusions
Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
doi:10.1001/archinternmed.2011.151
PMCID: PMC3687533  PMID: 21518940
7.  Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV? 
The Veterans Aging Cohort Study (VACS) Index, based on age and 8 routine clinical tests, is strongly correlated with 3 biomarkers of inflammation: interleukin 6 (IL-6), D-dimer, and soluble CD14 (sCD14). After adjustment for the VACS Index, D-dimer and sCD14, but not IL-6, remain independently associated with mortality.
Background. When added to age, CD4 count and human immunodeficiency virus type 1 (HIV-1) RNA alone (Restricted Index), hemoglobin, FIB-4 Index, hepatitis C virus (HCV), and estimated glomerular filtration rate improve prediction of mortality. Weighted and combined, these 7 routine clinical variables constitute the Veterans Aging Cohort Study (VACS) Index. Because nonroutine biomarkers of inflammation (interleukin 6 [IL-6]), coagulation (D-dimer), and monocyte activation (sCD14) also predict mortality, we test the association of these indices and biomarkers with each other and with mortality.
Methods. Samples from 1302 HIV-infected veterans on antiretroviral therapy were analyzed. Indices were calculated closest to date of collection. We calculated Spearman correlations stratified by HIV-1 RNA and HCV status and measured association with mortality using C statistics and net reclassification improvement (NRI).
Results. Of 1302 subjects, 915 had HIV-1 RNA <500 copies/mL and 154 died. The VACS Index was more correlated with IL-6, D-dimer, and sCD14 than the Restricted Index (P < .001). It was also more predictive of mortality (C statistic, 0.76; 95% confidence interval [CI], .72–.80) than any biomarker (C statistic, 0.66–0.70) or the Restricted Index (C statistic, 0.71; 95% CI, .67–.75). Compared to the Restricted Index alone, NRI resulted from incremental addition of VACS Index components (10%), D-dimer (7%), and sCD14 (4%), but not from IL-6 (0%).
Conclusions. Among HIV-infected individuals, independent of CD4, HIV-1 RNA, and age, hemoglobin and markers of liver and renal injury are associated with inflammation. Addition of D-dimer and sCD14, but not IL-6, improves the predictive accuracy of the VACS Index for mortality.
doi:10.1093/cid/cir989
PMCID: PMC3297653  PMID: 22337823
8.  Validating Smoking Data From the Veteran’s Affairs Health Factors Dataset, an Electronic Data Source 
Nicotine & Tobacco Research  2011;13(12):1233-1239.
Introduction:
We assessed smoking data from the Veterans Health Administration (VHA) electronic medical record (EMR) Health Factors dataset.
Methods:
To assess the validity of the EMR Health Factors smoking data, we first created an algorithm to convert text entries into a 3-category smoking variable (never, former, and current). We compared this EMR smoking variable to 2 different sources of patient self-reported smoking survey data: (a) 6,816 HIV-infected and -uninfected participants in the 8-site Veterans Aging Cohort Study (VACS-8) and (b) a subset of 13,689 participants from the national VACS Virtual Cohort (VACS-VC), who also completed the 1999 Large Health Study (LHS) survey. Sensitivity, specificity, and kappa statistics were used to evaluate agreement of EMR Health Factors smoking data with self-report smoking data.
Results:
For the EMR Health Factors and VACS-8 comparison of current, former, and never smoking categories, the kappa statistic was .66. For EMR Health Factors and VACS-VC/LHS comparison of smoking, the kappa statistic was .61.
Conclusions:
Based on kappa statistics, agreement between the EMR Health Factors and survey sources is substantial. Identification of current smokers nationally within the VHA can be used in future studies to track smoking status over time, to evaluate smoking interventions, and to adjust for smoking status in research. Our methodology may provide insights for other organizations seeking to use EMR data for accurate determination of smoking status.
doi:10.1093/ntr/ntr206
PMCID: PMC3223583  PMID: 21911825
9.  The Risk of Incident Coronary Heart Disease Among Veterans with and without HIV and Hepatitis C 
Background
Whether hepatitis C (HCV) confers additional coronary heart disease (CHD) risk among Human Immunodeficiency Virus (HIV) infected individuals is unclear. Without appropriate adjustment for antiretroviral therapy, CD4 count, and HIV-1 RNA, and substantially different mortality rates among those with and without HIV and HCV infection, the association between HIV, HCV, and CHD may be obscured.
Methods and Results
We analyzed data on 8579 participants (28% HIV+, 9% HIV+HCV+) from the Veterans Aging Cohort Study Virtual Cohort who participated in the 1999 Large Health Study of Veteran Enrollees. We analyzed data collected on HIV and HCV status, risk factors for and the incidence of CHD, and mortality from 1/2000–7/2007. We compared models to assess CHD risk when death was treated as a censoring event and as a competing risk. During the median 7.3 years of follow-up, there were 194 CHD events and 1186 deaths. Compared with HIV−HCV− Veterans, HIV+ HCV+ Veterans had a significantly higher risk of CHD regardless of whether death was adjusted for as a censoring event (adjusted hazard ratio (HR)=2.03, 95% CI=1.28–3.21) or a competing risk (adjusted HR=2.45, 95% CI=1.83–3.27 respectively). Compared with HIV+HCV− Veterans, HIV+ HCV+ Veterans also had a significantly higher adjusted risk of CHD regardless of whether death was treated as a censored event (adjusted HR=1.93, 95% CI=1.02–3.62) or a competing risk (adjusted HR =1.46, 95% CI=1.03–2.07).
Conclusions
HIV+HCV+ Veterans have an increased risk of CHD compared to HIV+HCV−, and HIV−HCV− Veterans.
doi:10.1161/CIRCOUTCOMES.110.957415
PMCID: PMC3159506  PMID: 21712519
viruses; coronary disease; mortality; multi morbidity
10.  HIV Replication, Inflammation, and the Effect of Starting Antiretroviral Therapy on Plasma Asymmetric Dimethylarginine, a Novel Marker of Endothelial Dysfunction 
Background
HIV infection is associated with premature development of cardiovascular disease (CVD). Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce CVD risk.
Methods
A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy (SMART) study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40L and P-selectin levels.
Results
At study entry, median (IQR) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n=114), participants randomized to immediate ART (n=134) had 10.3% lower ADMA levels (p=0.003) at 12 months; treatment differences in sCD40L (95% CI:-17 to 44%; p=0.53) and P-selectin (95% CI:-10 to 10%; p=0.95) were not significant. The difference in ADMA for those assigned immediate ART compared to those assigned ART deferral was greater among younger patients and those with higher levels of hsCRP and D-dimer (p≤0.05 for interaction for both), but not HIV RNA level at baseline (p=0.51).
Discussion
ART initiation leads to declines in ADMA levels, a marker of nitric-oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that up-regulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
doi:10.1097/QAI.0b013e318252f99f
PMCID: PMC3360839  PMID: 22421746
HIV infection; antiretroviral therapy; inflammation; endothelial dysfunction; asymmetric dimethylarginine (ADMA); CD40 ligand; P-selectin
11.  Alcohol Consumption and Risk of Postmenopausal Breast Cancer by Subtype: The Women's Health Initiative Observational Study 
Background
Alcohol consumption is a well-established risk factor for breast cancer. This association is thought to be largely hormonally driven, so alcohol use may be more strongly associated with hormonally sensitive breast cancers. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype.
Methods
We assessed the relationship between self-reported alcohol consumption and postmenopausal breast cancer risk among 87 724 women in the Women's Health Initiative Observational Study prospective cohort from 1993 through 1998. Multivariable adjusted Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results
A total of 2944 invasive breast cancer patients were diagnosed during follow-up through September 15, 2005. In multivariable adjusted analyses, alcohol consumption was positively related to risk of invasive breast cancer overall, invasive lobular carcinoma, and hormone receptor–positive tumors (all Ptrend ≤ .022). However, alcohol consumption was more strongly related to risk of certain types of invasive breast cancer compared with others. Compared with never drinkers, women who consumed seven or more alcoholic beverages per week had an almost twofold increased risk of hormone receptor–positive invasive lobular carcinoma (HR = 1.82; 95% CI = 1.18 to 2.81) but not a statistically significant increased risk of hormone receptor–positive invasive ductal carcinoma (HR = 1.14; 95% CI = 0.87 to 1.50; difference in HRs per drink per day among current drinkers = 1.15; 95% CI = 1.01 to 1.32, P = .042). The absolute rates of hormone receptor–positive lobular cancer among never drinkers and current drinkers were, 5.2 and 8.5 per 10 000 person-years, respectively, whereas for hormne receptor–positive ductal cancer they were 15.2 and 17.9 per 10 000 person-years, respectively.
Conclusions
Alcohol use may be more strongly associated with risk of hormone-sensitive breast cancers than hormone-insensitive subtypes, suggesting distinct etiologic pathways for these two breast cancer subtypes.
doi:10.1093/jnci/djq316
PMCID: PMC2943525  PMID: 20733117
12.  Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan) 
Cancer causes & control : CCC  2010;21(8):1213-1225.
The literature has consistently reported no association between low to moderate alcohol consumption and pancreatic cancer; however, a few studies have shown that high levels of intake may increase risk. Most single studies have limited power to detect associations even in the highest alcohol intake categories or to examine associations by alcohol type. We analyzed these associations using 1,530 pancreatic cancer cases and 1,530 controls from the Pancreatic Cancer Cohort Consortium (PanScan) nested case–control study. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression, adjusting for potential confounders. We observed no significant overall association between total alcohol (ethanol) intake and pancreatic cancer risk (OR = 1.38, 95% CI = 0.86–2.23, for 60 or more g/day vs. >0 to <5 g/day). A statistically significant increase in risk was observed among men consuming 45 or more grams of alcohol from liquor per day (OR = 2.23, 95% CI = 1.02–4.87, compared to 0 g/day of alcohol from liquor, P-trend = 0.12), but not among women (OR = 1.35, 95% CI = 0.63–2.87, for 30 or more g/day of alcohol from liquor, compared to none). No associations were noted for wine or beer intake. Overall, no significant increase in risk was observed, but a small effect among heavy drinkers cannot be ruled out.
doi:10.1007/s10552-010-9548-z
PMCID: PMC3098295  PMID: 20373013
Alcohol; Pancreatic cancer; Pooled analysis
13.  ALCOHOL CONSUMPTION, HYPERTENSION, AND TOTAL MORTALITY AMONG WOMEN 
American journal of hypertension  2009;22(11):1212-1218.
Background
Moderate alcohol consumption is associated with a reduced risk of total mortality among Caucasian women. Whether moderate alcohol consumption is associated with a reduced risk of total mortality among African American or hypertensive women is unclear.
Methods
We conducted a prospective study among 10,576 black and 105,610 white post-menopausal women from the Women’s Health Initiative, without a history of cancer or cardiovascular disease, who completed the baseline examinations in 1994–1998.
Results
During the mean 8 years of follow-up, 5608 women died. Moderate drinking (1–<7 drinks/week) was associated with a lower risk of total mortality among Caucasians (hazard ratio (HR) =0.81, 95% CI=0.72–0.91) and hypertensives (HR=0.76, 95% CI=0.65–0.87) as compared with lifetime abstention from alcohol. Among African American moderate drinkers the risk of total mortality was HR=0.94, 95% CI=0.67–1.3. Current drinking (<1 drink/month or greater) was associated with a lower risk of mortality among Caucasians, including hypertensives and non-hypertensives, and hypertensive African Americans (HR=0.74, 95% CI=0.54–0.99) but not among non-hypertensive African Americans (HR=1.31, 95% CI=0.79–2.16). The stratified comparisons among African Americans were affected by the low prevalence of moderate drinking (14.6%) and the low mortality rate (37.5/10,000) among the non-hypertensive lifetime abstainers.
Conclusion
Moderate drinking is associated with a lower risk of total mortality among Caucasian women. Current drinking is associated with a lower risk of total mortality among Caucasians, regardless of hypertensive status, and hypertensive but not non-hypertensive African American women. The latter observation was affected by the low mortality rate among the African American non-hypertensive lifetime abstainers.
doi:10.1038/ajh.2009.172
PMCID: PMC3104852  PMID: 19730413
alcohol; hypertension; mortality; women; race/ethnicity
14.  Evaluation of the AHA Cardiovascular Disease Prevention Guideline for Women 
Background
The 2007 update to the American Heart Association (AHA) Guidelines for Cardiovascular Disease Prevention in Women recommend a simplified approach to risk stratification. We assigned Women's Health Initiative (WHI) participants to risk categories as described in the guideline, and evaluated clinical event rates within and between strata.
Methods and Results
The WHI enrolled 161,808 women aged 50-79 years, and followed them prospectively for 7.8 years (mean). Applying the 2007 AHA guideline categories, 11% of women were high risk, 72% at-risk and 4% optimal risk; 13% of women did not fall into any category, that is, lacked risk factors but did not adhere to a healthy lifestyle (moderate intensity exercise for 30 minute most days and <7% of calories from saturated fat). Among high risk, at-risk and optimal risk women, rates of myocardial infarction (MI)/coronary death were 12.5, 3.1 and 1.1% /10-years (p for trend <0.0001); the event rate was 1.3% among women who could not be categorized. We observed a graded relationship between risk category and cardiovascular event rates for white, black, Hispanic and Asian women, although event rates differed among ethnic groups (p for interaction =0.002). The AHA guideline predicted coronary events with accuracy similar to current Framingham risk categories (Area under receiver operating characteristic curve [AUC] for Framingham risk 0.665, for AHA risk 0.664; p=0.94), but less well than proposed Framingham 10-year risk categories of <5%, 5-20%, >20% (AUC for Framingham risk 0.724, for AHA risk 0.664; p<0.0001).
Conclusions
Risk stratification as proposed in the 2007 AHA guideline is simple, accessible to patients and providers, and identifies cardiovascular risk with accuracy similar to that of the current Framingham algorithm.
doi:10.1161/CIRCOUTCOMES.108.842385
PMCID: PMC2841216  PMID: 20160160
women; prevention; risk factors
15.  The association between alcohol consumption and prevalent cardiovascular diseases among HIV infected and uninfected men 
Objective
To determine whether alcohol consumption is associated with cardiovascular disease (CVD) among HIV infected veterans
Methods
Using established thresholds for alcohol consumption, we analyzed cross-sectional data from 4743 men 51% HIV infected) from the Veterans Aging Cohort Study, a prospective cohort of HIV infected and demographically similar uninfected veterans. Using logistic regression, we estimated the odds ratio (OR) for the association between alcohol consumption and prevalent CVD.
Results
Among HIV infected and uninfected men respectively, hazardous drinking (33.2% vs. 30.9%,), alcohol abuse and dependence (20.9% vs. 26.2%), and CVD (14.6% vs. 19.8%) were common. Among HIV infected men, hazardous drinking (OR=1.43, 95% confidence interval (CI)=1.05-1.94) and alcohol abuse and dependence (OR=1.55, 95% CI=1.07-2.23) were associated with a higher prevalence of CVD compared with infrequent and moderate drinking. Among HIV uninfected men, past drinkers had a higher prevalence of CVD (OR=1.30, 95% CI=1.01-1.67). For HIV infected and uninfected men, traditional risk factors and kidney disease were associated with CVD.
Conclusions
Among HIV infected men, hazardous drinking and alcohol abuse and dependence were associated with a higher prevalence of CVD compared with infrequent and moderate drinking even after adjusting for traditional CVD risk factors, antiretroviral therapy, and CD 4 count.
doi:10.1097/QAI.0b013e3181c6c4b7
PMCID: PMC2858978  PMID: 20009766
alcohol consumption; alcohol abuse; alcohol dependence; HIV infection; cardiovascular disease; Veterans
16.  Duration of Lactation and Risk Factors for Maternal Cardiovascular Disease 
Obstetrics and gynecology  2009;113(5):974-982.
Objective:
To examine dose-response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease.
Methods:
We examined data from 139,681 postmenopausal women (median age 63 years) who reported at least 1 live birth upon enrolling in the Women's Health Initiative (WHI) observational study or controlled trials. Multivariable models were used to control for sociodemographic (age, parity, race, education, income, age at menopause), lifestyle, and family history variables when examining the impact of duration of lactation on risk factors for cardiovascular disease, including obesity (body mass index(BMI) at or above 30), hypertension, self-reported diabetes, hyperlipidemia, prevalent and incident cardiovascular disease.
Results:
Dose-response relationships were observed; in fully-adjusted models, women who reported a lifetime history of more than 12 months of lactation were less likely to have hypertension (OR=0.88, p<0.001), diabetes (OR= 0.80, p<0.001), hyperlipidemia (OR=0.81, p<0.001) or cardiovascular disease (OR= 0.91, p=0.008) than women who never breastfed, but they were not less likely to be obese. In models adjusted for all above variables and BMI, similar relationships were seen. Over an average of 7.9 years of postmenopausal participation in the WHI, women with a single live birth who breastfed for 7-12 months were significantly less likely to develop cardiovascular disease (HR 0.72 (0.53 to 0.97)) than women who never breastfed.
Conclusion:
Among postmenopausal women, increased duration of lactation was associated with a lower prevalence of hypertension, diabetes, hyperlipidemia and cardiovascular disease.
doi:10.1097/01.AOG.0000346884.67796.ca
PMCID: PMC2714700  PMID: 19384111
17.  The Association Between the Receipt of Lipid Lowering Therapy and HIV Status Among Veterans Who Met NCEP/ATP III Criteria for the Receipt of Lipid Lowering Medication 
ABSTRACT
OBJECTIVE
To examine the association between HIV infection status and the receipt of lipid lowering therapy based on National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP III) guidelines and to assess whether HIV viral load and hepatitis C (HCV) status alters that association.
PARTICIPANTS AND DESIGN
A cross-sectional analysis of survey, laboratory, and pharmacy data from 1,577 male participants (59% HIV infected) of the Veterans Aging Cohort Five-Site Study, a prospective observational cohort of U.S. veterans with and without HIV infection.
MEASUREMENTS
Receipt of lipid lowering therapy obtained from the VA pharmacy benefits management system was the main outcome.
RESULTS
The prevalence of lipid lowering therapy among HIV-infected and HIV-uninfected veterans was 15.4% vs. 37.9%, respectively,  < 0.01. Among veterans who met NCEP/ATP III criteria for lipid lowering therapy, HIV-infected veterans had a significantly lower prevalence for the receipt of lipid lowering therapy (adjusted odds ratio (OR) = 0.43, 95% confidence interval (C.I.) 0.28–0.67) as compared with HIV-uninfected veterans. Among HIV-infected veterans, log HIV viral load (adjusted OR = 0.57, 95% CI, 0.41–0.81) and HIV-HCV co-infection (adjusted OR = 0.31, 95% CI = 0.13–0.75) were negatively associated with receipt of lipid lowering therapy. Exposure to HAART was not associated with receipt of lipid lowering therapy.
CONCLUSIONS
Among those who met NCEP/ATP III criteria for lipid lowering therapy, HIV-infected veterans, particularly those with high HIV viral loads and HCV co-infection, were significantly less likely to receive lipid lowering therapy. This may be a modifiable mediator of cardiovascular disease among HIV-infected individuals.
doi:10.1007/s11606-008-0891-7
PMCID: PMC2642578  PMID: 19127386
HIV; cholesterol; hepatitis C; men; veterans; cardiovascular diseases
18.  Focus on the Heart: Alcohol Consumption, HIV Infection, and Cardiovascular Disease 
Alcohol Research & Health  2010;33(3):237-246.
With the advent of effective antiretroviral therapy, people infected with HIV have a longer life expectancy and, consequently, are likely to develop other chronic conditions also found in noninfected people, including cardiovascular disease (CVD). Alcohol consumption, which is common among HIV-infected people, may influence the risk of CVD. In noninfected adults, moderate alcohol consumption can reduce the risk of coronary heart disease (CHD), heart attacks, and the most common type of stroke, whereas heavy drinking increases the risk of these cardiovascular events. These relationships can be partially explained by alcohol’s effects on various risk factors for CVD, including cholesterol and other lipid levels, diabetes, or blood pressure. In HIV-infected people, both the infection itself and its treatment using combination antiretroviral therapy may contribute to an increased risk of CVD by altering blood lipid levels, inducing inflammation, and impacting blood-clotting processes, all of which can enhance CVD risk. Coinfection with the hepatitis C virus also may exacerbate CVD risk. Excessive alcohol use can further enhance CVD risk in HIV-infected people through either of the mechanisms described above. In addition, excessive alcohol use (as well as HIV infection) promote microbial translocation—the leaking of bacteria or bacterial products from the intestine into the blood stream, where they can induce inflammatory and immune reactions that damage the cardiovascular system.
PMCID: PMC3860509  PMID: 23584065
Alcohol consumption; alcohol use disorder; heavy drinking; alcohol and other drug effects and consequences; human immunodeficiency virus; antiretroviral therapy; combination antiretroviral therapy; cardiovascular disease; coronary heart disease; stroke
19.  Epidemiology of Cytokines 
American Journal of Epidemiology  2008;168(4):443-453.
Using multiplex technology, the authors investigated the laboratory and biologic variation of a panel of cytokines (interleukin (IL)-1a, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, interferon-inducible protein-10, monocyte chemoattractant protein-1, and tumor necrosis factor-α) over 18 months and their relations to cardiovascular disease risk factors, hormone therapy, and weight loss. Data were obtained from the Woman On the Move through Activity and Nutrition (WOMAN) Study, a randomized clinical trial investigating the effect of nonpharmacologic interventions on subclinical atherosclerosis among overweight, postmenopausal women in Pennsylvania. The present analysis (February 2002–August 2005) comprised 290 women aged 52–62 years (mean age = 57 years). Most of the cytokines were detectable in a majority of the samples, and the between-individual biologic variation was greater than the within-individual biologic and laboratory variation. There was little association between use of hormone therapy at baseline or change in hormone therapy by 18 months and cytokine levels. Weight loss was associated with a decrease in levels of IL-1 receptor antagonist, IL-6, and C-reactive protein. The results suggest that a wide panel of cytokines may be measured simultaneously from one sample. There is large unexplained variability in cytokine levels that is probably due to genetic-environmental associations.
doi:10.1093/aje/kwn132
PMCID: PMC2727275  PMID: 18579536
cytokines; hormones; inflammation; obesity; weight loss; women
20.  Abdominal aortic aneurysm events in the women’s health initiative: cohort study 
Objective To assess the association between potential risk factors and subsequent clinically important abdominal aortic aneurysm events (repairs and ruptures) in women.
Design Large prospective observational cohort study with mean follow-up of 7.8 years.
Setting 40 clinical centres across the United States.
Participants 161 808 postmenopausal women aged 50-79 enrolled in the women’s health initiative.
Main outcome measures Association of self reported or measured baseline variables with confirmed abdominal aortic aneurysm events assessed with multiple logistic regression.
Results Events occurred in 184 women and were strongly associated with age and smoking. Ever smoking, current smoking, and amount smoked all contributed independent risk. Diabetes showed a negative association (odds ratio 0.29, 95% confidence interval 0.13, 0.68), as did postmenopausal hormone therapy. Positive associations were also seen for height, hypertension, cholesterol lowering treatment, and coronary and peripheral artery disease.
Conclusions Our findings confirm the strong positive associations of clinically important abdominal aortic aneurysm with age and smoking in women and the negative association with diabetes previously reported in men.
doi:10.1136/bmj.a1724
PMCID: PMC2658825  PMID: 18854591
21.  The association between hepatitis C infection and prevalent cardiovascular disease among HIV-infected individuals 
AIDS (London, England)  2007;21(2):193-197.
Objective
To examine the association between hepatitis C and prevalent cardiovascular disease (CVD) among HIV-infected individuals.
Design
A cross-sectional analysis of data from the HIV–Longitudinal Interrelationships of Viruses and Ethanol (HIV–LIVE) cohort, a prospective cohort of HIV-infected individuals with current or past alcohol problems.
Methods
We analysed health questionnaire and laboratory data from 395 HIV-infected individuals (50.1% co-infected with hepatitis C) using logistic regression to estimate the odds ratio (OR) for the prevalence of CVD among those co-infected with hepatitis C and HIV compared with those infected with HIV alone.
Results
The prevalence of CVD was higher among those co-infected with hepatitis C compared with those with HIV alone (11.1 versus 2.5%, respectively). After adjusting for age, the OR for the prevalence of CVD was significantly higher among those with hepatitis C co-infection (adjusted OR 4.65, 95% confidence interval 1.70–12.71). The relationship between hepatitis C and CVD persisted when adjusting for age and other sociodemographic characteristics, substance use, and cardiovascular risk factors in separate regression models.
Conclusion
Co-infection with hepatitis C among a cohort of HIV-infected individuals was associated with a higher age-adjusted odds for the prevalence of CVD. These data suggest that hepatitis C infection may be associated with an increased risk of CVD among those co-infected with HIV.
doi:10.1097/QAD.0b013e3280118a0d
PMCID: PMC1805683  PMID: 17197810
Cardiovascular disease; cardiovascular risk factors; hepatitis C; HIV; myocardial infarction; substance abuse

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