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Clinical practice strongly relies on patients' self-report. Former professional American-style football players are hesitant to seek help for mental health problems, but may be more willing to report cognitive symptoms. We sought to assess the association between cognitive symptoms and diagnosed mental health problems and quality of life among a cohort of former professional players. In a cross-sectional design, we assessed self-reported cognitive function using items from the Quality of Life in Neurological Disorders (Neuro-QOL) Item Bank. We then compared mental health diagnoses and quality of life, assessed by items from the Patient-Reported Outcome Measurement Information System (PROMIS®), between former professional players reporting daily problems in cognitive function and former players not reporting daily cognitive problems. Of the 3758 former professional players included in the analysis, 40.0% reported daily problems due to cognitive dysfunction. Former players who reported daily cognitive problems were more likely to also report depression (18.0% vs. 3.3%, odds ratio [OR] = 6.42, 95% confidence interval [CI] [4.90–8.40]) and anxiety (19.1% vs. 4.3%, OR = 5.29, 95% CI [4.14–6.75]) than those without daily cognitive problems. Further, former players reporting daily cognitive problems were more likely to report memory loss and attention deficit(/hyperactivity) disorder and poorer general mental health, lower quality of life, less satisfaction with social activities and relationships, and more emotional problems. These findings highlight the potential of an assessment of cognitive symptoms for identifying former players with mental health, social, and emotional problems.

BACKGROUND: Professional American-style football players are among the largest athletes across contemporary sporting disciplines, and weight gain during the years of football participation is common. At present, the health implications of this early-life weight gain remain incompletely understood. We sought to define weight trajectories of former professional American-style football athletes and to establish their relationship with 5 health afflictions common in this population (cardiovascular disease, cardiometabolic disease, neurocognitive impairment, sleep apnea, and chronic pain). METHODS: A comprehensive health survey was distributed to former National Football League (NFL) players. Former players reported body weight at 4 key time points (high school, college, professional, and time of survey response) as well as maximal retirement weight. Logistic regression was used to assess associations between weight gain during and after football participation with health affliction. RESULTS: In this cohort of former NFL players (n=3,506, age 53±14 years), mean total weight increase from high school to time of survey response was 40±36 pounds, with the majority of weight gain occurring during and not after football participation. The prevalence of self-reported health afflictions ranged from 9% for cardiovascular disease to 28% for chronic pain. Weight gain during periods of active football participation (high school to college and college to professional) was independently associated with risk of multiple later life health afflictions in models adjusted for football exposure, post-career lifestyle variables, and post-career weight gain. CONCLUSIONS: Early-life weight gain among American-style football athletes is common and is associated with risk of adverse health profiles during later-life. These findings establish football-associated weight gain as a key predictor of post-career health and raise important questions about the central role of targeted weight gain in this population.

Background Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART. Design The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation. Methods All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count. Results The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age. Conclusion Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.

We have enrolled a cohort of former National Football League players (n = 3,506) who played since 1960 to assess potential long term health consequences associated with participating in the sport. Each participant has completed a self-administered questionnaire including reporting of physician-diagnosed health conditions. One of the early assessments was to evaluate whether anterior cruciate ligament (ACL) tears were associated with later life co-morbidities, including cardiovascular effects. We used Cox proportional hazards to estimate hazard ratios (HR) for joint replacement surgeries, myocardial infarction, sleep apnea, arthritis, dementia, and stroke by history of ACL tear during their professional career. For additional outcomes without date of occurrence reported we used logistic regression to estimate odds ratios adjusted for potential confounding variables in all models. After adjusting for covariates, former National Football League players who tore their ACL had approximately a twofold increase in muscular skeletal co-morbidities, including knee joint replacement and arthritis, compared with those without ACL tears. In addition, those with a history of ACL tears also had more than a 50% increased risk of myocardial infarction (HR 1.52; 95% confidence interval 0.97 to 2.38) and a slight increase in sleep apnea (HR 1.15; 95% confidence interval 0.96 to 1.38). ACL tears sustained by athletes may increase the risk of co-morbidities beyond the musculoskeletal system. As there are more than 100,000 ACL reconstructions annually in the United States, our findings could have widespread public health importance if these findings generalize to a population beyond professional football players. In conclusion, enhanced screening for other risk factors for these conditions in patients who have torn their ACL might identify those who could most benefit from prevention strategies.

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS and risk factors for MetS in ART-naive HIV-infected individuals starting ART.MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group trials and were followed long-term after these trials as part of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) are reported.At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts50 cells per cubic millimeter (aHR = 0.62, 95% CI = 0.43 to 0.90 for CD4500), and the risk was increased for HIV-1 RNA400 copies per milliliter (aHR = 1.55 (95% CI = 1.25 to 1.92) and use of a protease-inhibitor (PI)-based regimen [relative to no PI use, aHR = 1.25 (95% CI = 1.04 to 1.51) for any PI use].In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated.

Examine incidence and factors associated with loss to follow-up (LTFU) in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort.ALLRT is a prospective cohort of HIV-infected persons randomized to antiretroviral (ARV) regimens/strategies in ACTG trials and followed long-term after the trial ends. Person-years were calculated from ALLRT entry until loss to follow-up (LTFU; defined using off-study reasons or ≥ 3 consecutive missed visits), death/ severe debilitation/site closures, or June 2009 (censored). Poisson regression was used to examine LTFU factors separately among participants who were ARV naïve or ARV experienced at trial entry.Among 4,630 participants (22,524 person-years), 1,140 were lost to follow-up, 237 died, 29 were severely debilitated, and 443 were at sites that closed. The LTFU incidence was 5.5 and 4.2 per 100 person-years among previously ARV-naïve and ARV-experienced participants, respectively. In both groups, age ≤ 50, site location, being off ARVs, and viral load ≥ 400 copies/mL were associated with a higher risk of LTFU. Among ARV-naïve participants, male sex, education16 years, intravenous drug use, and cigarette smoking were also associated with LTFU.Knowledge of differential LTFU can help researchers identify participants at risk of LTFU in longitudinal HIV cohorts and design retention strategies, thereby limiting study bias. The identified factors should be included in inverse probability of weighting models to account for LTFU.

The authors examined the relation between individual and neighborhood socioeconomic status (SES) and type 2 diabetes incidence among African-American women in the prospective Black Women's Health Study. Participants have completed mailed biennial follow-up questionnaires since 1995. US Census block group characteristics were used to measure neighborhood SES. Incidence rate ratios were estimated in clustered survival regression models. During 12 years of follow-up of 46,382 participants aged 30-69 years, 3,833 new cases of type 2 diabetes occurred. In models that included both individual and neighborhood SES factors, incidence rate ratios were 1.28 (95% confidence interval: 1.15, 1.43) foror = 12 years of education relative toor = 17 years, 1.57 (95% confidence interval: 1.30, 1.90) for household income$15,000 relative to$100,000, and 1.65 (95% confidence interval: 1.46, 1.85) for lowest quintile of neighborhood SES relative to highest. The associations were attenuated after adjustment for body mass index, suggesting it is the key intermediate factor in the pathway between SES and diabetes. The association of neighborhood SES with diabetes incidence was present even among women who were more educated and had a higher family income. Efforts to reduce the alarming rate of diabetes in African-American women must focus on both individual lifestyle changes and structural changes in disadvantaged neighborhoods.

Few modifiable risk factors for type 2 diabetes have been documented in the high-risk population of US black women. The authors used data from 45,668 black women aged 21-69 years, followed biennially from 1995 to 2005 in the Black Women's Health Study, to estimate incidence rate ratios for type 2 diabetes comparing various levels of physical activity and television watching. Cox proportional hazards models were used to control confounding factors. During 10 years of follow-up, 2,928 incident cases of type 2 diabetes were identified. Vigorous activity was inversely associated with type 2 diabetes risk (P(trend)0.0001); the incidence rate ratio foror= 7 hours per week was 0.43 (95% confidence interval (CI): 0.31, 0.59) relative to no activity. Brisk walking foror= 5 hours per week was associated with reduced type 2 diabetes risk (incidence rate ratio=0.67, 95% CI: 0.49, 0.92) relative to no walking. Television watching was associated with an increased type 2 diabetes risk: The incidence rate ratio was 1.86 (95% CI: 1.54, 2.24) foror= 5 hours relative to1 hour of television per day, independent of physical activity. These observational data suggest that black women might reduce their risk of developing type 2 diabetes by increasing their time spent walking or engaged in vigorous physical activity and by limiting television watching.

Objective: Obesity has risen to epidemic proportions in the United States, leading to an emerging epidemic of type 2 diabetes. African-American women are disproportionately affected by both conditions. While an association of overall obesity with increasing risk of diabetes has been documented in black women, the effect of fat distribution, specifically abdominal obesity, has not been studied. We examined the association of BMI, abdominal obesity, and weight gain with risk of type 2 diabetes. Research Methods and Procedures: During eight years of follow-up of 49,766 women from the Black Women's Health Study, 2472 incident cases of diabetes occurred. Cox proportional hazard models were used to estimate incidence rate ratios (IRRs), with control for age, physical activity, family history of diabetes, cigarette smoking, years of education, and time period of data collection. Results: Sixty-one percent of participants had a BMI ≥25 kg/m2 (WHO definition of overweight). Compared with a BMI of 45 kg/m2 was 23 (95% confidence interval, 17.0 to 31.0). The IRR for the highest quintile of waist-to-hip ratio relative to the lowest was 2.3 (95% confidence interval, 2.0 to 2.7) after control for BMI. Furthermore, at every level of BMI, an increased risk was observed for high waist-to-hip ratio relative to low. Discussion: Central obesity, as well as overall obesity, is a strong risk factor for diabetes in African-American women. Efforts to reduce the prevalence of obesity in African-American women are of paramount importance.

OBJECTIVE—Inverse associations between magnesium and calcium intakes and risk of type 2 diabetes have been reported for studies in predominantly white populations. We examined magnesium, calcium, and major food sources in relation to type 2 diabetes in African-American women. RESEARCH DESIGN AND METHODS—This is a prospective cohort study including 41,186 participants of the Black Women’s Health Study without a history of diabetes who completed validated food frequency questionnaires at baseline. During 8 years of follow-up (1995–2003), we documented 1,964 newly diagnosed cases of type 2 diabetes. RESULTS—The multivariate-adjusted hazard ratio of type 2 diabetes for the highest compared with the lowest quintile of intake was 0.69 (95% CI 0.59–0.81; P trend CONCLUSIONS—These findings indicate that a diet high in magnesium-rich foods, particularly whole grains, is associated with a substantially lower risk of type 2 diabetes in U.S. black women.

Data on changes in metabolic syndrome (MetS) status in HIV-infected adults on antiretroviral therapy (ART) are limited.MetS was assessed at ART initiation and every 48 weeks on ART in ART-naive HIV-infected individuals from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort. MetS, defined using the Adult Treatment Panel III criteria, required at least 3 of the following: elevated fasting glucose, hypertension, elevated waist circumference, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol. Prevalence of MetS and the individual criteria were compared between ART initiation and during follow-up using McNemar test.At ART initiation, 450 (20%) ALLRT participants had MetS. After 96 weeks of ART, 37% of the 411 with MetS at ART initiation and with available data at this time point did not meet the MetS criteria. Among these participants, there was a dramatic decline in the proportion with low HDL (95% versus 26%, P0.0001). Among the 63% who continued to meet MetS criteria at week 96, the proportion with ≥4 criteria was higher at week 96 compared to at the time of ART initiation (48% versus 40%, P = 0.03); at week 96, the proportion with high triglycerides was greater (87% versus 69%, P0.0001) as was the proportion with high glucose (59% versus 42%, P0.0001).One in 5 ART-naive subjects met criteria for MetS at ART initiation. Although more than half of these individuals continued to have MetS after 96 weeks of ART, 37% with MetS at ART initiation no longer met criteria for MetS; this decrease was driven largely by increases in HDL cholesterol.

BackgroundDefining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.MethodsWe conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.ResultsHigher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.ConclusionsInterventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137.

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

Background: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited. Methods: We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC. Results: At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤50 cells/mm3 and 25% had CD4 >350 cells/mm3. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin’s disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1–4.08)] and recent CD4 (≤50 cells/mm3: 3.58, 1.22–10.45; 51–200 cells/mm3: 2.54, 1.30–5.0; 201–350 cells/mm3: 2.37, 1.32–4.26 vs. >350 cells/mm3) were associated with NADC. Conclusion: Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.

Type 2 diabetes mellitus is an increasingly serious health problem among African American women. Consumption of sugar-sweetened drinks was associated with an increased risk of diabetes in 2 studies but not in a third; however, to our knowledge, no data are available on African Americans regarding this issue. Our objective was to examine the association between consumption of sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes mellitus in African American women.A prospective follow-up study of 59,000 African American women has been in progress since 1995. Participants reported on food and beverage consumption in 1995 and 2001. Biennial follow-up questionnaires ascertained new diagnoses of type 2 diabetes. The present analyses included 43,960 women who gave complete dietary and weight information and were free from diabetes at baseline. We identified 2713 incident cases of type 2 diabetes mellitus during 338,884 person-years of follow-up. The main outcome measure was the incidence of type 2 diabetes mellitus.The incidence of type 2 diabetes mellitus was higher with higher intake of both sugar-sweetened soft drinks and fruit drinks. After adjustment for confounding variables including other dietary factors, the incidence rate ratio for 2 or more soft drinks per day was 1.24 (95% confidence interval, 1.06-1.45). For fruit drinks, the comparable incidence rate ratio was 1.31 (95% confidence interval, 1.13-1.52). The association of diabetes with soft drink consumption was almost entirely mediated by body mass index, whereas the association with fruit drink consumption was independent of body mass index.Regular consumption of sugar-sweetened soft drinks and fruit drinks is associated with an increased risk of type 2 diabetes mellitus in African American women. While there has been increasing public awareness of the adverse health effects of soft drinks, little attention has been given to fruit drinks, which are often marketed as a healthier alternative to soft drinks.

Background Previous studies of carbohydrate quality and risk of type 2 diabetes mellitus have yielded inconsistent findings. Because diet is in part culturally determined, a study of dietary factors in US black women is of interest. Methods We used data from the Black Women's Health Study, a prospective cohort study of 59 000 US black women, to examine the association of glycemic load, glycemic index, and cereal fiber with risk of type 2 diabetes. Diet was assessed at baseline in 1995 with a modified version of the National Cancer Institute–Block food frequency questionnaire. Results During 8 years of follow-up, there were 1938 incident cases of diabetes. Cox proportional hazards models were used to estimate incidence rate ratios (IRRs) for quintiles of dietary factors, while controlling for lifestyle and dietary factors. Glycemic index was positively associated with the risk of diabetes: the IRR for the highest quintile relative to the lowest was 1.23 (95% confidence interval [CI], 1.05-1.44). Cereal fiber intake was inversely associated with risk of diabetes, with an IRR of 0.82 (95% CI, 0.70-0.96) for the highest vs lowest quintiles of intake. Stronger associations were seen among women with a body mass index (calculated as weight in kilograms divided by height in meters squared) lower than 25: IRRs for the highest vs lowest quintile were 1.91 (95% CI, 1.16-3.16) for glycemic index ( P value for interaction, .12) and 0.41 (95% CI, 0.24-0.72) for cereal fiber intake ( P value for interaction, .05). Conclusion Increasing cereal fiber in the diet may be an effective means of reducing the risk of type 2 diabetes, a disease that has reached epidemic proportions in black women.

We prospectively assessed the association of neighborhood socioeconomic status (SES) with 10-year weight change and with incident obesity among 48,359 women in the Black Women's Health Study (BWHS). Lower neighborhood SES was significantly associated with 10-year weight gain after adjustment for individual SES and behavioral variables, such as physical activity and caloric intake. Low neighborhood SES was also associated with increased incidence of obesity during 10 years of follow-up among women of normal weight at baseline (BMI25 kg/m(2)). The associations were most evident among BWHS participants who had graduated from college. These prospective data suggest that lower neighborhood SES contributes to overweight and obesity in African-American women.

Objective: To assess differences in body circumferences and body mass index (BMI, kg/m 2 ) between antiretroviral treatment (ART) nao ¨ve HIV-infected and HIV-uninfected persons. Methods: Waist, arm, and thigh circumferences and BMI were measured within the ALLRT and NHANES cohorts between 1998 and 2007. ALLRT is a prospective, longitudinal study of U.S. participants enrolled in randomized HIV treatment studies conducted by the AIDS Clinical Trials Group (ACTG). NHANES is a representative group of the US population. The cohorts were analyzed in two time periods, to account for trends towards increased adiposity. Anthropometrics were displayed in percentiles by age and sex. Multiple linear regression models examined differences between cohorts. Results: ALLRT had more males (82% versus 48%, p,0.0001), more black participants (32% versus 23%, p,0.0001), and less Hispanics (21% versus 30%, p,0.0001) than NHANES. Mean BMI was smaller in ALLRT males and females compared to NHANES by 1.6–2.4 kg/m 2 (p,0.0001). Mean waist and arm circumferences in both sexes and time periods were significantly smaller in ALLRT than in NHANES (p,0.0001). Mean thigh circumference in ALLRT was also smaller than NHANES among males (p,0.0001 in both time periods) and females (p = 0.01 in the early time period). Conclusions: Differences in anthropometrics existed prior to ART initiation, in this large national cohort of HIV-infected individuals, compared to a representative HIV-uninfected cohort, indicating that HIV and its complications have important effects on body shape. Further longitudinal examination of anthropometrics in this HIV-infected cohort may provide additional insight into disease risk. Trial Registration: NCT00001137 at www.clinicaltrials.gov.