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1.  Low Social Support Is Associated With Shorter Leukocyte Telomere Length in Late Life: Multi-Ethnic Study of Atherosclerosis (MESA) 
Psychosomatic medicine  2013;75(2):10.1097/PSY.0b013e31828233bf.
Objective
The primary goal was to test the hypothesis that limited social support (SS) is related to shorter leukocyte telomere length (LTL), particularly in an older adult population.
Methods
Cross-sectional analyses were performed on 948 participants at Exam 1 of the Multi-Ethnic Study of Atherosclerosis (MESA), ages 45–84 years (18.4% White, 53.1% Hispanics, and 28.5% African-American). LTL was determined using qPCR and social support was measured with the ENRICHD social support inventory.
Results
Across the entire sample, SS was not associated with LTL (p = .87) after adjusting for demographic (age, gender, race/ethnicity, socioeconomic status), age X gender, age X race, health (body mass index, diabetes, pulse pressure), and lifestyle factors (smoking, physical activity, diet), however the interaction term Age (dichotomized) X SS was significant, p = .001. Stratification by age group revealed a positive association between SS (score range: 5–25) and LTL in the older (65–84 years) B(SE) = .005(.002), p = .007, but not younger participants (45–64 years), p = .12, after adjusting for covariates.
Conclusions
These results from a racially/ethnically diverse community sample of men and women provide initial evidence that low SS is associated with shorter LTL in adults aged 65 and older and is consistent with the hypothesis that social environment may contribute to rates of cellular aging, particularly in late life.
doi:10.1097/PSY.0b013e31828233bf
PMCID: PMC3881963  PMID: 23370895
telomere length; social support; cellular aging; loneliness; isolation; older adults
2.  Symptoms and Risk Factors for Stroke in a Community-Based Observational Sample in Viet Nam 
Background
Viet Nam is experiencing a health transition from infectious to chronic disease. Data on cardiovascular diseases, including strokes, are limited.
Methods
Data were randomly collected from six communities in Da Nang, Viet Nam, on participant demographics, medical history, blood pressure, anthropometrics and health behavior using World Health Organization (WHO) guidelines. Stroke symptoms were collected by self-report with the standardized Questionnaire for Verifying Stroke Free Status. Multivariate logistic regression was used to identify factors associated with the presence of stroke symptoms.
Results
1,621 adults were examined with a mean age of 52.0 years (± 12.5 years), of which 56.1% were women. 27.3% of the participants were found to have hypertension, 26.2% used tobacco, and 16.1% were overweight. More than two-thirds of the participants with hypertension were unaware of their condition. Almost one fourth of the participants were identified by the questionnaire as previously experiencing at least one stroke symptom. Age, rural residence, and education were associated with the presence of stroke symptoms. Models adjusted for demographics found hypertension, high cholesterol, reported severe chest pain, former smoking, and being overweight to be associated with a higher prevalence of stroke symptoms.
Conclusions
The high frequency of stroke symptoms in Da Nang calls for further evaluation and interventions to reduce hypertension and other risk factors for chronic disease.
doi:10.1016/j.jegh.2012.06.001
PMCID: PMC3607634  PMID: 23538875
stroke; symptoms; Viet Nam; community-based; risk factors
3.  The Epidemiology of Sleep Quality and Consumption of Stimulant Beverages among Patagonian Chilean College Students 
Sleep Disorders  2013;2013:910104.
Objectives. (1) To assess sleep patterns and parameters of sleep quality among Chilean college students and (2) to evaluate the extent to which stimulant beverage use and other lifestyle characteristics are associated with poor sleep quality. Methods. A cross-sectional study was conducted among college students in Patagonia, Chile. Students were asked to complete a self-administered questionnaire to provide information about lifestyle and demographic characteristics. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality. In addition, students underwent a physical examination to collect anthropometric measurements. Results. More than half of students (51.8%) exhibited poor sleep quality. Approximately 45% of study participants reported sleeping six hours or less per night and 9.8% used medications for sleep. In multivariate analysis, current smokers had significantly greater daytime dysfunction due to sleepiness and were more likely to use sleep medicines. Students who reported consumption of any stimulant beverage were 1.81 times as likely to have poor sleep quality compared with those who did not consume stimulant beverages (OR:1.81, 95% CI:1.21–2.00). Conclusions. Poor sleep quality is prevalent among Chilean college students, and stimulant beverage consumption was associated with the increased odds of poor sleep quality in this sample.
doi:10.1155/2013/910104
PMCID: PMC3671558  PMID: 23766919
4.  Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: The Cardiovascular Health Study 
Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989–1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r2=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5–0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20–1.4 (CC vs. AA) (p-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7–1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8–3.6 (CC vs. AA) (p-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.
doi:10.1016/j.mad.2012.03.002
PMCID: PMC3391009  PMID: 22449406
5.  Contribution of Multiple Chronic Conditions to Universal Health Outcomes 
OBJECTIVES
To determine the relative effect of five chronic conditions on four representative universal health outcomes.
DESIGN
Cross-sectional.
SETTING
Cardiovascular Health Study.
PARTICIPANTS
Five thousand two hundred and ninety-eight community-living participants aged 65 and older.
MEASUREMENTS
Multiple regression and Cox models were used to determine the effect of heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, depression, and cognitive impairment on self-rated health, 12 basic and instrumental activities of daily living (ADLs and IADLs), six-item symptom burden scale, and death.
RESULTS
Each condition adversely affected self-rated health (P<.001) and ADLs and IADLs (P<.001). For example, persons with HF performed 0.70 ± 0.08 fewer ADLs and IADLs than those without; persons with depression and persons with cognitive impairment performed 0.59 ± 0.04 and 0.58 ± 0.06 fewer activities, respectively, than those without these conditions. Depression, HF, COPD, and osteoarthritis were associated with 1.18 ± 0.04, 0.40 ± 0.08, 0.40 ± 0.05, and 0.57 ± 0.03 more symptoms, respectively, in individuals with these conditions than in those without. HF (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 1.97–4.10), COPD (2.62, 95% CI = 1.94–3.53), cognitive impairment (2.05, 95% CI = 1.47–2.85), and depression (1.47, 95% CI = 1.08–2.01) were each associated with death within 2 years. Several paired combinations of conditions had synergistic effects on ADLs and IADLs. For example, individuals with HF plus depression performed 2.0 fewer activities than persons with neither condition, versus the 1.3 fewer activities expected from adding the effects of the two conditions together.
CONCLUSION
Universal health outcomes may provide a common metric for measuring the effects of multiple conditions and their treatments. The varying effects of the conditions across universal outcomes could inform care priorities.
doi:10.1111/j.1532-5415.2011.03573.x
PMCID: PMC3622699  PMID: 21883118
multiple chronic conditions; patient-reported outcomes; universal health outcomes
6.  Leukocyte Telomere Length Is Associated With Noninvasively Measured Age-Related Disease: The Cardiovascular Health Study 
Background.
Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).
Methods.
LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima–media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4% male, 86.8% white, and 13.2% black).
Results.
Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = −132 [47] bp, p < .01), age (β [SE] = −107 [46], p = .02) or carotid thickness (β [SE] = −95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35%.
Conclusion.
LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.
doi:10.1093/gerona/glr173
PMCID: PMC3309872  PMID: 21934123
Leukocyte telomere length; Disease burden; Noninvasive measurements; Aging
7.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually by an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.
doi:10.3233/JAD-2011-110431
PMCID: PMC3577072  PMID: 21841254
Caffeine; coffee; cognition; tea
8.  Double burden: a cross-sectional survey assessing factors associated with underweight and overweight status in Danang, Vietnam 
BMC Public Health  2013;13:35.
Background
Many low- to middle-income countries are faced with an increasing prevalence of overweight/obesity while that for underweight remains high, a duality termed “double burden”; both are key risk factors for chronic diseases. This cross-sectional study assesses the prevalence and factors for underweight and overweight/obesity among adults in Danang, Vietnam, using WHO standard and suggested Asian-specific BMI cut-offs.
Methods
In 2010, 1713 residents age ≥35 years from 900 households in 6 of 56 urban, rural and mixed urban–rural communes in Danang were selected using multistage-cluster sampling methodology to participate; 1621 qualified adults enrolled. Participants completed a health survey based on WHO STEPwise Approach to Chronic Disease Risk Factor Surveillance and additional questions on chest pain and stroke symptoms. Anthropometric and other measurements were conducted. Relative risk regression was used to identify independent risk factors for underweight or overweight/obesity according to WHO standard cut-offs and suggested Asian-specific cut-offs (<18.5 kg/m2 or 23–27.49 kg/m2; and ≥27.5 kg/m2).
Results
We observed 12.4% prevalence of underweight and 16.0% for overweight/obesity using WHO standard. The prevalence of overweight/obesity doubled (33.7%) when Asian-specific cut-offs were applied. For both definitions, rural communes had the highest prevalence of underweight while urban communes had the highest prevalence of overweight/obesity. Being underweight was associated with less urbanization. Factors independently associated with being underweight included older age, rural living, current smoking, and lower systolic pressure. Factors independently associated with Asian-specific BMI definition for being overweight/obese included older age, urbanization, higher systolic pressure, and diabetes. Age was not an independent factor with WHO standard cut-offs; however, myocarial infarction and diabetes showed strong associations.
Conclusions
The double burden of underweight and overweight/obesity observed in Danang is consistent with patterns found for large cities in Vietnam that are undergoing rapid economic growth and urbanization of lifestyle. Factors independently associated with underweight and overweight/obesity status by WHO standard and Asian-specific definitions include urbanization and modifiable lifestyle factors. Further studies are needed to define ethnic specific BMI cut-offs for Vietnam and to explore strategies to reduce the rising prevalence of overweight/obesity.
doi:10.1186/1471-2458-13-35
PMCID: PMC3671199  PMID: 23316727
9.  Mid- and Late-Life Obesity: Risk of Dementia in the Cardiovascular Health Cognition Study 
Archives of neurology  2009;66(3):336-342.
Objectives
To evaluate associations between mid- and late-life obesity and risk of dementia.
Design
Prospective cohort followed 5.4 years from 1992/4 through 1999.
Setting
Community-dwelling sample in four US sites recruited from Medicare eligibility files.
Participants
2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.
Main Outcome Measures
Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.
Results
Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.
Conclusions
These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.
doi:10.1001/archneurol.2008.582
PMCID: PMC3513375  PMID: 19273752
10.  Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans 
Human Molecular Genetics  2012;21(24):5385-5394.
Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10−11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10−8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10−8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10−8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
doi:10.1093/hmg/dds382
PMCID: PMC3510758  PMID: 23001564
11.  Genital Tract Infections, Bacterial Vaginosis, HIV, and Reproductive Health Issues among Lima-Based Clandestine Female Sex Workers 
Sociodemographic and behavioral characteristics of 212 Peruvian female sex workers (FSWs) were analyzed. The association between genital tract infections (GTIs) and risk factors by multivariate analysis was evaluated. Eighty-eight percent of FSWs were diagnosed with at least one GTI (HSV-2 80.1%, BV 44.8%, candidiasis 9.9%, syphilis seropositivity 9.4%, Trichomonas vaginalis 2.4%, HIV seropositivity 2.4%). Reported condom use with clients was nearly universal (98.3%), but infrequent with husband/regular partners (7.3%). In multivariate analysis BV was negatively associated with more consistent condom use (PRR = 0.63, 95% CI, 0.42–0.96). Many had not visited a Sexually Transmitted Infection (STI) clinic or been tested for HIV in the past year (40.6%, 47.1%, resp.). Nonclient contraceptive use was low (57%) and induced abortion was common (68%). High GTI burden and abortions suggest that a services-access gap persists among marginalized FSWs. Continued health outreach programs and integrating family planning and reproductive health services into existing STI clinic services are recommended.
doi:10.1155/2012/739624
PMCID: PMC3395213  PMID: 22811592
12.  Comparing Years of Healthy Life, Measured in 16 Ways, for Normal Weight and Overweight Older Adults 
Journal of Obesity  2012;2012:894894.
Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The “Overweight paradox” appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.
doi:10.1155/2012/894894
PMCID: PMC3388309  PMID: 22778920
13.  Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience 
Genetic epidemiology  2011;35(3):159-173.
Genome-wide association study (GWAS) consortia and collaborations formed to detect genetic loci for common phenotypes or investigate gene-environment (G*E) interactions are increasingly common. While these consortia effectively increase sample size, phenotype heterogeneity across studies represents a major obstacle that limits successful identification of these associations. Investigators are faced with the challenge of how to harmonize previously collected phenotype data obtained using different data collection instruments which cover topics in varying degrees of detail and over diverse time frames. This process has not been described in detail. We describe here some of the strategies and pitfalls associated with combining phenotype data from varying studies. Using the Gene Environment Association Studies (GENEVA) multi-site GWAS consortium as an example, this paper provides an illustration to guide GWAS consortia through the process of phenotype harmonization and describes key issues that arise when sharing data across disparate studies. GENEVA is unusual in the diversity of disease endpoints and so the issues it faces as its participating studies share data will be informative for many collaborations. Phenotype harmonization requires identifying common phenotypes, determining the feasibility of cross-study analysis for each, preparing common definitions, and applying appropriate algorithms. Other issues to be considered include genotyping timeframes, coordination of parallel efforts by other collaborative groups, analytic approaches, and imputation of genotype data. GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia.
doi:10.1002/gepi.20564
PMCID: PMC3055921  PMID: 21284036
phenotype; harmonization; genome-wide association studies; GENEVA; consortia
14.  Leukocyte Telomere Length and Mortality in the Cardiovascular Health Study 
Background.
Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
Methods.
We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992–1993 and survived through 1997–1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
Results.
A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22–2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32–5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95–3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
Conclusion.
These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
doi:10.1093/gerona/glq224
PMCID: PMC3055278  PMID: 21289018
Telomere; Mortality; Cause of death; Cardiovascular disease; Heart failure
15.  Cognition and the Risk of Hospitalization for Serious Falls in the Elderly: Results From the Cardiovascular Health Study 
Background.
Many elderly adults fall every year, sometimes resulting in serious injury and hospitalization. Although impaired cognition is a risk factor for injurious falls, little is known about cognitive decline above the threshold of impairment and risk of serious falls in community-dwelling seniors.
Methods.
In total, 702 of 5,356 older adults participating in the Cardiovascular Health Study experienced an injurious fall between 1990 and 2005, as indicated by hospitalization records. General cognition was measured annually with the Modified Mini-Mental State Examination and processing speed with the Digit Symbol Substitution Test. The Cox regression model was used to calculate hazard ratio and 95% confidence interval with and without time-dependent covariates and adjusted for known risk factors.
Results.
Participants with slightly decreased Digit Symbol Substitution Test scores were at increased risk for a serious fall (hazard ratio = 1.58, 95% confidence interval = 1.15–2.17). The risk continued to increase with each quartile decrease in Digit Symbol Substitution Test score. Participants without prevalent cardiovascular disease at baseline and decreased Modified Mini-Mental State Examination scores (80–89) had a 45% increased risk for a serious fall and those at high risk for dementia (<80) were at twice the risk as participants scoring above 90 (hazard ratio = 2.16, 95% confidence interval = 1.60–2.91).
Conclusions.
Both decreased general cognition and decreased processing speed appear to be potential risk factors for serious falls in the elderly. When assessing the risk of serious falls in elderly patients, clinicians should consider usual factors like gait instability and sensory impairment as well as less obvious ones such as cardiovascular disease and cognitive function in nondemented adults.
doi:10.1093/gerona/glq115
PMCID: PMC2954237  PMID: 20584769
Elderly; Falls; Cognition; Epidemiology
16.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Purpose
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
Methods
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
Results
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Conclusions
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
doi:10.1002/pds.1979
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
17.  Medication Management Among Medicaid Myocardial Infarction Survivors 
Despite guidelines to direct appropriate medical management, the quality of care following acute myocardial infarction (AMI) may be lacking. This study characterizes medication utilization by Medicaid enrollees in the year following AMI, compares it to guidelines for secondary prevention and investigates associations with rehospitalization and survival. Using DSHS administrative claims data from Washington State, Medicaid enrollees who had an AMI in 2004 were selected. Data were de-identified and details of demographics, hospitalizations, ambulatory care, and prescriptions over the following 365 days were abstracted. Utilization of guideline-directed secondary prevention strategies was measured and associations with death and recurrent hospitalization were tested. The mortality rate was 13.4% and 38.7% were rehospitalized. Mean time to first rehospitalization was 188.6 days (SD 102.3). Prescriptions for angiotensin enzyme inhibitors or receptor blockers were initially filled by 54.0%, but year-long adherence declined to 33.3%. Beta blockers, aspirin and statins followed the same trend: 65.1% to 39.5%, 37.9% to 16.7% and 58.1% to 41.9% respectively. Twenty-two percent received all medications; 8.2% were adherent. Only the initial prescription of aspirin was significantly associated with a survival benefit (HR = 0.35, p=0.003). If the results suggested by the claims data are representative of care delivered to Medicaid enrollees, rates of application of guideline-directed medication are less than optimal. To improve survival and reduce re-hospitalization following AMI, changes in the access and delivery of healthcare could be implemented to improve medication management, both at time of discharge and over the year following AMI.
PMCID: PMC3107018  PMID: 21643550
Medicaid; Access to Care; Medication Adherence; Secondary Prevention; Cardiovascular; Myocardial Infarction; Characteristics of Care
18.  Genome-wide Analysis of Genetic Loci Associated with Alzheimer’s Disease 
Context
Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD).
Objective
In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction.
Design, Setting, and Participants
We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls).
Main outcome measure
Alzheimer’s Disease.
Results
We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003).
Conclusions
Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.
doi:10.1001/jama.2010.574
PMCID: PMC2989531  PMID: 20460622
genome-wide association study; genetic epidemiology; genetics; dementia; Alzheimer’s disease; cohort study; meta-analysis; risk
19.  Observed Changes in Risk during Naturopathic Treatment of Hypertension 
Few outcome assessments are published from complementary and alternative medicine (CAM) practices. We aimed to describe patient and practice characteristics of ND care for hypertension (HTN), quantify changes in blood pressure (BP), and evaluate the proportion achieving control of HTN during care. A retrospective, observational study of ND practice in HTN was performed in an outpatient clinic in WA State. Eighty-five charts were abstracted for the final analysis. At initiation of care, the mean patient age was 61 years, with 51% having stage 2 HTN, despite common use of anti-hypertensive medications (47%). Patients with both stage 1 and stage 2 HTN appeared to improve during care, with stage 2 patients achieving mean reductions of −26 mmHg (P < .0001) and −11 mmHg (P < .0001) in systolic BP (SBP) and diastolic BP (DBP), respectively. The proportion of patients achieving control (<140/90 mmHg) in both SBP and DBP was increased significantly from 14 to 44% (P < .033), although the statistical significance was not maintained upon correction for multiple comparisons. BP appears to improve during ND care for HTN, in a high-risk population. Randomized trials are warranted.
doi:10.1093/ecam/nep219
PMCID: PMC3137652  PMID: 21799695
20.  Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA)3 
Background
Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes.
Objective
With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation.
Design
Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant.
Results
After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller (β ± SE: −0.07 ± 0.03, P = 0.006). Categorical analysis showed that participants consuming ≥1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length.
Conclusions
Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations.
PMCID: PMC3037593  PMID: 18996878
21.  NSAID Use and Dementia Risk in the Cardiovascular Health Study: Role of APOE and NSAID Type 
Neurology  2007;70(1):17-24.
Background:
Epidemiologic and laboratory studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce risk of Alzheimer dementia (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.
Methods:
Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one ε4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant Aβ42.
Results:
Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% confidence interval or CI 0.60–0.96), and, in particular, AD (aHR 0.63, CI 0.45–0.88), but not VaD (aHR 0.92, CI 0.65–1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79 - 1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE ε4 allele (aHR 0.34, CI 0.18–0.65; aHR for others 0.88, CI 0.59–1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce Aβ42.
Conclusions:
Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE ε4 allele, and there was no advantage for Aβ42 lowering NSAIDs.
doi:10.1212/01.wnl.0000284596.95156.48
PMCID: PMC2877629  PMID: 18003940
22.  Association between insulin resistance and c-reactive protein among Peruvian adults 
Objective
Insulin resistance (IR), a reduced physiological response of peripheral tissues to the action of insulin, is one of the major causes of type 2 diabetes. We sought to evaluate the relationship between serum C-reactive protein (CRP), a marker of systemic inflammation, and prevalence of IR among Peruvian adults.
Methods
This population based study of 1,525 individuals (569 men and 956 women; mean age 39 years old) was conducted among residents in Lima and Callao, Peru. Fasting plasma glucose, insulin, and CRP concentrations were measured using standard approaches. Insulin resistance was assessed using the homeostasis model (HOMA-IR). Categories of CRP were defined by the following tertiles: <0.81 mg/l, 0.81-2.53 mg/l, and >2.53 mg/l. Logistic regression procedures were employed to estimate odds ratios (OR) and 95% confidence intervals (CI).
Results
Elevated CRP were significantly associated with increased mean fasting insulin and mean HOMA-IR concentrations (p < 0.001). Women with CRP concentration >2.53 mg/l (upper tertile) had a 2.18-fold increased risk of IR (OR = 2.18 95% CI 1.51-3.16) as compared with those in the lowest tertile (<0.81 mg/l). Among men, those in the upper tertile had a 2.54-fold increased risk of IR (OR = 2.54 95% CI 1.54-4.20) as compared with those in the lowest tertile.
Conclusion
Our observations among Peruvians suggest that chronic systemic inflammation, as evidenced by elevated CRP, may be of etiologic importance in insulin resistance and diabetes.
doi:10.1186/1758-5996-2-30
PMCID: PMC2883970  PMID: 20482756
23.  Does Ginkgo biloba reduce risk of cardiovascular events? 
Background
Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory (GEM) Study. The trial previously reported that Ginkgo biloba (G. biloba) had no effect on the primary outcome, incident dementia.
Methods and Results
The double-blind trial randomized 3069 participants over 75 years of age to 120 mg of G. biloba EGb 761 twice daily or placebo. Mean follow up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G. biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and gender. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G. biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207) or stroke (151) between G. biloba and placebo. There were 24 hemorrhagic strokes, 16 on G. biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease (PVD) events, 12 (0.8%) on G. biloba and 23 (1.5%) on placebo (p=0.04 exact test). Most of the PVD cases had either vascular surgery or amputation.
Conclusion
There was no evidence that G. biloba reduced total or CVD mortality or CVD events. There were more PVD events in the placebo arm. G. biloba cannot be recommended for preventing CVD. Further clinical trials of PVD outcomes might be indicated.
doi:10.1161/CIRCOUTCOMES.109.871640
PMCID: PMC2858335  PMID: 20123670
anticoagulation; peripheral vascular disease; cardiovascular disease; stroke; trials
24.  Is Maternal Periodontal Disease a Risk Factor for Preterm Delivery? 
American Journal of Epidemiology  2009;169(6):731-739.
Several studies have suggested an association between maternal periodontal disease and preterm delivery, but this has not been a consistent finding. In 2006–2007, the authors examined the relation between maternal periodontal disease and preterm delivery among 467 pregnant Thai women who delivered a preterm singleton infant (<37 weeks’ gestation) and 467 controls who delivered a singleton infant at term (≥37 weeks’ gestation). Periodontal examinations were performed within 48 hours after delivery. Participants’ periodontal health status was classified into 4 categories according to the extent and severity of periodontal disease. Logistic regression was used to estimate odds ratios and 95% confidence intervals. Preterm delivery cases and controls were similar with regard to mean probing depth, mean clinical attachment loss, and mean percentage of sites exhibiting bleeding on probing. After controlling for known confounders, the authors found that severe clinical periodontal disease was not associated with an increased risk of preterm delivery (odds ratio = 1.20, 95% confidence interval: 0.67, 2.16). In addition, there was no evidence of a linear increase in risk of preterm delivery or its subtypes associated with increasing severity of periodontal disease (Ptrend > 0.05). The results of this case-control study do not provide convincing evidence that periodontal disease is associated with preterm delivery or its subtypes among Thai women.
doi:10.1093/aje/kwn399
PMCID: PMC2727214  PMID: 19131565
periodontal diseases; premature birth
25.  IDENTIFYING MILD COGNITIVE IMPAIRMENT AT BASELINE IN THE GINKGO EVALUATION OF MEMORY (GEM) STUDY 
Aging & mental health  2009;13(2):171-182.
Objectives
To identify, characterize and compare the frequency of Mild Cognitive Impairment (MCI) subtypes at baseline in a large, late-life cohort (N=3,063) recruited into a dementia prevention trial.
Method
A retrospective, data-algorithmic approach was used to classify participants as cognitively normal or MCI with corresponding subtype (e.g., amnestic vs. non-amnestic, single domain vs. multiple domain) based on a comprehensive battery of neuropsychological test scores, with and without Clinical Dementia Rating (CDR) global score included in the algorithm.
Results
Overall, 15.7% of cases (n=480) were classified as MCI. Amnestic MCI was characterized as unilateral memory impairment (i.e., only verbal or only visual memory impaired) or bilateral memory impairment (i.e., both verbal and visual memory impaired). All forms of amnestic MCI were almost twice as frequent as non-amnestic MCI (10.0% vs. 5.7%). Removing the CDR = 0.5 (“questionable dementia”) criterion resulted in a near doubling of the overall MCI frequency to 28.1%.
Conclusion
Combining CDR and cognitive test data to classify participants as MCI resulted in overall MCI and amnestic MCI frequencies consistent with other large community-based studies, most of which relied on the “gold standard” of individual case review and diagnostic consensus. The present data-driven approach may prove to be an effective alternative for use in future large-scale dementia prevention trials.
doi:10.1080/13607860802380656
PMCID: PMC2767255  PMID: 19347684
MCI; Neuropsychology; Dementia Prevention Trials

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