Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies.

BACKGROUND: A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity. METHODS: In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity. FINDINGS: The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity. CONCLUSIONS: This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity. FUNDING: This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

Total and free 25-hydroxyvitamin D concentrations and risk of urinary incontinence in women participating in Nurses Health Studies I & II.

BACKGROUND: Urgency urinary incontinence (UUI) occurs in >40% of older women. Our objective was to examine the relationship of total and free plasma 25-hydroxyvitamin D (25(OH)D) and UUI to evaluate vitamin D status as a novel target for prevention of UUI. METHODS: We conducted a nested case control study using the Nurses' Health Study (NHS) and NHS II. Using stored plasma samples from 2000, we measured total 25(OH)D, free 25(OH)D, and intact parathyroid hormone (PTH) levels and examined their relationship to incident UUI from 2000 to 2013. Plasma biomarker levels were categorized as quartiles. Multivariable-adjusted odds ratios of UUI were estimated by conditional logistic regression models (with matching by age) across categories of each biomarker and covariates. RESULTS: The analytic sample included 398 cases of incident UUI and 398 matched controls with a mean age of 50 years. We found a strong correlation of plasma levels of total 25(OH)D with free 25(OH)D (r=0.5). Plasma total 25(OH)D and free 25(OH)D concentrations were negatively correlated with PTH (r=-0.08 AND -0.09, respectively). Overall, we found no evidence that levels of total plasma 25(OH)D, free 25(OH)D, or PTH were related to incident UUI after adjustment for obesity, physical activity, cigarette smoking, menopausal status, hypertension, and type 2 diabetes. CONCLUSIONS: Free plasma 25(OH)D by quartile, as well as total plasma 25(OH)D, was not associated with incident UUI in women. We found that plasma total and free 25(OH)D were highly correlated with each other and inversely correlated with PTH. Plasma free 25(OH)D did not provide additional predictive value in determining risk of UUI.

Age-dependent differences and similarities in the plasma proteomic signature of postoperative delirium.

Delirium is an acute confusional state and a common postoperative morbidity. Prevalent in older adults, delirium occurs at other ages but it is unclear whether the pathophysiology and biomarkers for the condition are independent of age. We quantified expression of 273 plasma proteins involved in inflammation and cardiovascular or neurologic conditions in 34 middle-aged and 42 older patients before and one day after elective spine surgery. Delirium was identified by the 3D-CAM and comprehensive chart review. Protein expression was measure by Proximity Extension Assay and results were analyzed by logistic regression, gene set enrichment, and protein-protein interactions. Twenty-two patients developed delirium postoperatively (14 older; 8 middle-aged) and 89 proteins in pre- or 1-day postoperative plasma were associated with delirium. A few proteins (IL-8, LTBR, TNF-R2 postoperatively; IL-8, IL-6, LIF, ASGR1 by pre- to postoperative change) and 12 networks were common to delirium in both age groups. However, there were marked differences in the delirium proteome by age; older patients had many more delirium-associated proteins and pathways than middle-aged subjects even though both had the same clinical syndrome. Therefore, there are age-dependent similarities and differences in the plasma proteomic signature of postoperative delirium, which may signify age differences in pathogenesis of the syndrome.

Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.

BACKGROUND: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. RESULTS: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. CONCLUSION: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.

Long-Term Consumption of Nuts (Including Peanuts, Peanut Butter, Walnuts, and Other Nuts) in Relation to Risk of Frailty in Older Women: Evidence from a Cohort Study.

BACKGROUND: Adherence to a healthy diet is inversely associated with frailty. However, the relationship between nuts, a key food group of Mediterranean diet, and frailty is unclear. OBJECTIVES: This study aimed to evaluate the association between nut consumption and frailty in an aging female population. METHODS: This population-based observational study included nonfrail women (≥60 y old) in the NHS from 11 states of the United States. Outcome was incident frailty, defined as having ≥3 of the FRAIL components (fatigue, lower strength, reduced aerobic capacity, multiple chronic conditions, and significant weight loss) and assessed every 4 y from 1992 to 2016. From 1990 to 2014, FFQs were used to assess the intakes of peanuts, peanut butter, walnuts (added in 1998), and other nuts at 4-y intervals. Exposure was total nut consumption, calculated as the sum of intakes of peanuts, peanut butter, walnuts, and other nuts and categorized into <1 serving/mo, 1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and ≥5 servings/wk. The relations of intakes of peanuts, peanut butter, and walnuts with frailty were also investigated separately. Cox proportional hazards models were used to assess the associations between nut consumption and frailty after adjusting for age, smoking, BMI, EI, diet quality, and medication use. RESULTS: Among 71,704 participants, 14,195 incident frailty cases occurred over 1,165,290 person-years. The adjusted HR (95% CI) for consuming ≥5 servings/wk of nuts was 0.80 (0.73, 0.87), as compared with <1 serving/mo. Higher intakes of peanuts and walnuts, but not peanut butter, were also inversely associated with frailty. CONCLUSIONS: This large prospective cohort study showed a strong and consistent inverse association between regular nut consumption and incident frailty. This suggests that nut consumption should be further tested as a convenient public health intervention for the preservation of health and well-being in older adults.

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

Childhood Abuse and Cognitive Function in a Large Cohort of Middle-Aged Women.

Cognitive function at middle age is of particular public health interest, as it strongly predicts later dementia. Children who have experienced abuse subsequently have worse cognitive function than those who have not. However, it remains unclear whether the association of abuse with cognitive function persists into middle age. In 2014-2016, 14,151 women ages 49-69 years who had previously responded to a childhood abuse questionnaire completed a cognitive battery. In models adjusted for childhood socioeconomic status and head trauma, combined physical, emotional, and sexual abuse was associated with lower scores on both Learning/Working Memory (severe abuse, lower scores similar to that observed in women 4.8 years older in our data) and Psychomotor Speed/Attention (severe abuse, lower scores similar to that observed in women to 2.9 years older in our data). Adjustment for adulthood socioeconomic status and health factors (e.g., smoking, hypertension) slightly attenuated associations. In exploratory analyses further adjusted for psychological distress, associations were attenuated. Women exposed versus unexposed to childhood abuse had poorer cognitive function at mid-life. Associations were particularly strong for learning and working memory and were not accounted for by adulthood health factors. Childhood abuse should be investigated as a potential risk factor for cognitive decline and dementia in old age.

Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial.

Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD] = 70.9[5.8] years) free of cardiovascular disease and cancer in two substudies in the VITAL 2 × 2 randomized trial of vitamin D3 (2000 IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8 years follow-up) and 794 had in-person assessments (nine tests; 2.0 years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI - 0.01, 0.02; p = 0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction = 0.84) and a significant interaction with self-reported race (p-interaction = 0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD = 0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2 years apart in age). Thus, vitamin D3 (2000 IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2-3 years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset of eligible VITAL participants: 9/14/2011.

Cortical proteins may provide motor resilience in older adults.

Motor resilience proteins may be a high value therapeutic target that offset the negative effects of pathologies on motor function. This study sought to identify cortical proteins associated with motor decline unexplained by brain pathologies that provide motor resilience. We studied 1226 older decedents with annual motor testing, postmortem brain pathologies and quantified 226 proteotypic peptides in prefrontal cortex. Twenty peptides remained associated with motor decline in models controlling for ten brain pathologies (FDR < 0.05). Higher levels of nine peptides and lower levels of eleven peptides were related to slower decline. A higher motor resilience protein score based on averaging the levels of all 20 peptides was related to slower motor decline, less severe parkinsonism and lower odds of mobility disability before death. Cortical proteins may provide motor resilience. Targeting these proteins in further drug discovery may yield novel interventions to maintain motor function in old age.

Long-term Intake of Gluten and Cognitive Function Among US Women.

Importance: Gluten avoidance has been suggested as having a benefit to cognitive health among the general population, given the link between gluten and cognitive impairment in patients with celiac disease. However, data are lacking in individuals without celiac disease. Objective: To examine whether gluten intake is associated with cognitive function in women without celiac disease. Design, Setting, and Participants: This cohort study included US women who participated in the longitudinal, population-based Nurses' Health Study II and had not previously or subsequently been diagnosed with celiac disease. Dietary data were collected from 1991 to 2015, and data on cognitive function were collected from 2014 to 2019. Data analysis was conducted from October 2020 to April 2021. Exposures: Energy-adjusted gluten intake, cumulatively averaged across questionnaire cycles prior to cognitive assessment. Main Outcomes and Measures: Three standardized cognitive scores assessed by the validated Cogstate Brief Battery: (1) psychomotor speed and attention score, (2) learning and working memory score, and (3) global cognition score. Higher scores indicated better performance. Results: The cohort included 13 494 women (mean [SD] age, 60.6 [4.6] years). The mean (SD) gluten intake was 6.3 (1.6) g/d. After controlling for demographic and lifestyle risk factors in linear regression, no significant differences in standardized cognitive scores (mean [SD], 0 [1]) by quintile of gluten intake were found across highest and lowest quintiles of gluten intake (psychomotor speed and attention: -0.02; 95% CI, -0.07 to 0.03; P for trend = .22; learning and working memory: 0.02; 95% CI, -0.03 to 0.07; P for trend = .30; global cognition: -0.002; 95% CI, -0.05 to 0.05; P for trend = .78). The null associations persisted after additional adjustment for major sources of dietary gluten (ie, refined grains or whole grains), comparing decile categories of gluten intake, using gluten intake updated at each previous questionnaire cycle, or modeling changes in gluten intake. Similarly, these associations were not materially altered in sensitivity analyses that excluded women who had reported cancer or dementia diagnosis or had not completed all dietary assessments. Conclusions and Relevance: In this study, long-term gluten intake was not associated with cognitive scores in middle-aged women without celiac disease. Our results do not support recommendations to restrict dietary gluten to maintain cognitive function in the absence of celiac disease or established gluten sensitivity.

Primary and Specialty Outpatient Visits for Older Women With Urinary Incontinence: A Comparison of Nurses to the General Population.

OBJECTIVE: We evaluated patterns of outpatient visits seen for urinary incontinence (UI) among women 65 years or older in the Nurses' Health Study and the general Medicare population. We were interested in understanding whether nurses, with high health literacy, may receive more care for UI than the general population. METHODS: Medicare Fee for Service claims data for women aged 66-91 years were compared for Nurses' Health Study participants (n = 3,213) and a propensity-matched sample from general Medicare Fee for Service beneficiaries (n = 3,213) with 1 or more outpatient evaluation and management visits for UI in 2012. We examined the mean number of outpatient visits for UI and the type of provider seen, using t tests and χ2 tests. Providers were categorized as specialist and nonspecialist providers using taxonomy codes. RESULTS: The percentage of women 65 years or older who had an outpatient visits for UI over 12 months was 6.4% in the Nurses' Health Study cohort and 5.4% in the general population. The mean number of office visits for UI in 2012 was similar between nurses and the matched general population (mean = 1.8 vs 1.8; P = 0.3). A small percentage of women saw both nonspecialists and specialists for UI (9.3% in the Nurses' Health Study and 10.0% in the Center for Medicare Services cohorts). CONCLUSIONS: We found that less than 7% of older women had outpatient evaluation of UI symptoms during a 12-month period, despite UI being very common in this age group. This was similar in nurses and the general population, suggesting that even high health care literacy does not increase UI care seeking.

Brief Preoperative Screening for Frailty and Cognitive Impairment Predicts Delirium after Spine Surgery.

BACKGROUND: Frailty and cognitive impairment are associated with postoperative delirium, but are rarely assessed preoperatively. The study was designed to test the hypothesis that preoperative screening for frailty or cognitive impairment identifies patients at risk for postoperative delirium (primary outcome). METHODS: In this prospective cohort study, the authors administered frailty and cognitive screening instruments to 229 patients greater than or equal to 70 yr old presenting for elective spine surgery. Screening for frailty (five-item FRAIL scale [measuring fatigue, resistance, ambulation, illness, and weight loss]) and cognition (Mini-Cog, Animal Verbal Fluency) were performed at the time of the preoperative evaluation. Demographic data, perioperative variables, and postoperative outcomes were gathered. Delirium was the primary outcome detected by either the Confusion Assessment Method, assessed daily from postoperative day 1 to 3 or until discharge, if patient was discharged sooner, or comprehensive chart review. Secondary outcomes were all other-cause complications, discharge not to home, and hospital length of stay. RESULTS: The cohort was 75 [73 to 79 yr] years of age, 124 of 219 (57%) were male. Many scored positive for prefrailty (117 of 218; 54%), frailty (53 of 218; 24%), and cognitive impairment (50 to 82 of 219; 23 to 37%). Fifty-five patients (25%) developed delirium postoperatively. On multivariable analysis, frailty (scores 3 to 5 [odds ratio, 6.6; 95% CI, 1.96 to 21.9; P = 0.002]) versus robust (score 0) on the FRAIL scale, lower animal fluency scores (odds ratio, 1.08; 95% CI, 1.01 to 1.51; P = 0.036) for each point decrease in the number of animals named, and more invasive surgical procedures (odds ratio, 2.69; 95% CI, 1.31 to 5.50; P = 0.007) versus less invasive procedures were associated with postoperative delirium. CONCLUSIONS: Screening for frailty and cognitive impairment preoperatively using the FRAIL scale and the Animal Verbal Fluency test in older elective spine surgery patients identifies those at high risk for the development of postoperative delirium.

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Long-Term Trajectories of Body Weight, Diet, and Physical Activity From Midlife Through Late Life and Subsequent Cognitive Decline in Women.

Healthy lifestyles are promising targets for prevention of cognitive aging, yet the optimal time windows for interventions remain unclear. We selected a case-control sample nested within the Nurses' Health Study (starting year 1976, mean age = 51 years), including 14,956 women aged ≥70 years who were free of both stroke and cognitive impairment at enrollment in a cognitive substudy (1995-2001). Cases (n = 1,496) were women with the 10% worst slopes of cognitive decline, and controls (n = 7,478) were those with slopes better than the median. We compared the trajectories of body mass index (weight (kg)/height (m)2), alternate Mediterranean diet (A-MeDi) score, and physical activity between groups, from midlife through 1 year preceding the cognitive substudy. In midlife, cases had higher body mass index than controls (mean difference (MD) = 0.59 units, 95% confidence interval (CI): 0.39, 0.80), lower physical activity (MD = -1.41 metabolic equivalent of task-hours/week, 95% CI: -2.07, -0.71), and worse A-MeDi scores (MD = -0.16 points, 95% CI: -0.26, -0.06). From midlife through later life, compared with controls, cases had consistently lower A-MeDi scores but a deceleration of weight gain and a faster decrease in physical activity. In conclusion, maintaining a healthy lifestyle since midlife may help reduce cognitive decline in aging. At older ages, both deceleration of weight gain and a decrease in physical activity may reflect early signs of cognitive impairment.

Prospective associations of happiness and optimism with lifestyle over up to two decades.

Greater levels of psychological well-being are associated with reduced disease and mortality risk, and lifestyle habits may be potential mechanisms underlying these relationships. Prospective studies show that positive psychological factors enhance the likelihood of adopting specific health behaviors; yet, whether they promote the adoption of multiple healthy behaviors, which can have a multiplicative effect on disease and mortality risk compared to individual behaviors, is unknown. We investigated whether happiness and optimism were related to a healthy lifestyle (characterized by multiple health behaviors) over 10-22 years of follow-up; we also explored bidirectional associations, assessing if a healthy lifestyle at baseline was related to greater likelihood of experiencing higher happiness and optimism over time. Women reported levels of happiness in 1992 (N = 52,133) and optimism in 2004 (N = 36,802). Health-related behaviors (physical activity, body mass index, diet, alcohol and tobacco consumption) were self-reported and combined into a lifestyle score, every four years from baseline until 2014. Multivariable generalized estimating equations with a Poisson distribution were used. Women with moderate and higher (versus lower) happiness levels were more likely to report sustaining healthy lifestyles (RR = 1.18, CI = 1.11-1.25; RR = 1.39, CI = 1.32-1.46, respectively). In secondary analyses, the magnitude of the inverse association was somewhat smaller (likelihood of sustaining higher happiness levels for baseline healthy versus unhealthy lifestyle, RR = 1.11, CI = 1.10-1.12). Results were similar when considering optimism as the exposure and in other secondary analyses (e.g., across individual habits). While bidirectional associations are apparent, these findings suggest pursuing happiness and optimism as modifiable determinants of lifestyle deserves further consideration.

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Outpatient Evaluation and Management Visits for Urinary Incontinence in Older Women.

PURPOSE: The aims of this investigation were to examine how often outpatient visits addressing urinary incontinence in women with self-reported incontinence symptoms occur and to explore characteristics associated with an outpatient visit for incontinence. MATERIALS AND METHODS: We studied the records of 18,576 women from the Nurses' Health Study who were 65 years old or older, reported prevalent incontinence symptoms in 2012 on a mailed questionnaire and were linked with Medicare utilization data. We compared demographic, personal and clinical characteristics in women with and without claims for outpatient visits for urinary incontinence. In logistic regression models we controlled for potential confounding factors, including age, race, parity, body mass index, medical comorbidities, smoking status, health seeking behavior, disability, physical function and geographic region. RESULTS: In this linkage between symptom report and insurance claims data we found that only 16% of older women with current incontinence symptoms also had an outpatient visit addressing incontinence in the prior 2 years. In multivariable adjusted models severe vs slight incontinence (OR 3.75, 95% CI 3.10-4.53) and urgency vs stress incontinence (OR 1.80, 95% CI 1.56-2.08) were the strongest predictors of undergoing outpatient evaluation. CONCLUSIONS: Overall only a small percent of women who report urinary incontinence symptoms also have medical outpatient visits for incontinence, which is a marker of care seeking. Our study highlights the discordance between the high prevalence of incontinence in older women and the lack of clinical assessment despite symptoms even among nurses with high health care literacy.

Comparison of treatment of early-stage breast cancer among Nurses' Health Study participants and other Medicare beneficiaries.

PURPOSE: Increasingly epidemiological cohorts are being linked to claims data to provide rich data for healthcare research. These cohorts tend to be different than the general United States (US) population. We will analyze healthcare utilization of Nurses' Health Study (NHS) participants to determine if studies of newly diagnosed incident early-stage breast cancer can be generalized to the broader US Medicare population. METHODS: Analytic cohorts of fee-for-service NHS-Medicare-linked participants and a 1:13 propensity-matched SEER-Medicare cohort (SEER) with incident breast cancer in the years 2007-2011 were considered. Screening leading to, treatment-related, and general utilization in the year following early-stage breast cancer diagnosis were determined using Medicare claims data. RESULTS: After propensity matching, NHS and SEER were statistically balanced on all demographics. NHS and SEER had statistically similar rates of treatments including chemotherapy, breast-conserving surgery, mastectomy, and overall radiation use. Rates of general utilization include those related to hospitalizations, total visits, and emergency department visits were also balanced between the two groups. Total spending in the year following diagnosis were statistically equivalent for NHS and SEER ($36,180 vs. $35,399, p = 0.70). CONCLUSIONS: NHS and the general female population had comparable treatment and utilization patterns following diagnosis of early-stage incident breast cancers with the exception of type of radiation therapy received. This study provides support for the larger value of population-based cohorts in research on healthcare costs and utilization in breast cancer.

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.