The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Characterizing the microbiome of patients with myeloproliferative neoplasms during a Mediterranean diet intervention.

Myeloproliferative neoplasms (MPNs) are a class of rare hematological malignancies that result in the overproduction of myeloid lineage cells. These malignancies result in increased cytokine production and inflammation, which correlate with worsened symptom burden and prognosis. Other than bone marrow transplantation, there is no cure for myeloproliferative neoplasms. As such, treatments focus on reducing thrombotic risk, inflammation, and symptom burden. Because current pharmacological treatments carry significant side effects, there is a need to explore low-risk therapies that may modulate inflammation and alleviate symptom burden. One potential way to achieve this is adherence to a Mediterranean (MED) diet, which is rich in anti-inflammatory foods, reduces inflammatory biomarkers, and beneficially alters the gut microbiome. We performed a 15-week clinical trial of 28 individuals with MPN who were randomized to dietary counseling based on either a Mediterranean diet or standard U.S. Guidelines for Americans. Our primary objective was to determine whether MPN patients could adopt a Mediterranean eating pattern when supported with dietician counseling. As exploratory endpoints, we investigated the impact of diet and inflammation on the gut microbiome. Using shotgun metagenomic sequencing, we found that microbiome diversity and composition were stable throughout the study duration in both cohorts. Furthermore, we discovered significant differences in the microbiomes between MPN subtypes, such as increased beta-dispersion in subjects with myelofibrosis. Lastly, we found several significant correlations between the abundance of multiple bacterial taxa and cytokine levels. Together, this study provides insight into the interaction between diet, inflammation, and the gut microbiome. IMPORTANCE The gut microbiome serves as an interface between the host and the diet. Diet and the gut microbiome both play important roles in managing inflammation, which is a key aspect of myeloproliferative neoplasm (MPN). Studies have shown that a Mediterranean (MED) diet can reduce inflammation. Therefore, we longitudinally characterized the gut microbiomes of MPN patients in response to Mediterranean or standard 2020 US Guidelines for Americans dietary counseling to determine whether there were microbiome-associated changes in inflammation. We did not find significant changes in the gut microbiome associated with diet, but we did find several associations with inflammation. This research paves the way for future studies by identifying potential mechanistic targets implicated in inflammation within the MPN gut microbiome.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase.

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients. Experimental Design: We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

Frequency of Consuming Breakfast Meals and After-Dinner Snacks Is not Associated with Postmenopausal Breast Cancer Risk: Women's Health Initiative Observational Study.

BACKGROUND: There has been little investigation into how the timing of meals and eating occasions associates with postmenopausal breast cancer risk. OBJECTIVE: We examined the association between the frequency of consuming breakfast meals and after-dinner snacks with the risk for postmenopausal breast cancer. METHODS: A prospective analysis of 74,825 postmenopausal women aged 49 to 81 y from the Women's Health Initiative Observational Study cohort. Breakfast and after-dinner snack intake were assessed at year 1 examination. Risk for invasive and in situ breast cancer diagnosed before 28 February 2020 was modeled with multivariable Cox proportional hazards regression models according to breakfast and after-dinner snack consumption frequencies. The models were adjusted for age, self-identified race/ethnicity, education, income, physical activity, smoking, alcohol intake, diet quality score (Healthy Eating Index 2015), energy intake, diabetic status, hormone therapy, and BMI. RESULTS: During the follow-up period, 5313 participants were diagnosed with invasive breast cancer and 1197 participants with in situ breast cancer. Compared with participants who did not eat breakfast, those with daily breakfast consumption was not associated with invasive breast cancer (HR: 1.04; 95% CI: 0.9, 1.19) nor in situ (HR: 1.25; 95% CI: 0.91, 1.74) breast cancer. There were monotonic higher point estimates of in situ breast cancer for each higher category of breakfast intake from 0 to 7 times per week (P-trend = 0.04, Wald test). Compared with consumption of daily after-dinner snacks, avoidance of after-dinner snacks was not associated with invasive breast cancer (HR: 0.97; 95% CI: 0.87, 1.08) nor in situ (HR: 1.12; 95% CI: 0.89, 1.42) breast cancer. CONCLUSIONS: There was no association between intake frequency of breakfast meals or after-dinner snack habits and with risk of breast cancer in postmenopausal women.

Longitudinal patterns of abdominal visceral and subcutaneous adipose tissue, total body composition, and anthropometric measures in postmenopausal women: Results from the Women's Health Initiative.

BACKGROUND: Abdominal adiposity, including visceral and subcutaneous abdominal adipose tissue (VAT and SAT), is recognized as a strong risk factor for cardiometabolic disease, cancer, and mortality. OBJECTIVE: The primary aim of this analysis is to describe longitudinal patterns of change in abdominal adipose tissue in postmenopausal women, overall and stratified by age, race/ethnicity, and years since menopause. METHODS: The data are from six years of follow up on 10,184 postmenopausal women (7828 non-Hispanic White women, 1423 non-Hispanic Black women, and 703 Hispanic women) who participated in the Women's Health Initiative (WHI). The WHI is a large prospective cohort study of postmenopausal women across the United States. All participants in this analysis had DXA scans in the 1990s as part of the WHI protocol. Hologic APEX software was used to re-analyze archived DXA scans and obtain measures of abdominal adipose tissue. Analyses examined differences in abdominal adipose tissue, overall adiposity, and anthropometric variables. RESULTS: There were important differences in VAT and SAT by age and race/ethnicity. In women <60 years, VAT increased over the follow-up period, while in women ≥70 years, VAT decreased. Non-Hispanic Black women had the highest levels of SAT. Hispanic women had the highest VAT levels. Women more than ten years since menopause had less SAT and more VAT than women less than ten years since menopause, resulting in a higher VAT/SAT ratio. There was a moderate to strong correlation between measures of abdominal adipose tissue and anthropometric measurements of body size. Still, there were substantial differences in the quantity of VAT and SAT within BMI and waist circumference categories. CONCLUSIONS: These results demonstrate differences in VAT and SAT according to age, race/ethnicity, time since menopause, and compared to standard measures of body composition in a large and diverse cohort of postmenopausal women.

Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women.

BACKGROUND: Glyphosate is the most commonly used herbicide in the world and is purported to have a variety of health effects, including endocrine disruption and an elevated risk of several types of cancer. Blood DNA methylation has been shown to be associated with many other environmental exposures, but to our knowledge, no studies to date have examined the association between blood DNA methylation and glyphosate exposure. OBJECTIVE: We conducted an epigenome-wide association study to identify DNA methylation loci associated with urinary glyphosate and its metabolite aminomethylphosphonic acid (AMPA) levels. Secondary goals were to determine the association of epigenetic age acceleration with glyphosate and AMPA and develop blood DNA methylation indices to predict urinary glyphosate and AMPA levels. METHODS: For 392 postmenopausal women, white blood cell DNA methylation was measured using the Illumina Infinium MethylationEPIC BeadChip array. Glyphosate and AMPA were measured in two urine samples per participant using liquid chromatography-tandem mass spectrometry. Methylation differences at the probe and regional level associated with glyphosate and AMPA levels were assessed using a resampling-based approach. Probes and regions that had an false discovery rate q<0.1 in ≥90% of 1,000 subsamples of the study population were considered differentially methylated. Differentially methylated sites from the probe-specific analysis were combined into a methylation index. Epigenetic age acceleration from three epigenetic clocks and an epigenetic measure of pace of aging were examined for associations with glyphosate and AMPA. RESULTS: We identified 24 CpG sites whose methylation level was associated with urinary glyphosate concentration and two associated with AMPA. Four regions, within the promoters of the MSH4, KCNA6, ABAT, and NDUFAF2/ERCC8 genes, were associated with glyphosate levels, along with an association between ESR1 promoter hypomethylation and AMPA. The methylation index accurately predicted glyphosate levels in an internal validation cohort. AMPA, but not glyphosate, was associated with greater epigenetic age acceleration. DISCUSSION: Glyphosate and AMPA exposure were associated with DNA methylation differences that could promote the development of cancer and other diseases. Further studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure. https://doi.org/10.1289/EHP10174.

Association of mammographic density with blood DNA methylation.

BACKGROUND: Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density. METHODS: White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings. RESULTS: On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, including HDLBP, TGFB2, CCT4, and PAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters of PAX8 and PF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density. CONCLUSION: Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.

Composite Score of Healthy Lifestyle Factors and Risk of Hepatocellular Carcinoma: Findings from a Prospective Cohort Study.

BACKGROUND: While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) have been described previously, their combined impact on HCC risk is unknown. METHODS: The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean diet, and sleep duration, and HCC risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese men and women. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI). Conditional logistic regression method was used to evaluate this composite lifestyle score-HCC risk association among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg) and anti-hepatitis C antibody. RESULTS: After a mean follow-up of 17.7 years, 561 participants developed HCC. Individuals with higher composite scores representing healthier lifestyles (range 0-8) were at significantly lower risk of HCC. Compared with the lowest composite score category (0-4), the HRs (95% CIs) for the composite scores of 5, 6, 7, and 8 were 0.67 (0.62-0.85), 0.61 (0.48-0.77), 0.49 (0.37-0.65), and 0.13 (0.06-0.30), respectively (P trend < 0.0001). A similar inverse association was observed in participants with negative HBsAg and anti-hepatitis C virus (HCV)-negative serology (HR, 0.38; 95% CI, 0.19-0.79; for the highest vs. the lowest category of the composite scores; P trend = 0.001). CONCLUSIONS: Healthy lifestyles protect against HCC development, especially for individuals without hepatitis B virus and HCV infections. IMPACT: This study highlights the importance of a comprehensive lifestyle modification strategy for HCC primary prevention.

Multi-Systemic Biological Risk and Cancer Mortality: The NHANES III Study.

Multi-systemic biological risk (MSBR), a proxy for allostatic load, is a composite index of biomarkers representing dysregulation due to responses to chronic stress. This study examined the association of an MSBR index with cancer mortality. The sample included n = 13,628 adults aged 20-90 from the NHANES III Linked Mortality File (1988-1994). The MSBR index included autonomic (pulse rate, blood pressure), metabolic (HOMAir, triglycerides, waist circumference), and immune (white blood cell count, C-reactive protein) markers. We fit Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of overall cancer mortality risk, according to quartiles (q) of the index. In multivariable models, compared to those in q1, q4 had a 64% increased risk for cancer mortality (HR = 1.64, 95% CI:1.13-2.40). The immune domain drove the association (HR per unit = 1.19, 95% CI:1.07-1.32). In stratified analyses, the HR for those with a BMI ≥ 25 was 1.12 per unit (95% CI:1.05-1.19) and those with a BMI < 25 was 1.04 per unit (95% CI:0.92-1.18). MSBR is positively associated with risk for cancer mortality in a US sample, particularly among those who are overweight or obese. The utilization of standard clinical measures comprising this index may inform population cancer prevention strategies.

The Association of Serum Carotenoids, Tocopherols, and Ascorbic Acid With Rapid Kidney Function Decline: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVE: Nutritional intervention targeting dietary intake modification is a major component of treatment for chronic kidney disease; however, little is known about the relationship between dietary intake and kidney function decline in individuals with preserved kidney function. DESIGN AND METHODS: In this prospective cohort study we examined the association of biomarkers of dietary intake with kidney function decline over a 5-year interval in 2,152 men and women with cystatin-C-based estimated glomerular filtration rate > 60 mL/minute/1.73 m2 from the Coronary Artery Risk Development in Young Adults study. The biomarkers of interest included carotenoids, tocopherols, and ascorbic acid. Multivariable logistic regression was used to explore the relationship between serum concentrations of the sum of 4 carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, and lutein/zeaxanthin), lycopene, α-tocopherol, γ-tocopherol, and ascorbic acid and rapid kidney function decline, defined as .15% decline in cystatin-C-based estimated glomerular filtration rate over 5 years. RESULTS: During the 5-year follow-up, 290 participants (13.5%) experienced rapid kidney function decline. Relative to individuals in the lowest quartile of serum carotenoids, those in the highest quartile had significantly lower odds of rapid kidney function decline in the fully adjusted model (odds ratio, 0.51; 95% confidence interval [CI], 0.32-0.80; P trend, .02). No association of levels of serum tocopherols, ascorbic acid, or lycopene with kidney function decline was found. There was no evidence that results differed for individuals with hypertension or diabetes. CONCLUSIONS: These results demonstrate that higher serum carotenoid levels, reflective of a fruit- and vegetable-rich dietary pattern, inversely associate with rapid kidney function decline in early middle adulthood and provide insight into how diet might play a role in chronic kidney disease prevention.

Comparative Effectiveness and Safety of Bariatric Procedures for Weight Loss: A PCORnet Cohort Study.

Background: There has been a dramatic shift in use of bariatric procedures, but little is known about their long-term comparative effectiveness. Objective: To compare weight loss and safety among bariatric procedures. Design: Retrospective observational cohort study, January 2005 to September 2015. (ClinicalTrials.gov: NCT02741674). Setting: 41 health systems in the National Patient-Centered Clinical Research Network. Participants: 65 093 patients aged 20 to 79 years with body mass index (BMI) of 35 kg/m2 or greater who had bariatric procedures. Intervention: 32 208 Roux-en-Y gastric bypass (RYGB), 29 693 sleeve gastrectomy (SG), and 3192 adjustable gastric banding (AGB) procedures. Measurements: Estimated percent total weight loss (TWL) at 1, 3, and 5 years; 30-day rates of major adverse events. Results: Total numbers of eligible patients with weight measures at 1, 3, and 5 years were 44 978 (84%), 20 783 (68%), and 7159 (69%), respectively. Thirty-day rates of major adverse events were 5.0% for RYGB, 2.6% for SG, and 2.9% for AGB. One-year mean TWLs were 31.2% (95% CI, 31.1% to 31.3%) for RYGB, 25.2% (CI, 25.1% to 25.4%) for SG, and 13.7% (CI, 13.3% to 14.0%) for AGB. At 1 year, RYGB patients lost 5.9 (CI, 5.8 to 6.1) percentage points more weight than SG patients and 17.7 (CI, 17.3 to 18.1) percentage points more than AGB patients, and SG patients lost 12.0 (CI, 11.6 to 12.5) percentage points more than AGB patients. Five-year mean TWLs were 25.5% (CI, 25.1% to 25.9%) for RYGB, 18.8% (CI, 18.0% to 19.6%) for SG, and 11.7% (CI, 10.2% to 13.1%) for AGB. Patients with diabetes, those with BMI less than 50 kg/m2, those aged 65 years or older, African American patients, and Hispanic patients lost less weight than patients without those characteristics. Limitation: Potential unobserved confounding due to nonrandomized design; electronic health record databases had missing outcome data. Conclusion: Adults lost more weight with RYGB than with SG or AGB at 1, 3, and 5 years; however, RYGB had the highest 30-day rate of major adverse events. Small subgroup differences in weight loss outcomes were observed. Primary Funding Source: Patient-Centered Outcomes Research Institute.

Diet Quality Scores Inversely Associated with Postmenopausal Breast Cancer Risk Are Not Associated with Premenopausal Breast Cancer Risk in the California Teachers Study.

Background: Evidence for the association between diet and breast cancer risk is inconsistent Thus, research that compares indexes of overall diet quality may provide new insight. Objective: We examined the association between diet quality indexes and pre- and postmenopausal breast cancer risk in a large prospective cohort. Methods: This was a prospective analysis of 96,959 women, aged 22-104 y, in the California Teachers Study cohort (1995-2011). Diet quality was characterized by 4 different indexes. Specifically, we examined Alternate Mediterranean Diet (aMED), Alternative Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), and Paleolithic index (PALEO) scores with the risk of developing breast cancer. We used multivariable Cox proportional hazards regression models to derive HRs and 95% CIs for breast cancer risk. Results: In the analysis of 42,517 women at risk of premenopausal breast cancer, there was no association between any of the indexes and incident breast cancer (346 cases). In the analysis of 54,442 women at risk of postmenopausal breast cancer at baseline, higher AHEI-2010, aMED, and DASH scores were inversely associated with incident breast cancer (3523 incident cases). Respectively, HRs (95% CIs) comparing quintile 5 to quintile 1 (reference) for AHEI-2010, aMED, and DASH indexes were 0.87 (0.78, 0.97; P-trend = 0.004), 0.91 (0.82, 1.02; P-trend = 0.03), and 0.89 (0.80, 1.00; P-trend = 0.03). The PALEO score was not associated with postmenopausal breast cancer (HR for quintile 5 compared with quintile 1: 1.05; 95% CI: 0.94, 1.17). Conclusions: Diet quality indexes that emphasize intake of whole grains, vegetables, fruits, legumes, and nuts and seeds and de-emphasize red and processed meats and sugar-sweetened beverages were modestly associated with a lower risk of incident postmenopausal breast cancer risk. However, they were not associated with premenopausal breast cancer, and the PALEO score was not associated with cancer risk regardless of menopausal status.

Occupational exposure to endocrine disrupting substances and the risk of breast Cancer: the Singapore Chinese health study.

BACKGROUND: Evidence from basic research links exposure to endocrine disrupting chemicals (EDCs) with a higher risk for breast cancer. However, there is less evidence from observational epidemiological research and the results are equivocal. Therefore, we examined the association between occupational exposure to substances where exposure to EDCs is likely and the risk of breast cancer. METHODS: A prospective study consisting of a population-based cohort of 33,458 Singaporean Chinese women aged 45-74 years enrolled in the Singapore Chinese Health Study (SCHS) from 1993 to 98 and followed through 2014. Subjects' self-reported occupational exposure and duration to industries, job titles, and substance types were garnered at baseline, and cases of incident breast cancer (N = 988) were determined by linkage with the Singapore Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for exposure to substances, job titles, and industries. RESULTS: There was no association between cumulative exposure to substances via occupation where EDC exposure is likely and risk of breast cancer. These results were consistent for hypothesized high (HR 0.94, 95% CI: 0.66-1.35), medium (HR 1.03 95% CI: 0.77-1.38) and low (HR 0.74, 95% CI 0.48-1.13) combined substance exposure groups when compared with those who were not exposed via occupation. Similar null associations were observed when examining job titles and industry categories. CONCLUSIONS: There was no association between EDC related occupational exposures and breast cancer risk in working women of the Singaporean Chinese Health Study. Future studies that employ rigorous methods with regard to exposure assessment of EDCs are needed.

Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women.

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes and homeostasis model-insulin resistance (HOMA-IR-a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0 and ≥30.0 kg/m2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis.

Circulating Cellular Adhesion Molecules and Cognitive Function: The Coronary Artery Risk Development in Young Adults Study.

OBJECTIVE: Higher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance. METHOD: Within the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992-1993, ages 25-37) and N = 2,848 in CARDIA year 15 (2000-2001, ages 33-45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010-2011, ages 43-55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function). RESULT: All CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p ≤ 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings. CONCLUSION: Higher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short-term memory, speed of processing, and executive function.

Twenty year fitness trends in young adults and incidence of prediabetes and diabetes: the CARDIA study.

AIMS/HYPOTHESIS: The prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age. METHODS: Participants were from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free from prediabetes/diabetes at baseline (year 0 [Y0]: 1985-1986). CRF was quantified by treadmill duration (converted to metabolic equivalents [METs]) at Y0, Y7 and Y20 and prediabetes/diabetes status was assessed at Y0, Y7, Y10, Y15, Y20 and Y25. We use an extended Cox model with CRF as the primary time-varying exposure. BMI was included as a time-varying covariate. The outcome was development of either prediabetes or diabetes after Y0. Model 1 included age, race, sex, field centre, CRF and BMI. Model 2 additionally included baseline (Y0) smoking, energy intake, alcohol intake, education, systolic BP, BP medication use and lipid profile. RESULTS: Higher fitness was associated with lower risk for developing incident prediabetes/diabetes (difference of 1 MET: HR 0.99898 [95% CI 0.99861, 0.99940], p < 0.01), which persisted (difference of 1 MET: HR 0.99872 [95% CI 0.99840, 0.99904], p < 0.01] when adjusting for covariates. CONCLUSIONS/INTERPRETATION: Examining participants who had fitness measured from young adulthood to middle age, we found that fitness was associated with lower risk for developing prediabetes/diabetes, even when adjusting for BMI over this time period. These findings emphasise the importance of fitness in reducing the health burden of prediabetes and diabetes.

Glycated hemoglobin and incident type 2 diabetes in singaporean chinese adults: the Singapore Chinese health study.

BACKGROUND: The American Diabetes Association recently included glycated hemoglobin in the diagnostic criteria for diabetes, but research on the utility of this biomarker in Southeast Asians is scant. The aim of this study was to evaluate the association between percent HbA1c and incident diabetes in an Asian population of adult men and women without reported diabetes. METHODS: Data analysis of 5,770 men and women enrolled in the Singapore Chinese Health Study who provided a blood sample at the follow-up I visit (1999-2004) and had no cancer and no reported history of diabetes or cardiovascular disease events. Diabetes was defined as self-report of physician diagnosis, identified at the follow-up II visit (2006-2010). RESULTS: Hazard ratios (and 95% confidence intervals) for incident diabetes by 5 categories of HbA1c were estimated with Cox regression models and continuous HbA1c with cubic spline analysis. Compared to individuals with an HbA1c ≤ 5.7% (≤39 mmol/mol), individuals with HbA1c 5.8-5.9% (40-41 mmol/mol), 6.0-6.1% (42-43 mmol/mol), 6.2-6.4% (44-47 mmol/mol), and ≥ 6.5% (≥48 mmol/mol) had significantly increased risk for incident diabetes during follow-up. In cubic spline analysis, levels below 5.7% HbA1c were not significantly associated with incident diabetes. CONCLUSIONS: Our study found a strong and graded association with HbA1c 5.8% and above with incident diabetes in Chinese men and women.

Beverage habits and mortality in Chinese adults.

BACKGROUND: There is limited research examining beverage habits, one of the most habitual dietary behaviors, with mortality risk. OBJECTIVE: This study examined the association between coffee, black and green tea, sugar-sweetened beverages (soft drinks and juice), and alcohol and all-cause and cause-specific mortality. METHODS: A prospective data analysis was conducted with the use of the Singapore Chinese Health Study, including 52,584 Chinese men and women (aged 45-74 y) free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. Beverages were examined with all-cause and cause-specific (cancer, CVD, and respiratory disease) mortality risk with the use of Cox proportional hazards regression. RESULTS: The associations between coffee, black tea, and alcohol intake and all-cause mortality were modified by smoking status. Among never-smokers there was an inverse dose-response association between higher amounts of coffee and black tea intake and all-cause, respiratory-related, and CVD mortality (black tea only). The fully adjusted HRs for all-cause mortality for coffee for <1/d, 1/d, and ≥2/d relative to no coffee intake were 0.89, 0.86, and 0.83, respectively (P-trend = 0.0003). For the same black tea categories the HRs were 0.95, 0.90, and 0.72, respectively (P-trend = 0.0005). Among ever-smokers there was no association between coffee or black tea and the outcomes. Relative to no alcohol, light to moderate intake was inversely associated with all-cause mortality (HR: 0.87; 95% CI: 0.79, 0.96) in never-smokers with a similar magnitude of association in ever-smokers. There was no association between heavy alcohol intake and all-cause mortality in never-smokers and a strong positive association in ever-smokers (HR: 1.56; 95% CI: 1.40, 1.74). Green tea and sugar-sweetened beverages were not associated with all-cause or cause-specific mortality. CONCLUSIONS: Higher coffee and black tea intake was inversely associated with mortality in never-smokers, light to moderate alcohol intake was inversely associated with mortality regardless of smoking status, heavy alcohol intake was positively associated with mortality in ever-smokers, and there was no association between sugar-sweetened beverages and green tea and mortality.

Glycated hemoglobin and all-cause and cause-specific mortality in Singaporean Chinese without diagnosed diabetes: the Singapore Chinese Health Study.

OBJECTIVE: Glycated hemoglobin (HbA1c) is a robust biomarker of the preceding 2 to 3 months average blood glucose level. The aim of this study was to examine the association between HbA1c and mortality in a cohort of Southeast Asians. RESEARCH DESIGN AND METHODS: Analysis of 7,388 men and women, mean age 62 years, from the Singapore Chinese Health Study who provided a blood sample at the follow-up I visit (1999-2004) and reported no history of diabetes, previous adverse cardiovascular events, or cancer. A total of 888 deaths were identified through 31 December 2011 via registry linkage. Participants represented a random study sample of potential control subjects for a nested case-control genome-wide association study of type 2 diabetes in the population. Hazard ratios (HRs) for all-cause and cause-specific mortality by six categories of HbA1c were estimated with Cox regression models. RESULTS: Relative to participants with an HbA1c of 5.4-5.6% (36-38 mmol/mol), participants with HbA1c ≥6.5% (≥48 mmol/mol) had an increased risk of all-cause, cardiovascular, and cancer mortality during an average of 10.1 years of follow-up; HRs (95% CIs) were 1.96 (1.56-2.46), 2.63 (1.77-3.90), and 1.51 (1.04-2.18), respectively. No level of HbA1c was associated with increased risk of respiratory mortality. Levels <6.5% HbA1c were not associated with mortality during follow-up. The results did not materially change after excluding observation of first 3 years post-blood draw. CONCLUSIONS: HbA1c levels consistent with undiagnosed type 2 diabetes (≥6.5%) are associated with an increased risk of all-cause and cause-specific mortality in Chinese men and women.

Dietary patterns and mortality in a Chinese population.

BACKGROUND: Limited research has examined the association between dietary patterns and mortality, especially in non-Western populations. OBJECTIVE: We examined the association of dietary patterns with all-cause mortality and cause-specific mortality in the Singapore Chinese Health Study, which included a unique ethnic population with strong Western and South Asian cultural influences. DESIGN: We conducted a prospective data analysis of the Singapore Chinese Health Study, which included 52,584 Chinese men and women (aged 45-74 y) who were free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. The following 2 major dietary patterns were identified by using a principal components analysis: a vegetable-, fruit-, and soy-rich (VFS) pattern and a dim sum- and meat-rich (DSM) dietary pattern. Pattern scores for each participant were calculated and examined with all-cause and cause-specific mortality risks by using a Cox proportional hazards regression. RESULTS: The VFS pattern was inversely associated with all-cause mortality and each cause-specific category (CVD, cancer, and respiratory) of mortality during the follow-up period. Compared with the lowest quintile of the VFS pattern, HRs for quintiles 2-5 for all-cause mortality were 0.90, 0.79, 0.80, and 0.75, respectively (P-trend < 0.0001). The DSM pattern was positively associated with CVD mortality in the whole population (HR for fifth quintile compared with first quintile: 1.23; 95% CI: 1.07, 1.40; P-trend = 0.001). Positive associations between the DSM pattern and cancer and all-cause mortality were only present in ever-smokers. In ever-smokers, relative to the first quintile, HRs for quintiles 2-5 of the DSM pattern for all-cause mortality were 1.04, 1.04, 1.13, and 1.24, respectively (P-trend < 0.0001). Similarly, HRs for quintiles 2-5 for cancer mortality were 1.08, 1.03, 1.25, and 1.34, respectively (P-trend < 0.0001). The DSM pattern was not associated with respiratory mortality. CONCLUSION: Dietary patterns are strongly associated with mortality in Chinese Singaporeans.