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Introduction: Albuminuria, an early marker of kidney damage, is a risk factor for chronic kidney disease (CKD) progression, cardiovascular disease (CVD), and death. Dietary sodium is a risk factor for elevated blood pressure, CVD, and all cause-mortality. It is particularly important in patients with CKD due to increased salt-sensitivity. It is unclear if dietary sodium reduction is associated with reduced albuminuria. Hypothesis: A low sodium diet will reduce albuminuria in patients with CKD. Methods: The Sodium Lowering and Urinary Protein Reduction (SUPER) Trial was a randomized, parallel trial testing the effect of a 24-week dietary sodium reduction intervention compared to usual diet on albuminuria in 151 CKD patients with albuminuria. Participants were eligible if they had an estimated glomerular filtration rate (eGFR) of 30-90 mL/min/1.73 m 2 and an albumin-to-creatinine ratio (ACR) of 30-1,500 mg/g. Intervention group participants received a dietician-led behavioral change intervention targeting sodium intake Results: Study participants were an average of 65.6 years old, 72% African American, and 48% women. Median baseline ACR was 180.3 mg/g in the intervention and 157.4 mg/g in the control group, respectively. Urinary sodium excretion was reduced by 15.5% and 0.0% in the intervention and control groups, respectively. Results for the primary and key secondary outcomes are presented in the Table. Conclusions: The dietician-led dietary sodium reduction intervention succeeded in significantly reducing dietary sodium and BP in patients with CKD and albuminuria. However, no significant differences were observed in ACR, albuminuria, or eGFR between treatment groups.

Introduction: Low-carbohydrate diets lead to weight loss and improvement in hemoglobin A1c and other cardiometabolic outcomes. However, there is limited research on how much of the glycemic effects of low-carbohydrate diets are mediated by weight loss. Hypothesis: The effect of a low-carbohydrate dietary intervention on hemoglobin A1c would be mediated by weight loss. Methods: We conducted a 6-month randomized clinical trial on the effects of a low-carbohydrate diet intervention (target Results: 150 participants (mean [SD] age 59 [8] years; 108 [72%] female; 88 [59%] Black) were randomized to either the low-carbohydrate diet intervention (75 participants) or usual diet (75 participants) arm. Mean (SD) HbA1c was 6.16% (0.30%) at baseline. Six-month data was collected on 142 participants (95%). Compared with the usual diet arm, the low-carbohydrate diet intervention arm had significantly greater 6-month reduction in HbA1c (net difference, -0.23% [95% CI, -0.32 to -0.14%]) and body weight (-5.9 kg [95% CI, -7.4 to -4.4 kg]). In mediation analyses, 59% of the total effect of intervention on 6-month change in hemoglobin A1c was mediated by weight measured at 3 months (Table). Conclusions: In mediation analyses, a substantial proportion (59%) of the total effect of intervention on 6-month change in hemoglobin A1c was mediated through weight measured at 3 months. Future research should further explore contributions of weight loss to reductions in glycemia in other populations.

Background: Low-carbohydrate diets decrease hemoglobin A1c among patients with type 2 diabetes mellitus. However, evidence on effects of low-carbohydrate diets on hemoglobin A1c among individuals with prediabetes is limited. Methods: We conducted a randomized parallel-group trial of 150 adults aged 40-70 years with untreated hemoglobin A1c from 6.0-6.9%. Participants were assigned to a healthy low-carbohydrate diet (target Results: Mean age was 59 years; 72% were female and 59% were Black. 95% completed the study. Participants in the low-carbohydrate arm had significantly greater 6-month decrease in hemoglobin A1c (net difference, -0.23% [95% CI, -0.32 to -0.14%]) , fasting plasma glucose (net difference, -10.3 mg/dL [95% CI, -15.7 to -4.9 mg/dL]) , and body weight (net difference, -5.9 kg [95% CI, -7.2 to -4.7 kg]) compared with usual diet arm. At 6 months, 53% in the low-carbohydrate arm and 32% in the usual diet arm had hemoglobin A1c Conclusion: A healthy low-carbohydrate diet led to improvements in glycemic and other cardiometabolic outcomes in adults with elevated hemoglobin A1c and could be recommended for prevention of type 2 diabetes mellitus. Disclosure K.S.Dorans: None. M.J.O'brien: None. G.I.Uwaifo: None. J.He: None. L.A.Bazzano: None. L.Qi: None. H.He: None. J.Chen: None. L.J.Appel: n/a. F.Hu: None. J.Samet: None. K.T.Mills: None. Funding National Institute of General Medical Sciences (1P20GM109036-01A1) . The California Walnut Commission (Folsom, CA) supported the study by providing walnuts. Shakes and bars were donated by The Simply Good Foods Company (Denver, CO) . Sugar replacement samples were provided by Swerve LLC (New Orleans, LA) .

BACKGROUND: Chronic kidney disease (CKD) is associated with anxiety and depression. Although the coronavirus disease 2019 (COVID-19) pandemic has increased stressors on patients with CKD, assessments of anxiety and its predictors and consequences on behaviors, specifically virus mitigation behaviors, are lacking. METHODS: From June to October 2020, we administered a survey to 1873 patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, asking participants about anxiety related to the COVID-19 pandemic. We examined associations between anxiety and participant demographics, clinical indexes, and health literacy and whether anxiety was associated with health-related behaviors and COVID-19 mitigation behaviors. RESULTS: The mean age of the study population was 70 years (SD=9.6 years), 47% were women, 39% were Black non-Hispanic, 14% were Hispanic, and 38% had a history of cardiovascular disease. In adjusted analyses, younger age, being a woman, Hispanic ethnicity, cardiovascular disease, household income

IMPORTANCE: After decades of decline, the US cardiovascular disease mortality rate flattened after 2010, and racial and ethnic differences in cardiovascular disease mortality persisted. OBJECTIVE: To examine 20-year trends in cardiovascular risk factors in the US population by race and ethnicity and by socioeconomic status. DESIGN, SETTING, AND PARTICIPANTS: A total of 50 571 participants aged 20 years or older from the 1999-2018 National Health and Nutrition Examination Surveys, a series of cross-sectional surveys in nationally representative samples of the US population, were included. EXPOSURES: Calendar year, race and ethnicity, education, and family income. MAIN OUTCOMES AND MEASURES: Age- and sex-adjusted means or proportions of cardiovascular risk factors and estimated 10-year risk of atherosclerotic cardiovascular disease were calculated for each of 10 two-year cycles. RESULTS: The mean age of participants ranged from 49.0 to 51.8 years and the proportion of women from 48.2% to 51.3% in the surveys. From 1999-2000 to 2017-2018, age- and sex-adjusted mean body mass index increased from 28.0 (95% CI, 27.5-28.5) to 29.8 (95% CI, 29.2-30.4); mean hemoglobin A(1c) increased from 5.4% (95% CI, 5.3%-5.5%) to 5.7% (95% CI, 5.6%-5.7%) (both P

ImportanceLow-carbohydrate diets decrease hemoglobin A1c (HbA1c) among patients with type 2 diabetes at least as much as low-fat diets. However, evidence on the effects of low-carbohydrate diets on HbA1c among individuals with HbA1c in the range of prediabetes to diabetes not treated by diabetes medications is limited.ObjectiveTo study the effect of a behavioral intervention promoting a low-carbohydrate diet compared with usual diet on 6-month changes in HbA1c among individuals with elevated untreated HbA1c.Design, Setting, and ParticipantsThis 6-month randomized clinical trial with 2 parallel groups was conducted from September 2018 to June 2021 at an academic medical center in New Orleans, Louisiana. Laboratory analysts were blinded to assignment. Participants were aged 40 to 70 years with untreated HbA1c of 6.0% to 6.9% (42-52 mmol/mol). Data analysis was performed from November 2021 to September 2022.InterventionsParticipants were randomized to a low-carbohydrate diet intervention (target Main Outcomes and MeasuresSix-month change in HbA1c was the primary outcome. Outcomes were measured at 0, 3, and 6 months.ResultsOf 2722 prescreened participants, 962 underwent screening, and 150 were enrolled (mean [SD] age, 58.9 [7.9] years; 108 women [72%]; 88 Black participants [59%]) and randomized to either the low-carbohydrate diet intervention (75 participants) or usual diet (75 participants) group. Six-month data were collected on 142 participants (95%). Mean (SD) HbA1c was 6.16% (0.30%) at baseline. Compared with the usual diet group, the low-carbohydrate diet intervention group had significantly greater 6-month reductions in HbA1c (net difference, –0.23%; 95% CI, –0.32% to –0.14%; P P P Conclusions and RelevanceIn this randomized clinical trial, a low-carbohydrate dietary intervention led to improvements in glycemia in individuals with elevated HbA1c not taking glucose-lowering medication, but the study was unable to evaluate its effects independently of weight loss. This diet, if sustained, might be a useful dietary approach for preventing and treating type 2 diabetes, but more research is needed.Trial RegistrationClinicalTrials.gov Identifier: NCT03675360

Habitat and water quality restoration projects are commonly used to enhance coastal resources or mitigate negative impacts of water quality stressors. Significant resources have been expended for restoration projects, yet much less attention has focused on evaluating broad regional outcomes beyond site-specific assessments. This study presents an empirical framework to evaluate multiple datasets in the Tampa Bay area (Florida, USA) to identify 1) the types of restoration projects that have produced the greatest improvements in water quality, and 2) over which time frames different projects may produce water quality benefits. Information on the location and date of completion of 887 restoration projects from 1971 to 2017 were spatially and temporally matched with water quality records at each of 45 long-term monitoring stations in Tampa Bay. The underlying assumption was that the developed framework could identify differences in water quality changes between types of restoration projects based on aggregate estimates of chlorophyll-a concentrations before and after the completion of one to many projects. Water infrastructure projects to control point source nutrient loading into the Bay were associated with the highest likelihood of chlorophyll-a reduction, particularly for projects occurring prior to 1995. Habitat restoration projects were also associated with reductions in chlorophyll-a, although the likelihood of reductions from the cumulative effects of these projects were less than those from infrastructure improvements alone. The framework is sufficiently flexible for application to different spatiotemporal contexts and could be used to develop reasonable expectations for implementation of future water quality restoration activities throughout the Gulf of Mexico.

Background Short-term exposure to air pollution has been associated with cardiovascular events, potentially by promoting endothelial cell activation and inflammation. A few large-scale studies have examined the associations and have had mixed results. Methods We included 3820 non-current smoking participants (mean age 56 years, 54% women) from the Framingham Offspring cohort examinations 7 (1998–2001) and 8 (2005–2008), and Third Generation cohort examination 1 (2002–2005), who lived within 50 km of a central monitoring station. We calculated the 1- to 7-day moving averages of fine particulate matter (PM2.5), black carbon (BC), sulfate (SO42-), nitrogen oxides (NOx), and ozone before examination visits. We used linear mixed effect models for P-selectin, monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1, lipoprotein-associated phospholipase A2 activity and mass, and osteoprotegerin that were measured up to twice, and linear regression models for CD40 ligand and interleukin-18 that were measured once, adjusting for demographics, life style and clinical factors, socioeconomic position, time, and meteorology. Results We found negative associations of PM2.5 and BC with P-selectin, of ozone with MCP-1, and of SO42- and NOx with osteoprotegerin. At the 5-day moving average, a 5 µg/m3 higher PM2.5 was associated with 1.6% (95% CI: − 2.8, − 0.3) lower levels of P-selectin; a 10 ppb higher ozone was associated with 1.7% (95% CI: − 3.2, − 0.1) lower levels of MCP-1; and a 20 ppb higher NOx was associated with 2.0% (95% CI: − 3.6, − 0.4) lower levels of osteoprotegerin. Conclusions We did not find evidence of positive associations between short-term air pollution exposure and endothelial cell activation. On the contrary, short-term exposure to higher levels of ambient pollutants were associated with lower levels of P-selectin, MCP-1, and osteoprotegerin in the Framingham Heart Study.

Background: In the US Diabetes Prevention Program (DPP) trial, a lifestyle intervention program focused on changes in diet and physical activity led to a 58% reduction in risk of developing type 2 diabetes. A variety of modifications to the DPP have been tested in clinical trials. We sought to compare the effects of different strategies for implementation of the US DPP on weight and other cardiometabolic outcomes. Methods: We conducted systematic searches of MEDLINE and Embase from January 2002 to August 2020. We included randomized controlled trials of adults that tested the effect of an intervention based on the US DPP on change in weight. Studies of at least 6 months duration were included. Two investigators independently extracted data. DPP implementation strategies were classified into eight different categories. Results: A total of 30 comparisons from 28 articles with 8,284 participants were included. Different strategies for implementing the DPP led to significant decreases in change in weight in the DPP compared with control arms during follow-up (Table). These strategies included intervention delivery through group sessions or combination of group and individual sessions. Additionally, interventions delivered by telehealth or by a combination of in-person and telehealth were effective. Conclusion: A number of different strategies for implementing the DPP lead to clinically meaningful decreases in weight. Disclosure K. S. Dorans: None. K. T. Mills: None. Y. Feng: None. A. A. Sethi: None. X. Li: None. J. He: None. Funding National Institute of General Medical Sciences (1P20GM109036-01A1)

Introduction: A significant proportion of persons with metabolic syndrome, prediabetes, or type 2 diabetes do not develop atherosclerotic cardiovascular disease (ASCVD). Discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-cholesterol (LDL-C) may help to explain underlying heterogeneity in ASCVD risk among these individuals. Hypothesis: We hypothesized that discordantly normal ApoB (> 100 mg/dL) would be associated with a lower atherosclerosis burden among individuals with metabolic disorders. Methods: There were 331 Bogalusa Heart Study participants with metabolic syndrome (n=107), prediabetes (n=291), or type 2 diabetes (n=34) and LDL-C > 100 who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Carotid plaque was defined as a focal wall thickening >1.5 mm. Modified Poisson regression with robust error variance estimated the long-term absence of plaque for normal ApoB after adjusting for established risk factors. Results: Participants were on average 36.3 years old at baseline, 202 (61.0%) were women, and 93 (29.9%) were African American. Overall, LDL-C explained 42.3% of the variability in ApoB as the lipoprotein markers were only modestly correlated (r=0.65). Participants with ApoB > 90 (74.6% versus 57.4%, p=0.001, Figure ). In multivariable modeling, persons with ApoB Conclusions: More than half of persons with metabolic disorders and elevated LDL-C had normal ApoB with a lower burden of carotid atherosclerosis over 13 years follow-up. ApoB better represents the atherogenic lipid burden among persons with metabolic disorders compared to LDL-C and may be especially helpful for persons with the pattern of high triglycerides and low HDL-cholesterol.

BACKGROUND AND AIMS: Women with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM. METHODS AND RESULTS: Using data from the National Health and Nutrition Examination Survey (NHANES) from 2007–2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history. CONCLUSION: Among parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.

Background Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally. Strong evidence supports the importance of diet and other lifestyle factors in preventing T2DM. Among individuals with T2DM, low-carbohydrate diets lead to decreases in hemoglobin A1c (HbA1c). However, research on the effects of low-carbohydrate diets on glycemic outcomes among individuals not currently on glucose-lowering medications who have elevated HbA1c is limited. Methods The objective of this randomized controlled trial is to study the effect of a healthy low-carbohydrate diet achieved through behavioral intervention and key food supplementation compared with usual diet on HbA1c and other metabolic risk factors among individuals with HbA1c from 6.0 to 6.9% who are not on glucose-lowering medications. In this parallel trial, 150 participants will be randomized to the intervention or control group for 6 months. The healthy low-carbohydrate diet target is Discussion We expect that the results from this study will lead to new approaches for developing and implementing dietary approaches (other than the most commonly used reduced fat diet) that will substantially reduce risk of cardiometabolic disease among adults with or at high risk of T2DM. The study intervention involves behavioral counseling and promotes consumption of dietary components thought to reduce risk of cardiometabolic disease and has expected applicability in clinical practice. Trial registration ClinicalTrials.gov NCT03675360. Registered on September 18, 2018 (prior to enrolment of the first participant).

Background Patients with chronic kidney disease (CKD) have an increased risk of peripheral arterial disease (PAD). The ankle–brachial index (ABI), a noninvasive measure of PAD, is a predictor of adverse events among individuals with CKD. In general populations, changes in ABI have been associated with mortality, but this association is not well understood among patients with CKD. Methods We conducted a prospective study of 2920 participants in the Chronic Renal Insufficiency Cohort Study without lower extremity revascularization or amputation at baseline and with at least one follow-up ABI measurement (taken at annual visits) during the first 4 years of follow-up. The ABI was obtained by the standard protocol. Results In Cox proportional hazard regression analyses, we found a U-shaped association of average annual change in ABI with all-cause mortality. After adjusting for baseline ABI and other covariates, compared with participants with an average annual change in ABI of 0– Conclusions This study indicates both larger decreases and increases in average annual changes in ABI (>0.04/year) were associated with higher mortality risk. Monitoring changes in ABI over time may facilitate risk stratification for mortality among individuals with CKD.

• Background: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally. Strong evidence supports the importance of diet and other lifestyle factors in preventing T2DM. Among individuals with T2DM, low-carbohydrate diets lead to decreases in hemoglobin A1c (HbA1c). However, research on the effects of low-carbohydrate diets on glycemic outcomes among individuals not currently on glucose-lowering medications who have elevated HbA1c is limited.• Methods: The objective of this randomized controlled trial is to study the effect of a healthy low-carbohydrate diet achieved through behavioral intervention and key food supplementation compared with usual diet on HbA1c and other metabolic risk factors among individuals with HbA1c from 6.0 to 6.9% who are not on glucose-lowering medications. In this parallel trial, 150 participants will be randomized to the intervention or control group for 6 months. The healthy low-carbohydrate diet target is Discussion: We expect that the results from this study will lead to new approaches for developing and implementing dietary approaches (other than the most commonly used reduced fat diet) that will substantially reduce risk of cardiometabolic disease among adults with or at high risk of T2DM. The study intervention involves behavioural counselling and promotes consumption of dietary components thought to reduce risk of cardiometabolic disease and has expected applicability in clinical practice.• Trial registration: Clinicaltrials.gov registry: https://clinicaltrials.gov/ct2/show/NCT03675360. Registered on September 18, 2018 (prior to enrolment of the first participant).

Background: Women with prior gestational diabetes (GDM) are at elevated risk of type 2 diabetes and cardiovascular disease. We sought to compare cardiometabolic risk factors among parous U.S. women ages 20 to 44 by history of GDM. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2016. We included 3562 parous women. We compared anthropometric measures, glycemic markers, blood pressure and lipids by self-reported history of GDM, both with and without adjusting for demographic and behavioral factors and waist circumference. Analyses took NHANES multi-stage survey design into account. Results: Women without history of GDM were younger and, in crude analyses, had more favorable cardiometabolic risk factor profile than women with history of GDM (Table). Similar patterns were observed after adjusting for age, race/ethnicity, education and smoking. After also adjusting for waist circumference, only hemoglobin A1c, fasting glucose, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were significantly higher among women with history of GDM compared to women without GDM. Conclusions: Among parous U.S. women ages 20 to 44, those with a history of GDM had less favorable cardiometabolic risk factor profiles than did women without GDM, though results were attenuated after adjusting for markers of demographics, behavior, and central obesity. Disclosure K.S. Dorans: None. L.A. Bazzano: None. J. He: None. Funding Tulane Center of Biomedical Research (P20GM109036)

Background: The increasing prevalence of diabetes mellitus, a major cause of morbidity and mortality worldwide, is a critical public health concern. Though a number of studies have evaluated the associations of metabolites with prediabetes and diabetes, further exploration in this relatively new field may identify novel biomarkers for predicting, detecting, and managing hyperglycemia and diabetes. Objective: We conducted a metabolome-wide association study among 805 white and 426 African-American participants of the Bogalusa Heart Study (BHS) to identify metabolites associated with markers of glycemia and diabetes. Methods: After rigorous quality control, 1,202 metabolites quantified by untargeted, ultra-high performance liquid chromatography tandem-mass spectroscopy were tested for association with fasting glucose, hemoglobin A1c and diabetes. Multiple regression analyses were run in race-stratified and combined samples, adjusting for age, sex, education, blood pressure, body mass index, HDL-cholesterol, smoking, eGFR, fasting glucose (for HbA1c and diabetes), and race (in combined analyses). For fasting glucose and HbA1c, those taking diabetes medications were excluded. Metabolites were considered significant if they were significant (P-5 ; Bonferroni corrected for 1,202 metabolites) in one race group and the entire cohort, with a similar trend observed in the other race group. Results: After Bonferroni corrections, among 72 metabolites significantly associated with at least one glycemic outcome, 27 were novel and in known pathways: 5 from amino acid, 1 from carbohydrate, 18 from lipid, 1 from xenobiotics, and 2 from nucleotide pathways. Metabolites consistently associated with diabetes are shown in the Table . Conclusions: These results identified novel metabolites associated with glycemic outcomes, providing additional evidence on the importance of serum metabolites in hyperglycemia and diabetes.

OBJECTIVE: To identify novel and confirm previously reported metabolites associated with SBP, DBP, and hypertension in a biracial sample of Bogalusa Heart Study (BHS) participants. METHODS: We employed untargeted, ultra-high performance liquid chromatography tandem mass spectroscopy metabolomics profiling among 1249 BHS participants (427 African-Americans and 822 whites) with BP and covariable data collected during the 2013 to 2016 visit cycle. A total of 1202 metabolites were tested for associations with continuous and binary BP phenotypes using multiple linear and logistic regression models, respectively, in overall and race-stratified analyses. RESULTS: A total of 24 novel metabolites robustly associated with BP, achieving Bonferroni-corrected P less than 4.16×10(−5) in the overall analysis and consistent effect sizes across race groups. The identified metabolites included three amino acid and nucleotide metabolites from histidine, pyrimidine, or tryptophan metabolism sub-pathways, seven cofactor and vitamin or xenobiotic metabolites from the ascorbate and aldarate metabolism, bacterial/fungal, chemical, and food component sub-pathways, 10 lipid metabolites from the eicosanoid, phosphatidylcholine, phosphatidylethanolamine, and sphingolipid metabolism sub-pathways, and four still unnamed metabolites. Six previously described metabolites were robustly confirmed by our study (Bonferroni-corrected P < 4.95×10(−4) and consistent effect directions across studies). Furthermore, previously reported metabolites for SBP, DBP, and hypertension demonstrated 5.92-fold, 4.77-fold, and 4.54-fold enrichment for nominally significant signals in the BHS (P=3.08×10(−10), 5.93×10(−8), and 2.30×10(−8), respectively). CONCLUSION: In aggregate, our study provides new information about potential molecular mechanisms underlying BP regulation. We also demonstrate reproducibility of findings across studies despite differences in study populations and metabolite profiling methods.

Background and aims To examine the associations between history of gestational diabetes mellitus (GDM) and breastfeeding with branched-chain amino acids (BCAA) and their metabolites in later life. Methods and results 638 women (mean age 48.0 y) who had participated in the Bogalusa Heart Study and substudies of pregnancy history had untargeted, ultrahigh performance liquid chromatography-tandem mass spectroscopy conducted by Metabolon© on serum samples. Metabolites were identified that were BCAA or associated with BCAA metabolic pathways. History of GDM at any pregnancy (self-reported, confirmed with medical records when possible) as well as breastfeeding were examined as predictors of BCAA using linear models, controlling for age, race, BMI, waist circumference, and menopausal status. None of the BCAA differed statistically by history of either GDM or breastfeeding, although absolute levels of each of the BCAA were higher with GDM and lower with breastfeeding. Of the 27 metabolites on the leucine, isoleucine and valine metabolism subpathway, 1-carboxyethylleucine, 1-carboxyethyvaline, and 3-hydroxy-2-ethylpropionate were higher in women with a history of GDM, but lower in women in women with a history of breastfeeding. Similar results were found for alpha-hydroxyisocaproate, 1-carboxyethylisoleucine, and N-acetylleucine. Conclusions GDM and breastfeeding are associated in opposite directions with several metabolites on the BCAA metabolic pathway.

Highlights • Not all individuals with prediabetes, T2D and/or MetS develop significant ASCVD. • Discordantly normal ApoB relative to high LDL-C may help explain such heterogeneity. • 51% of persons with metabolic disorders and high LDL-C had discordantly normal ApoB. • Lower ApoB associated with long-term absence of carotid plaque, while LDL-C did not. • Measurement of ApoB may be useful in young persons with metabolic disease., Objective A significant proportion of persons with metabolic syndrome (MetS), prediabetes, or type 2 diabetes (T2D) do not develop atherosclerotic cardiovascular disease (ASCVD). We sought to determine whether discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-C may help to explain heterogeneity in ASCVD risk among persons with metabolic disorders. Methods There were 278 Bogalusa Heart Study participants with MetS (n=95), prediabetes (n=233), or T2D (n=31) and LDL-C ≥100 mg/dL who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Multivariable modified Poisson regression estimated the long-term absence of carotid plaque for lower ApoB, continuously and categorically. Results Participants were on average 36.1 years old at baseline, 61.5% were women, and 31.7% were black. A total of 50.7% had discordantly normal ApoB (, Graphical abstract Image, graphical abstract

Objective— The objective of this study is to examine associations between short-term exposure to ambient air pollution and circulating biomarkers of systemic inflammation in participants from the Framingham Offspring and Third Generation cohorts in the greater Boston area. Approach and Results— We included 3996 noncurrent smoking participants (mean age, 53.6 years; 54% women) who lived within 50 km from a central air pollution monitoring site in Boston, MA, and calculated the 1- to 7-day moving averages of fine particulate matter (diameter3 higher 5-day moving average fine particulate matter (diameter Conclusions— Higher short-term exposure to relatively low levels of ambient air pollution was associated with higher levels of C-reactive protein, interleukin-6, and tumor necrosis factor receptor 2 but not fibrinogen or tumor necrosis factor α in individuals residing in the greater Boston area.

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002-2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (β = -0.003, 95% confidence interval: -0.006, -0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat.

Aims The objective of this study was to evaluate the association of chocolate consumption and heart failure (HF) in a large population of Swedish men. Methods We conducted a prospective cohort study of 31,917 men 45-79 years old with no history of myocardial infarction, diabetes, or HF at baseline who were participants in the population-based Cohort of Swedish Men study. Chocolate consumption was assessed through a self-administrated food frequency questionnaire. Participants were followed for HF hospitalization or mortality from January 1, 1998, to December 31, 2011, using record linkage to the Swedish inpatient and cause-of-death registries. Results During 14 years of follow-up, 2,157 men were hospitalized (n=1,901) or died from incident HF (n=256). Compared with subjects who reported no chocolate intake, the multivariable-adjusted rate ratio of HF was 0.88 (95% CI 0.78-0.99) for those consuming 1-3 servings per month, 0.83 (95% CI 0.72-0.94) for those consuming 1-2 servings per week, 0.82 (95% CI 0.68-0.99) for those consuming 3-6 servings per week, and 1.10 (95% CI 0.84-1.45) for those consuming ≥1 serving per day ( P for quadratic trend=.001). Conclusions In this large prospective cohort study, there was a J -shaped relationship between chocolate consumption and HF incidence. Moderate chocolate consumption was associated with a lower rate of HF hospitalization or death, but the protective association was not observed among individuals consuming ≥1 serving per day. Journal Subject Codes: Etiology: Epidemiology, Heart failure: Congestive

Objective Higher traffic-related air pollution has been associated with higher body mass index (BMI) among children. However, few studies have assessed the associations among adults. Methods Participants (N = 2,372) from the Framingham Offspring and Third Generation cohorts who underwent multidetector-computed tomography scans (2002–2005) were included. Residential-based proximity to the nearest major roadway and 1-year average levels of fine particulate matter (PM2.5) air pollution were estimated. BMI was measured at Offspring examination 7 (1998–2001) and Third Generation examination 1 (2002–2005); subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured using multidetector-computed tomography. Linear regression models were used for continuous BMI, SAT, and VAT and logistic models for the binary indicator of obesity (BMI ≥30 kg/m2), adjusting for demographic variables, individual- and area-level measures of socioeconomic position, and clinical and lifestyle factors. Results Participants who lived 60 m from a major roadway had 0.37 kg/m2 higher BMI (95% CI: 0.10 to 0.65 kg/m2), 78.4 cm3 higher SAT (95% CI: 4.5 to 152.3 cm3), and 41.8 cm3 higher VAT (95% CI: −4.7 to 88.2 cm3) than those who lived 440 m away. Conclusions Living closer to a major roadway was associated with higher overall and abdominal adiposity.

BACKGROUND: Exposure to ambient air pollution has been associated with lower lung function in adults, but few studies have investigated associations with radiographic lung and airway measures. METHODS: We ascertained lung volume, mass, density, visual emphysema, airway size, and airway wall area by computed tomography (CT) among 2,545 non-smoking Framingham CT sub-study participants. We examined associations of home distance to major road and PM(2.5) (2008 average from a spatiotemporal model using satellite data) with these outcomes using linear and logistic regression models adjusted for age, sex, height, weight, census tract median household value and population density, education, packyears of smoking, household tobacco exposure, cohort, and date. We tested for differential susceptibility by sex, smoking status (former vs never), and cohort. RESULTS: The mean participant age was 60.1 y (standard deviation 11.9). Median PM(2.5) level was 9.7 μg/m(3) (interquartile range 1.6). Living < 100 m from a major road was associated with a 108 mL (95% CI 8, 207) higher lung volume compared to ≥ 400 m away. There was also a log-linear association between proximity to road and higher lung volume. There were no convincing associations of proximity to major road or PM(2.5) with the other pulmonary CT measures. In subgroup analyses, road proximity was associated with lower lung density among men, and higher odds of emphysema among former smokers. CONCLUSIONS: Living near a major road was associated with higher average lung volume, but otherwise we found no association between ambient pollution and radiographic measures of emphysema or airway disease.

Few studies have examined associations between long-term exposure to fine particulate matter (PM2.5) and lung function decline in adults.To determine if exposure to traffic and PM2.5 is associated with longitudinal changes in lung function in a population-based cohort in the Northeastern United States, where pollution levels are relatively low.FEV1 and FVC were measured up to two times between 1995 and 2011 among 6,339 participants of the Framingham Offspring or Third Generation studies. We tested associations between residential proximity to a major roadway and PM2.5 exposure in 2001 (estimated by a land-use model using satellite measurements of aerosol optical thickness) and lung function. We examined differences in average lung function using mixed-effects models and differences in lung function decline using linear regression models. Current smokers were excluded. Models were adjusted for age, sex, height, weight, pack-years, socioeconomic status indicators, cohort, time, season, and weather.Living less than 100 m from a major roadway was associated with a 23.2 ml (95% confidence interval [CI], -44.4 to -1.9) lower FEV1 and a 5.0 ml/yr (95% CI, -9.0 to -0.9) faster decline in FEV1 compared with more than 400 m. Each 2 μg/m(3) increase in average of PM2.5 was associated with a 13.5 ml (95% CI, -26.6 to -0.3) lower FEV1 and a 2.1 ml/yr (95% CI, -4.1 to -0.2) faster decline in FEV1. There were similar associations with FVC. Associations with FEV1/FVC ratio were weak or absent.Long-term exposure to traffic and PM2.5, at relatively low levels, was associated with lower FEV1 and FVC and an accelerated rate of lung function decline.

Objective: To examine associations of proximity to major roadways, sustained exposure to fine particulate matter (PM2.5), and acute exposure to ambient air pollutants with adipokines and measures of glucose homeostasis among participants living in the northeastern United States. Methods: We included 5958 participants from the Framingham Offspring cohort examination cycle 7 (1998–2001) and 8 (2005–2008) and Third Generation cohort examination cycle 1 (2002–2005) and 2 (2008–2011), who did not have type 2 diabetes at the time of examination visit. We calculated 2003 annual average PM2.5 at participants' home address, residential distance to the nearest major roadway, and daily PM2.5, black carbon (BC), sulfate, nitrogen oxides (NOx), and ozone concentrations. We used linear mixed effects models for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) which were measured up to twice, and used linear regression models for adiponectin, resistin, leptin, and hemoglobin A1c (HbA1c) which were measured only once, adjusting for demographics, socioeconomic position, lifestyle, time, and seasonality. Results: The mean age was 51years and 55% were women. Participants who lived 64m (25th percentile) from a major roadway had 0.28% (95% CI: 0.05%, 0.51%) higher fasting plasma glucose than participants who lived 413m (75th percentile) away, and the association appeared to be driven by participants who lived within 50m from a major roadway. Higher exposures to 3- to 7-day moving averages of BC and NOx were associated with higher glucose whereas the associations for ozone were negative. The associations otherwise were generally null and did not differ by median age, sex, educational attainment, obesity status, or prediabetes status. Conclusions: Living closer to a major roadway or acute exposure to traffic-related air pollutants were associated with dysregulated glucose homeostasis but not with adipokines among participants from the Framingham Offspring and Third Generation cohorts. Keywords: Air pollution, Adipokines, Glucose homeostasis, Epidemiology, Particulate matter

Introduction: Exposure to air pollution has been positively associated with systemic inflammation. However, few large scale studies were conducted in regions with low levels of air pollution. We therefore studied the associations of air pollution with systemic inflammation biomarkers among participants in the Framingham Offspring and Third Generation cohorts in Greater Boston area. Methods: We measured C-reactive protein (CRP), fibrinogen, interleukin 6 (IL6), and tumor necrosis factor receptor 2 (TNFR2) in 3943 participants living within 50 km of a central site monitor in Boston. We calculated the 1-, 2-, 3-, 5-, and 7-day moving averages of fine particulate matter (PM 2.5 ), black carbon (BC), sulfate (SO 4 2- ), nitrogen oxides (NO x ), and ozone (O 3 ) prior to the exam visits. We used linear mixed effects models and linear regression models to evaluate repeated measures and cross-sectional associations respectively, adjusting for age, sex, individual and area level measures of socioeconomic position, lifestyle and clinical factors, time trend, and weather. We examined effect modification by age (>/≤ 65 years), sex, and diabetes history. Results: The mean age was 53(±14) years and 54% were women. PM 2.5 , BC, and SO 4 2- were positively associated with CRP across multiple moving averages, and were statistically significant at 5-day moving averages: a 5 μg/m 3 higher PM 2.5 or a 0.5 μg/m 3 higher BC was associated with 3.9% (95% CI: 0.5, 7.3) or 5.3% (95% CI: 0.1, 10.9) higher CRP, respectively. Positive associations were observed for PM 2.5 , BC, and NO x with IL6; and for BC, SO 4 2- , and O 3 with TNFR2. SO 4 2- and O 3 were negatively associated with fibrinogen. Associations of BC and NO x with CRP and of BC with IL6 were of a larger magnitude among participants with diabetes than those without. Conclusions: In a region in compliance with current US-EPA regulation, we find positive associations of short-term exposure to ambient air pollution with CRP, IL6 and TNFR2 but not for fibrinogen.

Objective: To study whether physical activity during adulthood or early life is associated with multiple sclerosis (MS) incidence in 2 prospective cohorts of women. Methods: Women in the Nurses9 Health Study (NHS) (n = 81,723; 1986–2004) and NHS II (n = 111,804; 1989–2009) reported recent physical activity at baseline and in selected follow-up questionnaires. Using this information, we calculated total metabolic equivalent hours of physical activity per week, a measure of energy expenditure. There were 341 confirmed MS cases with first symptoms after baseline. Participants also reported early-life activity. To estimate relative rates (RRs) and 95% confidence intervals (CIs), we used Cox proportional hazards models, adjusting for age, latitude of residence at age 15, ethnicity, smoking, supplemental vitamin D, and body mass index at age 18. Results: Compared with women in the lowest baseline physical activity quartile, women in the highest quartile had a 27% reduced rate of MS (RRpooled = 0.73, 95% CI 0.55–0.98; p-trend 0.08); this trend was not present in 6-year lagged analyses. Change in physical activity analyses suggested that women reduced activity before onset of MS symptoms. In NHS and NHS II, higher strenuous activity at ages 18–22 years was weakly associated with a decreased MS rate. However, in NHS II, total early-life activity at ages 12–22 was not associated with MS. Conclusions: Though higher physical activity at baseline was weakly associated with lower MS risk, this may have been due to women reducing physical activity in response to subclinical MS.

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002–2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (β = −0.003, 95% confidence interval: −0.006, −0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat.

Background Short‐term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community‐based studies have assessed this association. Methods and Results Two thousand thirty‐five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998–2001) and urinary creatinine‐indexed 8‐epi‐prostaglandin F 2α (8‐epi‐ PGF 2α ) at the seventh and eighth (2005–2008) examinations. We measured fine particulate matter ( PM 2.5 ), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1‐, 2‐, 3‐, 5‐, and 7‐day moving averages of each pollutant. Measured myeloperoxidase and 8‐epi‐ PGF 2α were log e transformed. We used linear regression models and linear mixed‐effects models with random intercepts for myeloperoxidase and indexed 8‐epi‐ PGF 2α , respectively. Models were adjusted for demographic variables, individual‐ and area‐level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM 2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2‐ to 7‐day moving averages of PM 2.5 and sulfate were consistently positively associated with 8‐epi‐ PGF 2α . Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. Conclusions Our community‐based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress.

Background: Exposure to traffic and ambient air pollution is associated with an increased risk of cardiovascular disease, potentially through atherosclerosis promotion. Few studies have assessed associations of these exposures with thoracic aortic calcium (TAC) or abdominal aortic calcium (AAC), which are correlates of atherosclerosis. Objective: We assessed whether living close to a major road and residential exposure to fine particulate matter (PM 2.5 ) were associated with TAC and AAC in a community-based Northeastern U.S. cohort. Methods: TAC was measured from 2002[[Unable to Display Character: –]]2005 and AAC up to two times (2002[[Unable to Display Character: –]]2005; 2008[[Unable to Display Character: –]]2011) among participants from the Framingham Offspring or Third Generation Cohorts. We first assessed associations of residential distance to a major road and PM 2.5 exposure (2003 annual average from a spatiotemporal model) with detectable aortic calcium. We used logistic regression for TAC and generalized estimating equations (logit link) for AAC. As aortic calcium scores were right-skewed, we next used linear regression models and mixed effects models to assess associations with log-transformed TAC and AAC, respectively, among participants with aortic calcium scores > 0 (95% CIs bootstrapped). We also assessed associations with AAC progression. Models were adjusted for demographic variables, individual and area-level markers of socioeconomic position and time. Results: Among 3518 participants with TAC or AAC measured, 52% had AAC measured twice. Mean age was 55.8 years; 50% female. There were no associations of distance to a major road or PM 2.5 with detectable TAC or AAC, though some estimates were in the opposite direction than expected ( Table ). There were no associations with extent of TAC or AAC ( Table ), or with AAC progression. Conclusions: Proximity to a major road and PM 2.5 were not associated with the presence or extent of aortic calcium, or with AAC progression in this cohort from a region with relatively low PM 2.5 levels. Future work should explore these associations in other populations.

Objective— Long-term exposure to traffic and particulate matter air pollution is associated with a higher risk of cardiovascular disease, potentially via atherosclerosis promotion. Prior research on associations of traffic and particulate matter with coronary artery calcium Agatston score (CAC), an atherosclerosis correlate, has yielded inconsistent findings. Given this background, we assessed whether residential proximity to major roadway or fine particulate matter were associated with CAC in a Northeastern US study. Approach and Results— We measured CAC ≤2 times from 2002 to 2005 and 2008 to 2011 among Framingham Offspring or Third-Generation Cohort participants. We assessed associations of residential distance to major roadway and residential fine particulate matter (2003 average; spatiotemporal model) with detectable CAC, using generalized estimating equation regression. We used linear mixed effects models to assess associations with log e (CAC). We also assessed associations with CAC progression. Models were adjusted for demographic variables, socioeconomic position markers, and time. Among 3399 participants, 51% had CAC measured twice. CAC was detectable in 47% of observations. At first scan, mean age was 52.2 years (standard deviation 11.7); 51% male. There were no consistent associations with detectable CAC, continuous CAC, or CAC progression. We observed heterogeneous associations of distance to major roadway with odds of detectable CAC by hypertensive status; interpretation of these findings is questionable. Conclusions— Our findings add to prior work and support evidence against strong associations of traffic or fine particulate matter with the presence, extent, or progression of CAC in a region with relatively low levels of and little variation in fine particulate matter.

Objectives Traffic and ambient air pollution exposure are positively associated with cardiovascular disease, potentially through atherosclerosis promotion. Few studies have assessed associations of these exposures with thoracic aortic calcium Agatston score (TAC) or abdominal aortic calcium Agatston score (AAC), systemic atherosclerosis correlates. We assessed whether living close to a major road and residential fine particulate matter (PM 2.5 ) exposure were associated with TAC and AAC in a Northeastern US cohort. Design Cohort study. Setting Framingham Offspring and Third Generation participants residing in the Northeastern USA. Participants and outcome measures Among 3506 participants, mean age was 55.8 years; 50% female. TAC was measured from 2002 to 2005 and AAC up to two times (2002–2005; 2008–2011) among participants from the Framingham Offspring or Third Generation cohorts. We first assessed associations with detectable TAC (logistic regression) and AAC (generalised estimating equation regression, logit link). As aortic calcium scores were right skewed, we used linear regression models and mixed-effects models to assess associations with natural log-transformed TAC and AAC, respectively, among participants with detectable aortic calcium. We also assessed associations with AAC progression. Models were adjusted for demographic variables, socioeconomic position indicators and time. Results There were no consistent associations of major roadway proximity or PM 2.5 with the presence or extent of TAC or AAC, or with AAC progression. Some estimates were in the opposite direction than expected. Conclusions In this cohort from a region with relatively low levels of and variation in PM 2.5 , there were no strong associations of proximity to a major road or PM 2.5 with the presence or extent of aortic calcification, or with AAC progression.

Background— Compared with no alcohol consumption, heavy alcohol intake is associated with a higher rate of heart failure (HF) whereas light-to-moderate intake may be associated with a lower rate. However, several prior studies did not exclude former drinkers, who may have changed alcohol consumption in response to diagnosis. This study aimed to investigate the association between alcohol intake and incident HF. Methods and Results— We conducted a prospective cohort study of 33 760 men aged 45 to 79 years with no HF, diabetes mellitus, or myocardial infarction at baseline participating in the Cohort of Swedish Men Study. We excluded former drinkers. At baseline, participants completed a food frequency questionnaire and reported other characteristics. HF was defined as hospitalization for or death from HF, ascertained by Swedish inpatient and cause-of-death records from January 1, 1998, through December 31, 2011. We constructed Cox proportional hazards models to estimate multivariable-adjusted incidence rate ratios. During follow-up, 2916 men were hospitalized for (n=2139) or died (n=777) of incident HF. There was a U-shaped relationship between total alcohol intake and incident HF ( P =0.0004). There was a nadir at light-to-moderate alcohol intake: consuming 7 to Conclusions— In this cohort of Swedish men, there was a U-shaped relationship between alcohol consumption and HF incidence, with a nadir at light-to-moderate intake. Heavy intake did not seem protective.

Background: The relationship between alcohol intake and incident heart failure (HF) is complex. Compared with no alcohol consumption, heavy alcohol intake is associated with higher HF risk whereas light or moderate consumption may be associated with lower risk. Methods: We analyzed 34,581 men 45-79 years old with no history of HF, diabetes mellitus or myocardial infarction (MI) who were participants in the population-based Cohort of Swedish Men study. We excluded former drinkers. At baseline, participants reported how frequently they consumed specific alcoholic beverages in the past year and other characteristics. HF was defined as hospitalization for or death from HF (primary diagnosis), ascertained by Swedish inpatient and cause-of-death records from January 1, 1998 to December 31, 2011. Due to missing values for two covariates, we used Markov chain Monte Carlo multiple imputation to simulate 5 complete datasets. We used Cox proportional hazards models to estimate rate ratios and 95% confidence intervals, adjusting for age, total energy intake, education, body mass index, physical activity, a dietary component score, cigarette smoking, marital status, family history of MI before age 60, history of hypertension and history of high cholesterol. Results: At baseline, mean age was 58.6 years. There were 1592 incident cases of HF over the follow-up period. Compared with never drinkers, the multivariable-adjusted rate of HF was 19% lower among men who drank Conclusions: Light-to-moderate drinking is associated with lower rate of HF compared with never drinking, but the association was not statistically significant.