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Background The time constraints and reprioritization of personal health associated with having children may lead women to adopt less healthy lifestyles. We assessed the patterns of change in weight and lifestyle behaviours associated with having children and whether these differ between primiparous and multiparous women. Methods Data were from Surveys 3 and 5 of the 1973–1978 birth cohort of the Australian Longitudinal Study on Women’s Health. In women who were nulliparous at Survey 3, we assessed changes in weight, energy intake, diet (diet quality, macronutrients and micronutrients), physical activity and sitting time by parity status at Survey 5 using one-way analysis of covariance. Results Of 4927 eligible women, 2503 gave birth (1090 primiparous and 1413 multiparous) by Survey 5. Women who had given birth 6 years later increased weight (1.0 kg; 95% CI 0.5, 1.5), energy intake (833.9 kJ/day; 95% CI 706.7, 961.1) and diet quality (1.5 units; 95% CI 0.8, 2.1), but decreased physical activity [–405.0 Metabolic Equivalent of Task.min/week; 95% CI –464.2, –345.8] and sitting time (–1.8 h/day; 95% CI –1.9, –1.6) (adjusted mean differences) relative to those who remained nulliparous. In subgroup analysis involving further stratification by parity, the increase in diet quality was only seen in women who became primiparous and the decrease in sitting time was more marked in multiparous women. Conclusion Childbearing is associated with increased weight and energy intake, decreased physical activity, increased diet quality and decreased sitting time. More research targeting weight, energy intake and physical activity for improvement in women during the childbearing years is warranted.

DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case–control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases (N = 168). Controls (N = 163) were matched to cases on sex, year of birth, country of birth, and blood sample type using incidence density sampling. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450K Beadchip. Global measures of DNA methylation were defined as the median methylation M value, calculated for each of 13 CpG subsets representing genomic function, mean methylation and location, and reliability of measurement. Conditional logistic regression was conducted to assess associations between these global measures of methylation and gastric cancer risk, adjusting for Helicobacter pylori and other potential confounders. We tested nonlinear associations using quintiles of the global measure distribution. A genome-wide association study of DNA methylation and gastric cancer risk was also conducted (N = 484,989 CpGs) using conditional logistic regression, adjusting for potential confounders. Differentially methylated regions (DMR) were investigated using the R package DMRcate. We found no evidence of associations with gastric cancer risk for individual CpGs or DMRs (P > 7.6 × 10−6). No evidence of association was observed with global measures of methylation (OR 1.07 per SD of overall median methylation; 95% confidence interval, 0.80–1.44; P = 0.65). We found no evidence that blood DNA methylation is prospectively associated with gastric cancer risk.Prevention Relevance: We studied DNA methylation in blood to try and predict who was at risk of gastric cancer before symptoms developed, by which stage survival is poor. We did not find any such markers, but the importance of early diagnosis in gastric cancer remains, and the search for markers continues.

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Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10(−14)), ~0.6% (P = 2 × 10(−7)), and ~8.7% (P = 7 × 10(−87)) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P

STUDY QUESTION Do extrinsic factors including lifestyle, psychosocial factors and healthcare professional engagement independently contribute to weight gain in women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Women with PCOS had a higher rate of weight gain than women without PCOS which was most marked in those with unhealthy lifestyles. WHAT IS KNOWN ALREADY Women with PCOS have a higher prevalence of overweight/obesity and greater weight gain than women without PCOS. The association of lifestyle factors with weight change in PCOS is not known. STUDY DESIGN, SIZE, DURATION The study was a population-based observational study with data collected from seven surveys over 19 years (N = 14 127; Survey 1) involving women with and without PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS We used data from the 1973–1978 birth cohort of the Australian Longitudinal Study on Women’s Health. MAIN RESULTS AND THE ROLE OF CHANCE Women with PCOS gained more weight annually (0.26 kg/year; 95% CI 0.12, 0.39; P < 0.0001) and over 19 years (4.62 kg; 95% CI 3.04, 6.21; P < 0.0001) than women without PCOS (adjusted analyses). For all women, there were positive associations between weight gain and energy intake, sitting time and stress; inverse associations with fibre intake and physical activity (PA); and no associations with diet quality, glycaemic index, healthcare utilization, depression or anxiety. There were interactions between lifestyle factors (energy intake P = 0.006, glycaemic index P = 0.025, sitting time P = 0.041 and PA P = 0.021), PCOS status and time such that weight gain varied between women with and without PCOS according to these factors. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include the use of self-reported measures such as diet, PA, sitting time, psychological factors and health care utilization. WIDER IMPLICATIONS OF THE FINDINGS While women with PCOS are more prone to weight gain, lifestyle factors have a more profound impact on weight gain in women with PCOS than without PCOS. These study findings have implications for understanding the mechanisms of weight gain in women with PCOS. They also highlight the importance of early lifestyle intervention as soon as PCOS is diagnosed to address modifiable extrinsic factors and prevent excess weight gain and worsening of the clinical features of PCOS. STUDY FUNDING/COMPETING INTEREST(S) M.A.A. is funded by the Monash International Tuition Scholarship and Monash Graduate Scholarship and L.J.M. is funded by a National Heart Foundation Future Leader Fellowship. The authors declared no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation.We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality.Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y).The MDS, E-DII, and AHEI were associated (P 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns.Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality.

BackgroundConflicting evidence surrounds the effect of dietary macronutrient intake (fat, carbohydrate and protein) on cardiovascular disease (CVD), particularly in women.MethodsWomen (aged 50–55 years) were recruited into the Australian Longitudinal Study on Women’s Health. Women were divided into quintiles according to their carbohydrate and saturated fat intake as a percentage of total energy intake (TEI). The primary endpoint was new-onset CVD (heart disease/stroke). Secondary endpoints included all-cause mortality, incident hypertension, obesity and/or diabetes mellitus. Multivariate logistic regression models assessed for associations with the primary and secondary endpoints, with adjustment for confounders.ResultsA total of 9899 women (mean age 52.5±1.5 years) were followed for 15 years, with 1199 incident CVD and 470 deaths. On multivariable analysis, higher carbohydrate intake was associated with lower CVD risk (ptrendtrend=0.69) or between saturated fat intake and CVD (ptrend=0.29) or mortality (ptrend=0.25). Both increasing saturated fat and carbohydrate intake were significantly inversely associated with hypertension, diabetes mellitus and obesity (ptrendConclusionsIn middle-aged Australian women, moderate carbohydrate intake (41.0%–44.3% of TEI) was associated with the lowest risk of CVD, without an effect on total mortality. Increasing saturated fat intake was not associated with CVD or mortality and instead correlated with lower rates of diabetes, hypertension and obesity.

Background: A few studies have linked dietary patterns and sleep to cognitive decline. Objective: To examine the independent and joint associations of dietary patterns and sleep with cognitive decline. Methods: Our analysis included 2,307 participants aged 55– 89 years at baseline from the China Health and Nutrition Survey. Dietary intake was assessed using weighing methods in combination with 24 h dietary recalls for three consecutive days. Exploratory factor analysis was applied to identify major dietary factors. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Results: Five dietary patterns were identified: dairy-fruits-fast foods, grains-vegetables-pork, plant-based food, beans-mushroom, and beverages-nuts patterns. Beans-mushroom pattern and sleep duration of 8 h/day were defined as healthy habits. There was a positive association between the beans-mushroom pattern and change in the global cognitive Z-score over seven years (β (95% CI) for quintile 5 versus quintile 1:0.17 (0.05, 0.30)). Compared to individuals with sleep duration of 8 h/day, those with sleep duration of≤5 h/day (β (95% CI): – 0.23 (– 0.45, – 0.00)) or > 10 h/day (– 0.52 (– 0.73, – 0.32)) had a greater decrease in global cognitive Z-score. Compared to individuals with no healthy patterns, those with a healthy dietary pattern only (β (95% CI): 0.18 (0.08, 0.28)), healthy sleep pattern only (0.13 (0.04, 0.23), and both healthy dietary and sleep patterns (0.19 (0.08, 0.31)) had a relative increase in global cognitive Z-score. Conclusion: Our findings highlight the importance of involving both diet and sleep as intervention priorities for the potential prevention of cognitive decline.

Previous studies of dietary patterns and pancreatic cancer risk have been inconclusive; we aimed to investigate the association of Mediterranean Diet Score (MDS), Alternative Healthy Eating Index-2010 (AHEI-2010), and Dietary Inflammatory Index (DII®) with risk of pancreatic cancer.We used data from the Melbourne Collaborative Cohort Study including 33,690 men and women aged 40-69 years at recruitment in 1990-1994. A total of 258 incident cases of pancreatic cancer was identified over an average of 23.7 years of follow-up. Hazard ratios (HR) were estimated using Cox regression, with age as the underlying time metric, adjusting for potential confounders including sex, height, country of birth, education, socio-economic position, physical activity, energy intake, smoking status, pack-years smoking, years since quitting smoking, and alcohol intake.A healthier diet as assessed by the AHEI-2010 was associated with a lower risk of pancreatic cancer [HRAdherence to a healthier diet, as assessed by the AHEI-2010, may reduce the risk of pancreatic cancer.

Background and aims Little is known about how weight trajectories among women during menopausal transition and beyond may be related to risk of type 2 diabetes mellitus (T2DM). The aim of this study was to examine associations between body mass index (BMI) trajectories over 20 years, age of obesity onset, cumulative obese-years and incidence of T2DM among middle-aged women. Methods and results 12,302 women enrolled in the Australian Longitudinal Study on Women's Health (ALSWH) were surveyed in 1996 (Survey 1, age 45–50), 1998 and then every three years to 2016. Self-reported weight and height were collected for up to eight time points. Incident diabetes was assessed via validated self-report of physician-diagnosed diabetes. Growth mixture models were used to identify distinct BMI trajectories. A total of 1380 (11.2%) women newly developed T2DM over an average 16 years of follow-up. Seven distinct BMI trajectories were identified with differential risk of developing T2DM. Initial BMI was positively associated with T2DM risk. We also observed that risk of T2DM was positively associated with rapid weight increase, early age of obesity onset and greater obese-years. Conclusion Slowing down weight increases, delaying the onset of obesity, or reducing cumulative exposure to obesity may substantially lower the risk of developing T2DM.

Background: Mechanisms for how Helicobacter pylori infection affects risk of gastroesophageal reflux disease (GERD) and Barrett's esophagus are incompletely understood and might differ by sex. Methods: In a case–control study nested in the Melbourne Collaborative Cohort Study with 425 GERD cases and 169 Barrett's esophagus cases (identified at 2007–2010 follow-up), we estimated sex-specific odds ratios for participants who were H. pylori seronegative versus seropositive at baseline (1990–1994). To explore possible mechanisms, we (i) compared patterns of H. pylori-induced gastritis by sex using serum pepsinogen-I and gastrin-17 data and (ii) quantified the effect of H. pylori seronegativity on Barrett's esophagus mediated by GERD using causal mediation analysis. Results: For men, H. pylori seronegativity was associated with 1.69-fold [95% confidence interval (CI), 1.03–2.75] and 2.28-fold (95% CI, 1.27–4.12) higher odds of GERD and Barrett's esophagus, respectively. No association was observed for women. H. pylori-induced atrophic antral gastritis was more common in men (68%) than in women (56%; P = 0.015). For men, 5 of the 15 per 1,000 excess Barrett's esophagus risk from being seronegative were mediated by GERD. Conclusions: Men, but not women, who were H. pylori seronegative had increased risks of GERD and Barrett's esophagus. A possible explanation might be sex differences in patterns of H. pylori-induced atrophic antral gastritis, which could lead to less erosive reflux for men. Evidence of GERD mediating the effect of H. pylori on Barrett's esophagus risk among men supports this proposed mechanism. Impact: The findings highlight the importance of investigating sex differences in the effect of H. pylori on risk of GERD and Barrett's esophagus in future studies.

Limited evidence exists on the link between inflammation and epigenetic aging. We aimed to (a) assess the cross-sectional and prospective associations of 22 inflammation-related plasma markers and a signature of inflammaging with epigenetic aging and (b) determine whether epigenetic aging and inflammaging are independently associated with mortality. Blood samples from 940 participants in the Melbourne Collaborative Cohort Study collected at baseline (1990–1994) and follow-up (2003–2007) were assayed for DNA methylation and 22 inflammation-related markers, including well-established markers (eg, interleukins and C-reactive protein) and metabolites of the tryptophan–kynurenine pathway. Four measures of epigenetic aging (PhenoAge, GrimAge, DunedinPoAm, and Zhang) and a signature of inflammaging were considered, adjusted for age, and transformed to Z scores. Associations were assessed using linear regression, and mortality hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox regression. Cross-sectionally, most inflammation-related markers were associated with epigenetic aging measures, although with generally modest effect sizes (regression coefficients per SD ≤ 0.26) and explaining altogether between 1% and 11% of their variation. Prospectively, baseline inflammation-related markers were not, or only weakly, associated with epigenetic aging after 11 years of follow-up. Epigenetic aging and inflammaging were strongly and independently associated with mortality, for example, inflammaging: HR = 1.41, 95% CI = 1.27–1.56, p = 2 × 10−10, which was only slightly attenuated after adjustment for 4 epigenetic aging measures: HR = 1.35, 95% CI = 1.22–1.51, p = 7 × 10−9). Although cross-sectionally associated with epigenetic aging, inflammation-related markers accounted for a modest proportion of its variation. Inflammaging and epigenetic aging are essentially nonoverlapping markers of biological aging and may be used jointly to predict mortality.

We examined associations between sex-specific alcohol intake trajectories and alcohol-related cancer risk using data from 22 756 women and 15 701 men aged 40 to 69 years at baseline in the Melbourne Collaborative Cohort Study. Alcohol intake for 10-year periods from age 20 until the decade encompassing recruitment, calculated using recalled beverage-specific frequency and quantity, was used to estimate group-based sex-specific intake trajectories. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for primary invasive alcohol-related cancer (upper aerodigestive tract, breast, liver and colorectum). Three distinct alcohol intake trajectories for women (lifetime abstention, stable light, increasing moderate) and six for men (lifetime abstention, stable light, stable moderate, increasing heavy, early decreasing heavy, late decreasing heavy) were identified. 2303 incident alcohol-related cancers were diagnosed during 485 525 person-years in women and 789 during 303 218 person-years in men. For men, compared with lifetime abstention, heavy intake (mean ≥ 60 g/day) at age 20 to 39 followed by either an early (from age 40 to 49) (early decreasing heavy; HR = 1.75, 95% CI: 1.25-2.44) or late decrease (from age 60 to 69) (late decreasing heavy; HR = 1.94, 95% CI: 1.28-2.93), and moderate intake (mean60 g/day) at age 20 to 39 increasing to heavy intake in middle-age (increasing heavy; HR = 1.45, 95% CI: 1.06-1.97) were associated with increased risk of alcohol-related cancer. For women, compared with lifetime abstention, increasing intake from age 20 (increasing moderate) was associated with increased alcohol-related cancer risk (HR = 1.25, 95% CI: 1.06-1.48). Similar associations were observed for colorectal (men) and breast cancer. Heavy drinking during early adulthood might increase cancer risk later in life.

Introduction Long-term effects of physical activity and television (TV) viewing on mortality have been inferred from observational studies. The associations observed do not allow for inferences about the effects of population interventions and could be subject to bias due to time-varying confounding. Methods Using data from the Australian Diabetes, Obesity and Lifestyle Study, collected in 1999–2000 (T0), 2004–2005 (T1), and 2011–2012 (T2), we applied the parametric g-formula to estimate cumulative risks of death under hypothetical interventions on physical activity and/or TV viewing determined from self-report while adjusting for time-varying confounding. Results In the 6377 participants followed up for 13 yr from 2004 to 2005 to death or censoring in 2017, 781 participants died. The observed cumulative risk of death was 12.2%. The most effective hypothetical intervention was to increase weekly physical activity to >300 min (risk ratio (RR), 0.66 (0.46–0.86) compared with a “worst-case” scenario; RR, 0.83 (0.73–0.94) compared with no intervention). Reducing daily TV viewing to

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.

Background and aims Low-carbohydrate diets (LCDs) are increasingly popular but may be nutritionally inadequate. We aimed to examine if carbohydrate restriction in midlife is associated with risk of developing type 2 diabetes (T2DM), and if this association differs by previous gestational diabetes (GDM) diagnosis. Methods and results Dietary intake was assessed for 9689 women from the Australian Longitudinal Study on Women's Health in 2001 (aged 50–55) and 2013 (aged 62–67) via validated food frequency questionnaires. Average long-term carbohydrate restriction was assessed using a low-carbohydrate diet score (highest quartile (Q4) indicating lowest proportion of energy from carbohydrates). Incidence of T2DM between 2001 and 2016 was self-reported at 3-yearly surveys. Log-binomial regression was used to estimate relative risks (RR) and 95% CIs. During 15 years of follow-up, 959 women (9.9%) developed T2DM. Carbohydrate restriction was associated with T2DM after adjustment for sociodemographic factors, history of GDM diagnosis and physical activity (Q4 vs Q1: RR 1.27 [95% CI 1.10, 1.48]), and this was attenuated when additionally adjusted for BMI (1.10 [0.95, 1.27]). Carbohydrate restriction was associated with lower consumption of fruit, cereals and high-fibre bread, and lower intakes of these food groups were associated with higher T2DM risk. Associations did not differ by history of GDM (P for interaction >0.15). Conclusion Carbohydrate restriction was associated with higher T2DM incidence in middle-aged women, regardless of GDM history. Health professionals should advise women to avoid LCDs that are low in fruit and grains, and to consume a diet in line with current dietary recommendations.

Background Socio-economic inequalities in mortality are well established, yet the contribution of intermediate risk factors that may underlie these relationships remains unclear. We evaluated the role of multiple modifiable intermediate risk factors underlying socio-economic-associated mortality and quantified the potential impact of reducing early all-cause mortality by hypothetically altering socio-economic risk factors. Methods Data were from seven cohort studies participating in the LIFEPATH Consortium (total n = 179 090). Using both socio-economic position (SEP) (based on occupation) and education, we estimated the natural direct effect on all-cause mortality and the natural indirect effect via the joint mediating role of smoking, alcohol intake, dietary patterns, physical activity, body mass index, hypertension, diabetes and coronary artery disease. Hazard ratios (HRs) were estimated, using counterfactual natural effect models under different hypothetical actions of either lower or higher SEP or education. Results Lower SEP and education were associated with an increase in all-cause mortality within an average follow-up time of 17.5 years. Mortality was reduced via modelled hypothetical actions of increasing SEP or education. Through higher education, the HR was 0.85 [95% confidence interval (CI) 0.84, 0.86] for women and 0.71 (95% CI 0.70, 0.74) for men, compared with lower education. In addition, 34% and 38% of the effect was jointly mediated for women and men, respectively. The benefits from altering SEP were slightly more modest. Conclusions These observational findings support policies to reduce mortality both through improving socio-economic circumstances and increasing education, and by altering intermediaries, such as lifestyle behaviours and morbidities.

Men with prostate cancer experience side effects for which a supportive social environment may be beneficial. We examined the association between four measures of social connectedness and mortality after a prostate cancer diagnosis. Male participants in the Melbourne Collaborative Cohort Study in 1990-1994, who developed incident prostate cancer and attended follow-up in 2003-2007, were eligible for the study. Information on social connectedness, collected at follow-up, included (i) living arrangement; (ii) frequency of visits to friends/relatives and (iii) from friends/relatives; (iv) weekly hours of social activities. A total of 1,421 prostate cancer cases was observed (338 all-cause deaths, 113 from prostate cancer), including 867 after follow-up (150 all-cause deaths, 55 from prostate cancer) and 554 before follow-up (188 all-cause deaths, 58 from prostate cancer). Cox models stratified by tumour Gleason score and stage, and sequentially adjusted for socioeconomic, health- and lifestyle-related confounders, were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between social connectedness and all-cause mortality after prostate cancer. Men who reported living alone before diagnosis had higher overall mortality (HR = 1.6, 95% CI: 1.0-2.5), after adjustment for socioeconomic, health and lifestyle confounders. Lower mortality was observed for men with more social activities (p-trend = 0.07), but not in comprehensively adjusted models. Consistent with these findings, men living alone after prostate cancer diagnosis had higher mortality (HR = 1.3, 95% CI: 0.9-1.9). Lower mortality was observed with increasing socializing hours in the age-adjusted model (p-trend = 0.06) but not after more comprehensive adjustment. Our findings suggest that living with someone, but not other aspects of social connectedness, may be associated with decreased mortality for men with prostate cancer.

Background Adherence to a traditional Mediterranean diet has been associated with lower mortality and cardiovascular disease risk. The relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time remains unknown. Methods We used the parametric G-formula to account for time-dependent confounding, in order to assess the relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time. We included healthy Melbourne Collaborative Cohort Study participants attending a visit during 1995–1999. Questionnaires assessed diet and physical activity at each of three study waves. Deaths were identified by linkage to national registries. We estimated mortality risk over approximately 14 years (1995–2011). Results Of 22,213 participants, 2163 (9.7%) died during 13.6 years median follow-up. Sustained high physical activity and adherence to a Mediterranean-style diet resulted in an estimated reduction in all-cause mortality of 1.82 per 100 people (95% confidence interval (CI): 0.03, 3.6). The population attributable fraction was 13% (95% CI: 4, 23%) for sustained high physical activity, 7% (95% CI: − 3, 17%) for sustained adherence to a Mediterranean-style diet and 18% (95% CI: 0, 36%) for their combination. Conclusions A small reduction in mortality may be achieved by sustained elevated physical activity levels in healthy middle-aged adults, but there may be comparatively little gain from increasing adherence to a Mediterranean-style diet.

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

Background Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. Methods Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors. Results From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with 0.16). Conclusions The relationship between TV time and all-cause mortality may change with age. It may also be more pronounced in those who are otherwise inactive or who have a pro-inflammatory diet.

An unhealthy diet is a recognized risk factor in the pathophysiology of numerous chronic noncommunicable diseases (NCD), including obesity, type 2 diabetes (T2DM), and cardiovascular diseases (CVD). This is, at least in part, due to unhealthy diets causing chronic low-grade inflammation in the gut and systemically. To characterize the inflammatory potential of diet, we developed the Dietary Inflammatory Index (DII®). Following this development, around 500 papers have been published, which examined the association between the DII, energy-adjusted DII (E-DII™), and the children's DII (C-DII™) and many chronic NCDs including obesity and cardiometabolic diseases. Although a previous narrative review published in 2019 briefly summarized the evidence in this area, there was a significant increase in papers on this topic since 2020. Therefore, the purpose of this narrative review is to provide an in-depth updated review by including all papers until July 2021 on DII and its relationship with obesity, T2DM, and CVD. Furthermore, we aim to identify potential gaps in the literature and provide future directions for research. Most studies found that DII was associated with an increased risk of obesity, T2DM, and CVD with some relationships being sex-specific. However, we identified the paucity of papers describing associations between dietary inflammation and T2DM and its risk factors. Few studies used gold-standard measures of cardiometabolic risk factors. We also identified the lack of interventional studies designed to change the inflammatory potential of diets and study its effect on cardiometabolic risk factors and diseases. We recommend that such interventional studies are needed to assess if changes in DII, representing the inflammatory potential of diet, independently of changes in body composition can modulate cardiometabolic risk factors and diseases.

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N=7,431) and validation (N=4,307) samples. Using paired genetic-methylation data (N=4,307), gene-environment interactions (i.e. PGS x lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs) and BMI (85 CpGs), and 2) two epigenetic aging measures, PhenoAge and GrimAge. In the validation sample, PGS explained ∼1.4% (P=1×10−14), ∼0.6% (P=2×10−7) and ∼8.7% (P=7×10−87) of variance in smoking initiation, alcohol consumption and BMI, respectively. Nominally significant interaction effects (PPhenoAge and GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoke (interaction term: -0.02, P=0.06) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.03, P=0.04). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify their effects on blood DNA methylation. Potential associations were observed for epigenetic aging measures, which should be replicated in additional studies.

Diet quality indices (DQIs) can be useful predictors of diet–disease relationships, including non-communicable disease (NCD) multimorbidity. We aimed to investigate whether overall diet quality (DQ) predicted NCD, multimorbidity, and all-cause mortality. Women from the 1945–51 cohort of the Australia Longitudinal Study on Women’s Health (ALSWH) were included if they: responded to S3 in 2001 and at least one survey between 2004 (S4) and 2016 (S8), and had no NCD history and complete dietary data at S3. DQ was summarized by the Healthy Eating Index for Australian Adults-2013 (HEIFA-2013), Mediterranean Diet Score (MDS), and Alternative Healthy Eating Index-2010 (AHEI-2010). Outcomes included each NCD (diabetes mellitus (DM), coronary heart disease (CHD), hypertension (HT), asthma, cancer (except skin cancer), depression and/or anxiety) independently, multimorbidity, and all-cause mortality. Repeated multivariate logistic regressions were used to test associations between DQIs and NCD outcomes across the 15 years of follow-up. The mean (±sd) of DQIs of participants (n = 5350) were 57.15 ± 8.16 (HEIFA-2013), 4.35 ± 1.75 (MDS), and 56.01 ± 10.32 (AHEI-2010). Multivariate regressions indicated that women reporting the highest quintile of AHEI-2010 had lower odds of DM (42–56% (S5–S8)), HT (26% (S8)), asthma (35–37% (S7, S8)), and multimorbidity (30–35% (S7, S8)). The highest quintile of HEIFA-2013 and MDS had lower odds of HT (26–35% (S7, S8), 24–27% (S6–S8), respectively) and depression and/or anxiety (30% (S6): 30–34% (S7, S8)). Our findings support evidence that DQ is an important predictor of some NCDs and a target for prevention in middle-aged women.

Background Helicobacter pylori (H.pylori) infection causes atrophic gastritis and gastric cancer. Ironically, decreased gastric acid production in those with atrophic gastritis might reduce harmful gastroesophageal refluxate, thereby reducing gastroesophageal reflux disease (GERD) and Barrett’s oesophagus (BE) risk. Methods In two nested case-control studies with 425 GERD and 169 BE cases, we compared sex-specific GERD and BE risk in H.pylori seronegative participants with seropositive participants. Where seronegativity was associated with increased BE risk, we quantified the effect mediated by GERD using a Monte Carlo simulation-based g-computation approach to estimate interventional effects. Moreover, we classified participants into gastritis types using serum pepsinogen-I and gastrin-17 data. Results For men, H.pylori seronegativity was associated with 1.69-fold (CI:1.03-2.75) and 2.14-fold (CI:1.18-3.88) higher odds for GERD and BE respectively. Five (33%) out of the 15 per 1000 excess BE risk from being seronegative was mediated by GERD. No association was observed for women. Among those seropositive, the proportion with atrophic antral gastritis was higher for men than for women (68% vs 56%; p = 0.015). Conclusions H.pylori seronegativity was associated with increased GERD and BE risk for men but not women, which could be partly explained by the higher proportion of H.pylori-associated atrophic antral gastritis in men. Evidence of GERD mediating seronegativity’s effect on BE supports this explanation. Key messages Whilst H.pylori infection might reduce GERD and BE risk, this is potentially a by-product of atrophic gastritis, a risk factor for gastric cancer. Treating GERD could partly reduce the excess BE risk for seronegative individuals.

Background Inflammation is a key feature of aging and a cause of numerous diseases. We investigated the association of 35 blood markers involved in inflammatory processes with age and mortality and developed a signature of ‘inflammaging’. Methods Thirty-five blood markers relating to the kynurenine pathway, vitamin status, and inflammation were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994, median age 59 years) and follow-up (2003-2007, median age 70 years). Associations of each marker with age and all-cause mortality were assessed using linear and Cox regression, respectively. A signature of inflammaging was obtained via Lasso regression of age on the markers and tested for association with mortality; we compared mortality associations for this signature and two weighted scores across all markers associated with age and mortality, respectively. Results Most markers (29/35) were associated with age, with strongest associations observed for cystatin C, neopterin, quinolinic acid, and the kynurenine/tryptophan ratio, PAr index, and 3-hydroxykynurenine/xanthurenic acid ratio. Many markers (14/35) showed strong associations with mortality in particular neopterin, quinolinic acid, HK/XA, PAr index, CRP, IL-6 and KTr. The inflammaging signature included six markers and showed strong association with mortality (HR = 1.5, 95%CI: 1.3-1.7), almost as strong as the association of weighted scores combining all measured markers. Conclusions Our study highlights the key role played by markers of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. Key messages A signature of ‘inflammaging’ based on 6 markers may be useful to better predict mortality.

Background Reproductive-aged women are at high risk of developing obesity, and diet quality is a potential modifiable risk factor. There is limited research exploring postpartum diet quality. Methods Using data from the Australian Longitudinal Study on women’s Health of women, who reported having previously given birth, we investigated the association between time since childbirth and diet quality, and differences in energy, macronutrients, micronutrient intake, and diet quality assessed by the dietary guideline index (DGI) in women stratified by time from last childbirth, early (≤6 months; n = 558) and late (7–12 months; n = 547), and others (>12 months post childbirth; n = 3434). Results From this cohort, 4539 participants completed a food frequency questionnaire and were included in this analysis. Overall, diet quality was higher in early and late postpartum women (mean DGI score 89.8±10.5 and 90.0±10.2, respectively) compared to others (>12 months post childbirth), (85.2±11.7; p 12 months), smoking compared with non-smoking and medium income level compared with no income was negatively associated with diet quality. Conclusions A lower diet quality in women >12 months post childbirth may be reflective of increased pressures, balancing childrearing and return to work responsibilities. This highlights the need to support women beyond the postpartum period to improve modifiable factors associated with weight gain, including diet quality, to optimize health and reduce chronic disease risk. Key messages Diet quality; nutrition; obesity; prevention; postpartum; reproductive; women

Background Alcohol consumption is causally linked to several cancer sites but the evidence for stomach cancer is still inconclusive. We aimed to quantify the association between alcohol intake and risk of stomach cancer, including subtypes. Methods We pooled data from two cohort studies including 452,958 individuals enrolled in the European Prospective Investigation into Cancer in 1992-98 and 38,756 Australians enrolled in the Melbourne Collaborative Cohort Study in 1990-94. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident stomach cancer were estimated using Cox regression. Results 1,225 incident stomach cancers were diagnosed over 7,094,637 person-years. Alcohol intake was not associated with overall stomach cancer risk. We observed a weak positive dose-response association for lifetime intake with non-cardia stomach cancer (HR = 1.03, 95% CI: 1.00-1.06/per 10 g/day increment), which is the more common type (77.6% of cases), and a weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) (phomogeneity=0.006). These associations did not differ appreciably by smoking or Helicobacter pylori infection status. Differences in HRs between diffuse-type and intestinal-type cancer were minimal (phomogeneity=0.97). HRs of 1.50 (95% CI: 1.12-2.01) for non-cardia and 0.53 (95% CI: 0.27-1.02) for cardia cancer were observed for a life course trajectory characterised by sustained heavy drinking compared with light drinking (phomogeneity=0.01). Conclusions Lifetime alcohol intake was associated with increased risk of non-cardia stomach cancer. The inverse association for cardia cancer indicates aetiologic differences between subsites. Key messages Limiting long-term alcohol consumption, and avoiding heavy use in particular, might be beneficial in preventing non-cardia stomach cancer.

Background Lifestyle behaviours may worsen following childbirth due to barriers such as time constraints and reduced prioritization of personal health. We therefore aimed to assess the patterns of change in weight and lifestyle behaviours following childbirth in a longitudinal community-based cohort. Methods Data from surveys 3 and 5 (ages 25-30 and 31-36 years) of the 1973-8 birth cohort of the Australian Longitudinal Study on Women’s Health were used. We assessed changes in weight, energy intake, diet (diet quality, macronutrients and micronutrients), physical activity and sitting time in parous women compared to those who remained nulliparous by survey 5 using one-way analysis of covariance. Results Of 4927 nulliparous women at survey 3, 2503 became parous by survey 5. Over 6 years, parous women had an increase in weight (1 kg; 95%CI 0.50, 1.54), higher energy intake (833.3 kJ/day; 95%CI 706.07, 960.52), better diet quality (1.4 units; 95%CI 0.81, 2.08), lower physical activity (-370.5 METmin/day; 95%CI -427.07, -313.87) and less sitting time (-1.8 hours/day; 95%CI -1.93, -1.60) than nulliparous women on adjusted analyses. On stratification of parity, the improvement in diet quality was only present in primiparous women and sitting time decreased with higher parity. Conclusion There is a worsening in weight and some lifestyle behaviours following childbirth in Australian women. While higher parity was associated with further decreases in sitting time, improvements in diet quality were not maintained. Key message Women need support to maintain healthy lifestyle behaviours amidst the challenges of caring for children, particularly with increasing family size.

Background Women with polycystic ovary syndrome (PCOS) have a higher prevalence of overweight/obesity and greater weight gain than women without PCOS. The association of lifestyle factors with weight change in PCOS is not known. Methods We used data from the 1973-78 birth cohort of the Australian Longitudinal Study on Women’s Health collected from seven surveys over 19 years (N = 14127 survey 1). Linear mixed-effects models were used to examine associations between diet, physical activity, and sitting time with weight change, after adjustment for socio-demographics, psychological factors, and health care utilisation. Results Women with PCOS gained more weight annually (0·26 kg/year, 95% CI 0·13, 0·39; P Conclusions Women with PCOS had a higher rate of weight gain than women without PCOS. This was most marked in those with indicators of unhealthy lifestyles. Increased stress, energy intake and sitting time and lower physical activity contributed to weight gain in women with and without PCOS. Key messages The findings reinforce the importance of early and ongoing lifestyle intervention and the potential use of specific lifestyle factors for weight gain prevention and management in PCOS.

Educational inequalities in mortality have been observed for decades, however the underlying biological mechanisms are not well known. We assessed the mediating role of altered aging of immune cells functioning captured by DNA methylation changes in blood (known as epigenetic clocks) in educational associated all-cause mortality. Data were from eight prospective population-based cohort studies, representing 13,021 participants. We found educational inequalities in mortality were larger for men than for women, estimated by hazard differences and ratios. Epigenetic clocks explained approximately 50% of educational inequalities in mortality for men, while the proportion was small for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the WHO risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.