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Purpose: We aimed to investigate the associations between parental BMI and offspring BMI trajectories and to explore whether the parent-offspring BMI growth trajectory association differed according to family SEP or social mobility., Methods: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Children's weight and height were collected from 1 to 18 years. Parents' height and weight were reported pre-pregnancy. We assessed family SEP by measuring parents' and grandparents' educational attainment, social class, and social mobility by changes in education attainment across generations. Multilevel models were used to develop trajectories and assess patterns of change in offspring BMI, to associate parental BMI with these trajectories, and explore whether these associations differed by family SEP and social mobility., Results: 13,612 children were included in the analyses. The average BMI of offspring whose parents were overweight or obese was higher throughout childhood and adolescence, compared to those with parents of normal BMI. Parental and grandparental low SEP were associated with higher child BMI, but there was little evidence of modification of parent-offspring associations. For example, at age 15 years the predicted mean BMI difference between children of overweight or obese mothers versus normal-weight mothers was 12.5 % (95 %CI: 10.1 % to 14.7 %) and 12.2 % (95 %CI: 10.3 % to 13.7 %) for high and low grandparental SEP, respectively., Discussion: These findings strengthen the evidence that higher parental BMI and lower family SEP were associated with higher offspring BMI, but we did not observe strong evidence that family SEP modifies the parental-offspring BMI association., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation influences tumour progression and cancer prognosis, but its role preceding breast cancer (BC) and its prognostic implications remain inconclusive., Methods: We studied pre-diagnostic plasma inflammatory biomarkers in 1538 women with BC from the EPIC study. Cox proportional hazards models assessed their relationship with all-cause and BC-specific mortality, adjusting for tumour characteristics and lifestyle factors., Results: Over a 7-year follow-up after diagnosis, 229 women died, 163 from BC. Elevated IL-6 levels were associated with increased all-cause mortality risk (HR 1-SD 1.25, 95% CI 1.07-1.47). Among postmenopausal, IL-6 was associated with higher all-cause (HR 1-SD 1.41, 95% CI 1.18-1.69) and BC-specific mortality (HR 1-SD 1.31, 95% CI 1.03-1.66), (P Heterogeneity (pre/postmenopausal)  < 0.05 for both), while IL-10 and TNFα were associated with all-cause mortality only (HR 1-SD 1.19, 95% CI 1.02-1.40 and HR 1-SD 1.28, 95% CI 1.06-1.56). Among ER+PR+, IL-10 was associated with all-cause and BC-specific mortality (HR 1-SD 1.35, 95% CI 1.10-1.65 and HR 1-SD 1.42 95% CI 1.08-1.86), while TNF-α was associated with all-cause mortality in HER2- (HR 1-SD 1.31, 95% CI 1.07-1.61). An inflammatory score predicted higher all-cause mortality, especially in postmenopausal women (HR 1-SD 1.30, 95% CI 1.07-1.58)., Conclusions: Higher pre-diagnosis IL-6 levels suggest poorer long-term survival among BC survivors. In postmenopausal survivors, elevated IL-6, IL-10, and TNFα and inflammatory scores seem to predict all-cause mortality., (© 2024. The Author(s).)

Background: Omega-3 fatty acids derived from seafood acids may influence cardiac arrhythmogenesis, whereas the role of the major plant-derived omega-3 fatty acid, alpha-linolenic acid (ALA), on atrial fibrillation (AF) is largely unknown., Objectives: We aimed to investigate the association between ALA intake and risk of incident AF overall and in subjects with a low intake of marine omega-3 fatty acids., Methods: We followed a total of 54,260 middle-aged men and women enrolled into the Danish Diet, Cancer, and Health cohort for development of AF using nationwide registries. Intake of ALA was assessed using a validated food frequency questionnaire and modeled as a restricted cubic spline. Statistical analyses were conducted using Cox proportional hazards regression., Results: We identified a total of 4902 incident AF events during a median of 16.9 y of follow-up. In multivariable analyses, we observed indications of a statistically nonsignificant inverse association between ALA intake and risk of AF up to an ALA intake of 2.5 g/d, whereas no appreciable association was found for higher intakes of ALA. A statistically significant dose-dependent negative association was found between ALA intake and risk of AF in individuals consuming < 250 mg marine omega-3 fatty acids daily, whereas no association was found in those with a higher intake of marine omega-3 fatty acids., Conclusions: Intake of ALA was associated with a lower risk of AF in individuals consuming a low intake of marine omega-3 fatty acids. This finding is novel and warrants further investigation., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts., Methods: Participants from EPIC (n = 17,943, 69.1% women) and UK Biobank (n = 426,223, 53.2% women) with data on anthropometric indexes and C-reactive protein (CRP) were included in this cross-sectional analysis. A subset of women in EPIC also had at least one measurement for interleukins, tumour necrosis factor alpha, interferon gamma, leptin, and adiponectin. Four distinct body shape phenotypes were derived by a principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). PC1 described overall adiposity, PC2 tall with low WHR, PC3 tall and centrally obese, and PC4 high BMI and weight with low WC and HC, suggesting an athletic phenotype. ABSI, HI, waist-to-height ratio and waist-to-hip index (WHI) were also calculated. Linear regression models were carried out separately in EPIC and UK Biobank stratified by sex and adjusted for age, smoking status, education, and physical activity. Results were additionally combined in a random-effects meta-analysis., Results: Traditional anthropometric indexes, particularly BMI, WC, and weight were positively associated with CRP levels, in men and women. Body shape phenotypes also showed distinct associations with CRP. Specifically, PC2 showed inverse associations with CRP in EPIC and UK Biobank in both sexes, similarly to height. PC3 was inversely associated with CRP among women, whereas positive associations were observed among men., Conclusions: Specific indexes of body size and body fat distribution showed differential associations with inflammation in adults. Notably, our results suggest that in women, height may mitigate the impact of a higher WC and HC on inflammation. This suggests that subtypes of adiposity exhibit substantial variation in their inflammatory potential, which may have implications for inflammation-related chronic diseases., (© 2024. The Author(s).)

Introduction: Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality., Methods: In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols)., Results: Plant-sourced nitrate intake was inversely associated with all-cause mortality [HR Q5vsQ1 : 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses., Conclusion: Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality., (© 2024. The Author(s).)

Primary liver cancer is globally on the rise, partially due to poor diets and sedentary lifestyles. Shifting to more plant-based diets may lower the risk. We aimed to estimate the effect of replacing total red meat, unprocessed red meat and processed red meat with legumes on primary liver cancer in a free-living population. We analyzed data from 126,744 UK Biobank participants who completed ≥ two 24 h diet recalls. Baseline characteristics were collected from the initial assessment visit. Information on liver cancer diagnoses was collected via external linkage to inpatient hospital episodes or central cancer registries. Cox proportional hazards regression models were used to estimate the substitution of 15 g/day of legumes with 15 g/day of total red meat, unprocessed red meat or processed red meat on liver cancer risk, using the leave-one-out food substitution model. During a median follow-up time of 11.1 years, 173 participants developed liver cancer. In the fully adjusted models, no association was observed when substituting 15 g/day of legumes with total red meat (HR: 1.02 (95% CI 0.96-1.08)), unprocessed red meat (HR: 1.00 (95% CI 0.94-1.06)) or processed red meat (HR: 1.09 (95% CI 0.99-1.21)). Overall, little evidence of an association between replacing red meat with legumes and liver cancer was observed. Further research in other study populations with longer follow-up time is warranted.

The healthy lifestyle index (HLI), defined as the unweighted sum of individual lifestyle components, was used to investigate the combined role of lifestyle factors on health-related outcomes. We introduced weighted outcome-specific versions of the HLI, where individual lifestyle components were weighted according to their associations with disease outcomes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the association between the standard and the outcome-specific HLIs and the risk of T2D, CVD, cancer, and all-cause premature mortality. Estimates of the hazard ratios (HRs), the Harrell's C-index and the population attributable fractions (PAFs) were compared. For T2D, the HR for 1-SD increase of the standard and T2D-specific HLI were 0.66 (95% CI: 0.64, 0.67) and 0.43 (0.42, 0.44), respectively, and the C-index were 0.63 (0.62, 0.64) and 0.72 (0.72, 0.73). Similar, yet less pronounced differences in HR and C-index were observed for standard and outcome-specific estimates for cancer, CVD and all-cause mortality. PAF estimates for mortality before age 80 were 57% (55%, 58%) and 33% (32%, 34%) for standard and mortality-specific HLI, respectively. The use of outcome-specific HLI could improve the assessment of the role of lifestyle factors on disease outcomes, thus enhancing the definition of public health recommendations., (© 2024. The Author(s).)

Purpose of Review: This review highlights recent developments in understanding the role of dietary fibre and specific fibre types on risk and management of cardiometabolic disease with a focus on the causal pathways leading to cardiometabolic diseases, namely weight management, glycaemic control, and lipid levels, as well as the latest findings for cardiovascular disease outcomes such as coronary heart disease, stroke, and mortality. Evidence for mechanisms through gut microbiota are also briefly reviewed., Recent Findings: Dietary fibre intake is associated with improved weight management, the extent of which may depend on the subtype of dietary fibre. Overall dietary fibre intake reduces blood glucose and HbA1c, however soluble fibres may be particularly effective in reducing HbA1c, fasting blood glucose and blood lipids. Individual meta-analyses and umbrella reviews of observational studies on dietary fibre, as well as major fibre types, observed inverse associations with incident coronary heart disease, stroke, and mortality due to cardiovascular disease. As different types of fibres exerted different health benefits, fibre diversity (i.e. combinations of fibres) should be further investigated., Summary: Dietary fibres improve both short-term and long-term cardiometabolic disease risk factors and outcomes, and thus should be on every menu., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Individuals with both atrial fibrillation (AF) and myocardial infarction (MI) have higher mortality compared with individuals with only 1 condition. Whether mortality differs according to the temporal order of AF and MI is unclear., Methods and Results: We included participants from the FHS (Framingham Heart Study) from 1960 and onwards. We assessed the hazard ratio (HR) of new-onset AF and MI, and mortality according to MI and AF status (prevalent and interim) using multivariable-adjusted Cox proportional hazards models. Interim diseases were modeled as time-varying variables. For the analysis of new-onset AF, 10 923 participants (55% women; mean±SD age, 54±8 years) were included. For new-onset MI, 10 804 participants (55% women; mean±SD age, 54±8 years) were included. Compared with no MI, the hazard of new-onset AF was higher in participants with prevalent (HR, 1.60 [95% CI, 1.32-1.94]) and interim MI (HR, 3.96 [95% CI, 3.18-4.91]). Both ST-segment-elevation MI and non-ST-segment-elevation MI were associated with new-onset AF. Interim AF, not prevalent AF, was associated with higher hazard rate of new-onset MI (HR, 2.21 [95% CI, 1.67-2.92]). Interim AF was associated with both ST-segment-elevation MI and non-ST-segment-elevation MI. Mortality was significantly greater among participants with AF and MI compared with participants with 1 of the 2, regardless of temporal order., Conclusions: We report a bidirectional association between AF and MI, which was observed for both non-ST-segment-elevation MI and ST-segment-elevation MI. Participants with both AF and MI had considerably higher mortality compared with participants with only 1 of the 2 conditions, regardless of order.

Background: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality., Methods: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed., Results: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality., Conclusions: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk., (© 2024. World Health Organization.)

Different approaches have been used for translation of the EAT-Lancet reference diet into dietary scores that can be used to assess health and environmental impact. Our aim was to compare the different EAT-Lancet diet scores, and to estimate their associations with all-cause mortality, stroke incidence, and greenhouse gas emissions. We did a systematic review (PROSPERO, CRD42021286597) to identify different scores representing adherence to the EAT-Lancet reference diet. We then qualitatively compared the diet adherence scores, including their ability to group individuals according the EAT-Lancet reference diet recommendations, and quantitatively assessed the associations of the diet scores with health and environmental outcome data in three diverse cohorts: the Danish Diet, Cancer and Health Cohort (DCH; n=52 452), the Swedish Malmö Diet and Cancer Cohort (MDC; n=20 973), and the Mexican Teachers' Cohort (MTC; n=30 151). The DCH and MTC used food frequency questionnaires and the MDC used a modified diet history method to assess dietary intake, which we used to compute EAT-Lancet diet scores and evaluate the associations of scores with hazard of all-cause mortality and stroke. In the MDC, dietary greenhouse gas emission values were summarised for every participant, which we used to predict greenhouse gas emissions associated with varying diet adherence scores on each scoring system. In our review, seven diet scores were identified (Knuppel et al, 2019; Trijsburg et al, 2020; Cacau et al, 2021; Hanley-Cook et al, 2021; Kesse-Guyot et al, 2021; Stubbendorff et al, 2022; and Colizzi et al, 2023). Two of the seven scores (Stubbendorff and Colizzi) were among the most consistent in grouping participants according to the EAT-Lancet reference diet recommendations across cohorts, and higher scores (greater diet adherence) were associated with decreased risk of mortality (in the DCH and MDC), decreased risk of incident stroke (in the DCH and MDC for the Stubbendorff score; and in the DCH for the Colizzi score), and decreased predicted greenhouse gas emissions in the MDC. We conclude that the seven different scores representing the EAT-Lancet reference diet had differences in construction, interpretation, and relation to disease and climate-related outcomes. Two scores generally performed well in our evaluation. Future studies should carefully consider which diet score to use and preferably use multiple scores to assess the robustness of estimations, given that public health and environmental policy rely on these estimates., Competing Interests: Declaration of interests AS, UE, and ES were all involved in constructing one of the EAT–Lancet diet scores investigated (Stubbendorff et al(8)). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Epidemiological evidence suggests that a potential association between dietary protein intake and cardiovascular disease (CVD) may depend on the protein source, that is, plant- or animal-derived, but past research was limited and inconclusive., Objectives: To evaluate the association of dietary plant- or animal-derived protein consumption with risk of CVD, and its components ischemic heart disease (IHD) and stroke., Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study included 16,244 incident CVD cases (10,784 IHD and 6423 stroke cases) and 15,141 subcohort members from 7 European countries. We investigated the association of estimated dietary protein intake with CVD, IHD, and stroke (total, fatal, and nonfatal) using multivariable-adjusted Prentice-weighted Cox regression. We estimated isocaloric substitutions of replacing fats and carbohydrates with plant- or animal-derived protein and replacing food-specific animal protein with plant protein. Multiplicative interactions between dietary protein and prespecified variables were tested., Results: Neither plant- nor animal-derived protein intake was associated with incident CVD, IHD, or stroke in adjusted analyses without or with macronutrient-specified substitution analyses. Higher plant-derived protein intake was associated with 22% lower total stroke incidence among never smokers [HR 0.78, 95% confidence intervals (CI): 0.62, 0.99], but not among current smokers (HR 1.08, 95% CI: 0.83, 1.40, P-interaction = 0.004). Moreover, higher plant-derived protein (per 3% total energy) when replacing red meat protein (HR 0.52, 95% CI: 0.31, 0.88), processed meat protein (HR 0.39, 95% CI: 0.17, 0.90), and dairy protein (HR 0.54, 95% CI: 0.30, 0.98) was associated with lower incidence of fatal stroke., Conclusion: Plant- or animal-derived protein intake was not associated with overall CVD. However, the association of plant-derived protein consumption with lower total stroke incidence among nonsmokers, and with lower incidence of fatal stroke highlights the importance of investigating CVD subtypes and potential interactions. These observations warrant further investigation in diverse populations with varying macronutrient intakes and dietary patterns., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The relationship between combined genetic predisposition and lifestyle and the risk of incident atrial fibrillation (AF) is unclear. Therefore, we aimed to assess a possible interaction between lifestyle and genetics on AF risk., Methods: We included AF cases and a randomly drawn subcohort of 4040 participants from the Danish Diet, Cancer and Health cohort. Lifestyle risk factors were assessed, a score was calculated, and participants were categorised as having a poor, intermediate, or ideal lifestyle. We calculated a genetic risk score comprising 142 variants, and categorised participants into low (quintile 1), intermediate (quintiles 2-4) or high (quintile 5) genetic risk of AF., Results: 3094 AF cases occurred during a median follow-up of 12.9 years. Regardless of genetic risk, incidence rates per 1000 person-years were gradually higher with worse lifestyle. For participants with high genetic risk, the incidence rates of AF per 1000 person-years were 5.0 (95% CI 3.4 to 7.3) among individuals with ideal lifestyle, 6.6 (95% CI 5.4 to 8.1) among those with intermediate lifestyle and 10.4 (95% CI 9.2 to 11.8) among participants with poor lifestyle. On an additive scale, there was a positive statistically significant interaction between genetic risk and lifestyle (relative excess risk due to interaction=0.86, 95% CI 0.68 to 1.03, p<0.001)., Conclusions: The rates of AF increased gradually with worse lifestyle within each category of genetic risk. We found a positive interaction on an additive scale between genetic risk and lifestyle, suggesting that risk factor modification is especially important in individuals with a high genetic risk of AF., Competing Interests: Competing interests: HKJ received lecture fees from Abbott Denmark, Amgen Denmark and Biosense Webster, Europe. There are no other conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk., (© 2023. Springer Nature B.V.)

Purpose: Previously reported associations of protein-rich foods with stroke subtypes have prompted interest in the assessment of individual amino acids. We examined the associations of dietary amino acids with risks of ischaemic and haemorrhagic stroke in the EPIC study., Methods: We analysed data from 356,142 participants from seven European countries. Dietary intakes of 19 individual amino acids were assessed using validated country-specific dietary questionnaires, calibrated using additional 24-h dietary recalls. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of ischaemic and haemorrhagic stroke in relation to the intake of each amino acid. The role of blood pressure as a potential mechanism was assessed in 267,642 (75%) participants., Results: After a median follow-up of 12.9 years, 4295 participants had an ischaemic stroke and 1375 participants had a haemorrhagic stroke. After correction for multiple testing, a higher intake of proline (as a percent of total protein) was associated with a 12% lower risk of ischaemic stroke (HR per 1 SD higher intake 0.88; 95% CI 0.82, 0.94). The association persisted after mutual adjustment for all other amino acids, systolic and diastolic blood pressure. The inverse associations of isoleucine, leucine, valine, phenylalanine, threonine, tryptophan, glutamic acid, serine and tyrosine with ischaemic stroke were each attenuated with adjustment for proline intake. For haemorrhagic stroke, no statistically significant associations were observed in the continuous analyses after correcting for multiple testing., Conclusion: Higher proline intake may be associated with a lower risk of ischaemic stroke, independent of other dietary amino acids and blood pressure., (© 2023. The Author(s).)

Aims: Obesity is a major risk factor for atrial fibrillation (AF). Compared with stable weight, gaining weight was associated with a higher risk of incident AF in observational studies. The results, however, are conflicting regarding weight loss and risk of AF. This study aimed to assess the association between 5-year weight changes and risk of incident AF., Methods and Results: The study was based on participants from the Danish Diet, Cancer, and Health Cohort. Body mass index (BMI) was assessed at a baseline examination and at a second examination 5 years later. Diagnoses of AF and co-morbidities were retrieved from the Danish National Patient Registry. In total, 43 758 participants without prior AF were included. The median age was 61 years and 54% were female. During a median follow-up of 15.7 years, 5312 individuals had incident AF (incidence rate 8.6/1000 person-years). Compared with stable weight, weight gain between 2.5 and 5 BMI units (kg/m2) was associated with a higher risk of AF [hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.09-1.41]. Weight gain of 5 or more BMI units (kg/m2) was associated with a HR of 1.95 (95% CI 1.48-2.56) of incident AF. However, there was no statistically significant association between weight loss and risk of AF., Conclusion: Five-year weight gain was associated with greater risk of AF compared with stable weight in the Danish Diet, Cancer, and Health Cohort. There was no statistically significant association between weight loss and risk of AF., Competing Interests: Conflict of interest: H.K.J. received lecture fees from Abbott Denmark and Biosense Webster, Europe. There are no other conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Obesity may track across generations, due to genetics and shared family environmental factors, or possibly intrauterine programming. However, many studies only assess associations between maternal body mass index (BMI) and offspring BMI in childhood. To determine whether maternal and paternal associations with offspring BMI differ and whether associations persist into adulthood, a systematic review and meta-analysis was done. PubMed, Embase, Web of Science, and Google Scholar (to October 2022) were searched. Observational studies reporting associations between maternal or paternal BMI and adult offspring BMI were included. Offspring BMIs were reported as continuous or categorical measures. Forty-six studies were included in the systematic review. Meta-analyses were conducted using random-effects models. Parental BMI was positively associated with offspring BMI in adulthood. The pooled mother-offspring standardized mean difference (SMD) was 0.23 (95% confidence interval [CI]: 0.20, 0.26), and father-offspring SMD was similar: 0.22 (95% CI: 0.19, 0.25) in adjusted models. Offspring of mothers with overweight or obesity had the same risk of higher BMI as offspring of fathers with overweight or obesity. If these associations are causal, they support interventions targeting all family members, rather than focusing solely on mothers, to obtain a healthy weight development among offspring., (© 2023 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Introduction: Dementia after stroke is common and is a great concern for patients and their caregivers. The objective was to investigate if intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) was associated with lower risk of dementia after stroke., Patients and Methods: When IVT was introduced in Denmark, not all eligible patients were treated due to restricted access. We conducted a nationwide register-based cohort study of all patients with AIS in Denmark from 2004 to 2011. IVT-treated patients were propensity score-matched with comparable non-treated patients. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for all-cause and vascular dementia 2, 5, and 10 years after stroke., Results: Of the 5919 patients eligible for the study, 2305 IVT-treated patients were propensity score-matched with 2305 non-treated patients. Mean (SD) age was 66.6 (13.3) and 61.2% were male. Rate of all-cause dementia was lower for the IVT-treated 2 years (8.4/1000 person years (PY) vs 13.6/1000 PY, HR 0.63 (0.40-0.99)) and 5 years after stroke (7.3/1000 PY vs 11.4/1000 PY, HR 0.65 (0.46-0.91)). 10 years after stroke, the rates of all-cause dementia remained in favor of IVT (8.0/1000 PY vs 9.8/1000 PY, HR 0.83 (0.64-1.07)). IVT-treated had lower rates of vascular dementia 2 years (2.4/1000 PY vs 7.4/1000 PY, HR 0.33 (0.15-0.71)), 5 years (2.3/1000 PY vs 6.2/1000 PY, HR 0.38 (0.23-0.65)), and 10 years after stroke (3.0/1000 PY vs 5.4/1000 PY, HR 0.56 (0.38-0.81))., Conclusion: IVT treatment was associated with lower long-term risk of both vascular and all-cause dementia after AIS., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Background: Large language models have had a huge impact on natural language processing (NLP) in recent years. However, their application in epidemiological research is still limited to the analysis of electronic health records and social media data., Objectives: To demonstrate the potential of NLP beyond these domains, we aimed to develop prediction models based on texts collected from an epidemiological cohort and compare their performance to classical regression methods., Methods: We used data from the British National Child Development Study, where 10,567 children aged 11 years wrote essays about how they imagined themselves as 25-year-olds. Overall, 15% of the data set was set aside as a test set for performance evaluation. Pretrained language models were fine-tuned using AutoTrain (Hugging Face) to predict current reading comprehension score (range: 0-35) and future BMI and physical activity (active vs inactive) at the age of 33 years. We then compared their predictive performance (accuracy or discrimination) with linear and logistic regression models, including demographic and lifestyle factors of the parents and children from birth to the age of 11 years as predictors., Results: NLP clearly outperformed linear regression when predicting reading comprehension scores (root mean square error: 3.89, 95% CI 3.74-4.05 for NLP vs 4.14, 95% CI 3.98-4.30 and 5.41, 95% CI 5.23-5.58 for regression models with and without general ability score as a predictor, respectively). Predictive performance for physical activity was similarly poor for the 2 methods (area under the receiver operating characteristic curve: 0.55, 95% CI 0.52-0.60 for both) but was slightly better than random assignment, whereas linear regression clearly outperformed the NLP approach when predicting BMI (root mean square error: 4.38, 95% CI 4.02-4.74 for NLP vs 3.85, 95% CI 3.54-4.16 for regression). The NLP approach did not perform better than simply assigning the mean BMI from the training set as a predictor., Conclusions: Our study demonstrated the potential of using large language models on text collected from epidemiological studies. The performance of the approach appeared to depend on how directly the topic of the text was related to the outcome. Open-ended questions specifically designed to capture certain health concepts and lived experiences in combination with NLP methods should receive more attention in future epidemiological studies., (© Rasmus Wibaek, Gregers Stig Andersen, Christina C Dahm, Daniel R Witte, Adam Hulman. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI) and vice versa. This bidirectional association relies on shared risk factors as well as on several direct and indirect mechanisms, including inflammation, atrial ischaemia, left ventricular remodelling, myocardial oxygen supply-demand mismatch and coronary artery embolism, through which one condition can predispose to the other. Patients with both AF and MI are at greater risk of stroke, heart failure and death than patients with only one of the conditions. In this Review, we describe the bidirectional association between AF and MI. We discuss the pathogenic basis of this bidirectional relationship, describe the risk of adverse outcomes when the two conditions coexist, and review current data and guidelines on the prevention and management of both conditions. We also identify important gaps in the literature and propose directions for future research on the bidirectional association between AF and MI. The Review also features a summary of methodological approaches for the study of bidirectional associations in population-based studies., (© 2023. Springer Nature Limited.)

Aims: Alcohol intake is a well-established risk factor for atrial fibrillation (AF). However, evidence on the effects of changes in alcohol intake to primary AF prevention is sparse. The aim of this study was to examine the association between 5-year changes in alcohol intake and the risk of incident AF., Methods and Results: This study was based on the Danish cohort study Diet, Cancer and Health. Lifestyle factors were assessed using questionnaires at a recruitment research examination and a second examination 5 years later. Diagnoses of AF and comorbidities were retrieved from the Danish National Patient Registry. 43 758 participants without prior AF were included. The median age was 61 (25th-75th percentile 58-66) years and 54% were female. Over a median follow-up time of 15.7 years, 5312 participants had incident AF (incidence rate 8.6/1000 person-years). Compared with stable intake, increases in alcohol intake to ≥21 drinks/week from ≤6.9 drinks/week (HR: 1.38, 95% CI: 1.09-1.72) or 14-20.9 drinks/week (HR: 1.27, 95% CI: 1.01-1.59) at baseline were associated with a higher risk of AF. In contrast, we did not observe a statistically significant association between reductions in alcohol intake and the risk of AF., Conclusion: A 5-year increase in alcohol intake was associated with a greater risk of AF compared with a stable low/moderate intake., Competing Interests: Conflict of interest: H.K.J. received lecture fees from Abbott Denmark and Biosense Webster, Europe. There are no other conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The EAT-Lancet reference diet has been proposed as a healthy dietary pattern to reduce food-related climate impacts, but little is known regarding associations with bodyweight development. This study investigated adherence to the EAT-Lancet diet in midlife and development in weight and waist circumference (WC) after five years., Design: The Danish Diet, Cancer and Health cohort recruited participants in 1993-1997. At baseline, data on diet, lifestyle, and anthropometry were collected. Participants self-reported weight and WC five years later. In total, 44,194 participants were included in analyses of weight (43,678 for WC). Baseline adherence to the EAT-Lancet diet was scored 0-14 points. Multiple linear regression was used to estimate associations between the EAT-Lancet diet and development in weight and WC after five years. Poisson regression was used to estimate risk ratios (RR) of obesity (≥30 kg/m 2 ) or elevated WC., Results: Adherence to the EAT-Lancet diet was not associated with follow-up weight, adjusting for baseline weight and confounders (11-14 vs 0-7 points β: -0.08, 95% CI: -0.27, 0.11 kg), but was associated with lower follow-up WC adjusting for baseline WC and confounders (β: -0.38, 95% CI: -0.69, -0.07 cm), and was associated with lower risk of obesity and elevated WC (RR 0.89, 95% CI: 0.82, 0.98, and 0.95, 95% CI: 0.93, 0.96, respectively)., Conclusion: Adherence to the EAT-Lancet diet in midlife was associated with lower WC but not weight after five years follow up, taking baseline into account. Our findings suggest that greater adherence to the EAT-Lancet diet does not contribute to development of obesity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

General obesity is a recognized risk factor for various metabolically related diseases, including hypertension, dyslipidemia, and pre-diabetes. In epidemiological studies, anthropometric variables such as height and weight are often self-reported. However, misreporting of self-reported data may bias estimates of associations between anthropometry and health outcomes. Further, few validation studies have compared self-reported and measured waist circumference (WC). This study aimed to quantify the agreement between self-reported and measured height, weight, body mass index (BMI), WC, and waist-to-height ratio (WHtR), and to investigate associations of these anthropometric measures with cardiometabolic biomarkers. A total of 39,514 participants aged above 18 years were included into the Diet, Cancer, and Health-Next Generation Cohort in 2015-19. Self-reported and measured anthropometric variables, blood pressure, and cardiometabolic biomarkers (HbA1c, lipid profiles, C-reactive protein and creatinine) were collected by standard procedures. Pearson correlations (r) and Lin's concordance correlations were applied to evaluate misreporting. Misreporting by age, sex and smoking status was investigated in linear regression models. Multivariable regression models and Receiver Operating Characteristic analyses assessed associations of self-reported and measured anthropometry with cardiometabolic biomarkers. Self-reported height was overreported by 1.07 cm, and weight was underreported by 0.32 kg on average. Self-reported BMI and WC were 0.42 kg/m2 and 0.2 cm lower than measured, respectively. Self-reported and measured height, weight, BMI, WC and WtHR were strongly correlated (r = 0.98, 0.99, 0.98, 0.88, 0.86, respectively). Age, sex, smoking, and BMI contributed to misreporting of all anthropometric measures. Associations between self-reported or measured anthropometric measures and cardiometabolic biomarkers were similar in direction and strength. Concordance between self-reported and measured anthropometric measures, including WC, was very high. Self-reported anthropometric measures were reliable when estimating associations with cardiometabolic biomarkers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Infant feeding practices have been hypothesized to influence offspring's body mass index (BMI) later in life, and women with overweight or obesity tend to wean their infants earlier than women with healthy BMI. We, therefore, aimed to investigate how much early age of weaning mediated the maternal-offspring adiposity relationship. The study included 4920 mother-child pairs from the Avon Longitudinal Study of Parents and Children birth cohort. G-computation was applied to estimate the natural direct (NDE) and indirect (NIE) effects, via the age of weaning (<3 months, 3 months, >3 months), of maternal pre-pregnancy overweight or obesity on offspring's BMI and fat mass index. The NDE of maternal overweight or obesity on offspring BMI at 17 years old was 2.63 kg/m 2 (95% CI: 2.27 to 2.99). The NIE via the age of weaning was 0.02 kg/m 2 (95% CI: 0.00 to 0.04), corresponding to 0.8% of the total effect. Similar results were observed for the offspring's fat mass index. The NDE and NIE were similar to the main analyses when we looked at the relationship stratified by breastfeeding status. Our study found a minimal influence of age of weaning on the pathway between maternal and offspring adiposity, indicating the age of weaning may not be a key mediator.

Background: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI)., Methods: We evaluated body shape with the allometric "a body shape index" (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Results: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961-1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951-1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822-0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835-0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049-1.098), for post-menopausal women (HR = 1.117; 1.085-1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076-1.132), and for ER + PR + subtypes (HR = 1.122; 1.080-1.165; n = 3101), but not for PR- subtypes., Conclusions: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases., (© 2023. The Author(s).)

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival., (© 2023. The Author(s).)

Background: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive., Methods: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method., Results: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HR Q5vs.Q1 :0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HR Q5vs.Q1 :0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HR Q5vs.Q1 :1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HR Q5vs.Q1 :1.11, 95%CI:0.94, 1.31), heme (HR Q5vs.Q1 :0.95; 95%CI:0.84, 1.07) or non-heme iron (HR Q5vs.Q1 :1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99)., Conclusions: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Type 2 diabetes is a global health problem. While a healthy diet lowers risk of type 2 diabetes, less is known about diets with low climate impact. This study aimed to investigate adherence to the EAT-Lancet diet and risk of type 2 diabetes in a Danish setting., Methods: In the Danish Diet, Cancer and Health cohort, dietary data were collected using a validated 192-item food frequency questionnaire, at recruitment in 1993-1997. In total, 54,232 participants aged 50-64 years at baseline with no previous cancer or diabetes diagnoses were included in the current analyses. The EAT-Lancet diet score was used to assess adherence to the EAT-Lancet diet. Participants scored 0 (non-adherence) or 1 (adherence) point for each of the 14 dietary components of the diet score (range 0-14 points). Participants were followed through register linkage until type 2 diabetes diagnosis or censoring. Hazard ratios and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regression models., Results: During a median 15-year follow-up period, 7130 participants developed type 2 diabetes. The hazard ratio for developing type 2 diabetes was 0.78 (95% CI 0.71; 0.86) for those with highest EAT-Lancet diet scores (11-14 points) compared to those with lowest scores (0-7 points) after adjusting for potential confounders. After further adjusting for potential mediators, including BMI, the corresponding hazard ratio was 0.83 (95% CI 0.76; 0.92)., Conclusion: Greater adherence to the EAT-Lancet diet was associated with a lower risk of developing type 2 diabetes in a middle-aged Danish population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort., Methods: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI)., Results: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile., Discussion: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention., (Copyright © 2022 by The American College of Gastroenterology.)

Background: Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival., Methods: The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality., Results: We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HR 1-SD 0.92; 95%CI 0.87-0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR 1-SD 1.06; 95%CI 1.00-1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality., Conclusions: Greater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors., (© 2023. The Author(s).)

Background: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts., Methods: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases., Results: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded., Conclusions: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted., (© 2023. The Author(s).)

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; P trend  = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; P trend  = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; P trend  = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; P trend  = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, P trend  = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, P trend  = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; P trend  = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; P trend  = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors., Methods: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM)., Results: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women)., Conclusions: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors., Impact: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population., (©2022 American Association for Cancer Research.)

Background: Epidemiological studies have demonstrated an association between the degree of food processing in our diet and the risk of various chronic diseases. Much of this evidence is based on the international Nova classification system, which classifies food into four groups based on the type of processing: (1) Unprocessed and minimally processed foods, (2) Processed culinary ingredients, (3) Processed foods, and (4) "Ultra-processed" foods (UPF). The ability of the Nova classification to accurately characterise the degree of food processing across consumption patterns in various European populations has not been investigated so far. Therefore, we applied the Nova coding to data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in order to characterize the degree of food processing in our diet across European populations with diverse cultural and socio-economic backgrounds and to validate this Nova classification through comparison with objective biomarker measurements., Methods: After grouping foods in the EPIC dataset according to the Nova classification, a total of 476,768 participants in the EPIC cohort (71.5% women; mean age 51 [standard deviation (SD) 9.93]; median age 52 [percentile (p)25-p75: 58-66] years) were included in the cross-sectional analysis that characterised consumption patterns based on the Nova classification. The consumption of food products classified as different Nova categories were compared to relevant circulating biomarkers denoting food processing, measured in various subsamples (N between 417 and 9,460) within the EPIC cohort via (partial) correlation analyses (unadjusted and adjusted by sex, age, BMI and country). These biomarkers included an industrial transfatty acid (ITFA) isomer (elaidic acid; exogenous fatty acid generated during oil hydrogenation and heating) and urinary 4 - methyl syringol sulfate (an indicator for the consumption of smoked food and a component of liquid smoke used in UPF)., Results: Contributions of UPF intake to the overall diet in % grams/day varied across countries from 7% (France) to 23% (Norway) and their contributions to overall % energy intake from 16% (Spain and Italy) to >45% (in the UK and Norway). Differences were also found between sociodemographic groups; participants in the highest fourth of UPF consumption tended to be younger, taller, less educated, current smokers, more physically active, have a higher reported intake of energy and lower reported intake of alcohol. The UPF pattern as defined based on the Nova classification (group 4;% kcal/day) was positively associated with blood levels of industrial elaidic acid ( r = 0.54) and 4 - methyl syringol sulfate ( r = 0.43). Associations for the other 3 Nova groups with these food processing biomarkers were either inverse or non-significant (e.g., for unprocessed and minimally processed foods these correlations were -0.07 and -0.37 for elaidic acid and 4 - methyl syringol sulfate, respectively)., Conclusion: These results, based on a large pan-European cohort, demonstrate sociodemographic and geographical differences in the consumption of UPF. Furthermore, these results suggest that the Nova classification can accurately capture consumption of UPF, reflected by stronger correlations with circulating levels of industrial elaidic acid and a syringol metabolite compared to diets high in minimally processed foods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huybrechts, Rauber, Nicolas, Casagrande, Kliemann, Wedekind, Biessy, Scalbert, Touvier, Aleksandrova, Jakszyn, Skeie, Bajracharya, Boer, Borné, Chajes, Dahm, Dansero, Guevara, Heath, Ibsen, Papier, Katzke, Kyrø, Masala, Molina-Montes, Robinson, Santiuste de Pablos, Schulze, Simeon, Sonestedt, Tjønneland, Tumino, van der Schouw, Verschuren, Vozar, Winkvist, Gunter, Monteiro, Millett and Levy.)

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD ( β = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Aims: This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors., Methods and Results: EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%)., Conclusions: In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk., Competing Interests: Conflict of interest: All the authors have nothing relevant to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses., Methods: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined., Results: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer., Conclusions: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer., Impact: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk., Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk., Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50 years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases., Results: Mean age at baseline was 50.2 years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite., Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk., (© 2022. Springer Nature B.V.)

Background: The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear., Methods: We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression., Results: During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively)., Conclusions: The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention., (© 2022. The Author(s).)