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Abstract 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.

Abstract Background Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 ( − 2.7 to 4.0)), step count (β − 124.0 ( − 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/20990

In 2019, the EAT-Lancet Commission proposed a Planetary Health Diet (PHD) to address challenges toward sustainable and healthy diets. However, its suitability within the Dutch context and a comparison with the Dutch Dietary Guidelines (DDG) needs investigation. Our study aimed to compare the PHD with DDG in terms of food groups, servings, nutritional content, and adequacy in adults. We modeled two theoretical diets, the PHD (PHD-NL) and another based on the DDG (DDG-NL), using the Dutch National Food Consumption Survey (FCS-2016) and Dutch Food Composition Database to calculate the nutritional content and compared it with the Dutch Dietary Reference Values (DRVs). The PHD included higher quantities of vegetables, fish, legumes, and nuts, while the DDG suggested more significant amounts of cereals, tubers, starchy vegetables, dairy, and red meat. We observed differences in macronutrient distribution; while both diets lacked sufficient vitamin D, calcium content was lower in the PHD-NL. The PHD-NL had higher levels of fiber, vegetable protein, unsaturated fats, and non-heme iron, while vitamins B2, B6, B12, and calcium were lower than the DDG-NL diet. The PHD-NL has nutritional adequacy in the Dutch context, except for vitamin D and calcium, although it is essential to be cautious with iron because of the bioavailability of non-heme iron in plant-based diets. These findings have implications for the adoption of a sustainable diet according to nutritional requirements, population health status, and sociocultural context, as well as compliance with specific dietary behaviors of populations.

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 Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. Methods and findings We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. Conclusions These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860. Jakub G Sobiecki and team aim to develop a biomarker score able to discriminate between Mediterranean diet and habitual diet, and test its association with incident type 2 diabetes in a European cohort. Author summary Why was this study done? Epidemiological evidence has indicated that greater self-reported adherence to the Mediterranean diet may be associated with lower risk of new onset type 2 diabetes (T2D), but there has been uncertainty about the magnitude of association due to subjective reporting of diet. A combination of nutritional biomarkers could better assess diet–disease associations, but this approach has rarely been considered for overall diet quality, particularly for the association between the Mediterranean diet and T2D. What did the researchers do and find? Blood carotenoids and fatty acids can be used as an objective measure of adherence to the Mediterranean diet, as indicated by results from a trial (n = 128) of adopting Mediterranean diet with provision of its key foods to study participants. These biomarkers discriminated well between the trial participants under the Mediterranean diet intervention and those randomised to continuation of habitual diet (C-statistic = 0.88). In a study across 8 European countries (n = 22,202), adherence to the Mediterranean diet, estimated using a combination of nutritional biomarkers, was associated with lower risk of new onset T2D, with a stronger relationship compared to that with self-reported Mediterranean diet. The hazard ratios (HRs) (95% confidence interval (CI)) per standard deviation of adherence were 0.71 (0.65 to 0.77) and 0.90 (0.86 to 0.95), respectively. What do these findings mean? Adherence to the Mediterranean diet may be more beneficial for the primary prevention of T2D than previously estimated from observational dietary studies. Even small upward differences in objectively measured Mediterranean diet may be associated with a sizeable reduction of the risk of T2D at the population level. Causal interpretation of these findings is limited by potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding.

Background The Healthy Reference Diet (HRD) was created to formulate dietary guidelines that would be healthy and sustainable. We aimed to construct a diet score measuring adherence to the HRD and to explore its association with cardiovascular events and environmental impact. Methods and Results We included 35 496 participants from the population‐based EPIC‐NL (European Prospective Investigation into Cancer and Nutrition‐Netherlands) study. HRD scores were calculated using data from food frequency questionnaires (0–140). Data on morbidity and mortality were retrieved through linkage with national and death registries. Data on environmental impact indicators were obtained from life cycle assessments. Associations between adherence to the HRD and cardiovascular events were estimated with Cox proportional hazard models. Linear regression analysis was conducted for the adherence to the HRD and each environmental indicator. High adherence to the HRD was associated with 14%, 12%, and 11% lower risks of cardiovascular disease (hazard ratio [HR]Q4vsQ1, 0.86 [95% CI, 0.78–0.94]), coronary heart disease (HRQ4vsQ1, 0.88 [95% CI, 0.78–1.00]), and total stroke (HRQ4vsQ1, 0.89 [95% CI, 0.72–1.10]), respectively. High HRD adherence was associated with 2.4% (95% CI, −5.0 to 0.2) lower greenhouse gas emissions, 3.9% (95% CI, −5.2 to −2.6) less land use, 0.5% (95% CI, −2.6 to 1.6), less freshwater eutrophication, 3.3% (95% CI, −5.8 to −0.8), less marine eutrophication, 7.7% (95% CI, −10.8 to −4.6), less terrestrial acidification, and 32.1 % (95% CI, 28.5–35.7) higher blue water use. Conclusions High adherence to the HRD was associated with lower risk of cardiovascular disease, coronary heart disease, and modestly lower levels of most environmental indicators but a higher level of blue water use.

BackgroundEpidemiological 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.MethodsAfter 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).ResultsContributions 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).ConclusionThese 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.

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project ‘Effects of Low-Level Air Pollution: A Study in Europe’ (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), ozone (O3), and 8 PM2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m3), PM2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m3), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10−5/m) with psychiatric disorders mortality, as well as with suicide (NO2: HR = 1.13 [95 % CI: 0.92, 1.38]; PM2.5: HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O3 and 8 PM2.5 components with any of the three mortality outcomes. Long-term exposure to NO2, PM2.5, and BC may lead to premature mortality from psychiatric disorders and suicide.

Background: The aim of this study is to determine the correlations between dietary fatty acid (FA) intakes and plasma phospholipid (PL) FA levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: The dietary intake of 60 individual FAs was estimated using centre-specific validated dietary questionnaires. Plasma PL FA concentrations of these FAs were measured in non-fasting venous plasma samples in nested case-control studies within the EPIC cohort (n = 4923, using only non-cases). Spearman rank correlations were calculated to determine associations between FA intakes and plasma PL FA levels. Results: Correlations between FA intakes and circulating levels were low to moderately high (−0.233 and 0.554). Moderate positive correlations were found for total long-chain n-3 poly-unsaturated FA (PUFA) (r = 0.354) with the highest (r = 0.406) for n-3 PUFA docosahexaenoic acid (DHA). Moderate positive correlations were also found for the non-endogenously synthesized trans-FA (r = 0.461 for total trans-FA C16-18; r = 0.479 for industrial trans-FA (elaidic acid)). Conclusions: Our findings indicate that dietary FA intakes might influence the plasma PL FA status to a certain extent for several specific FAs. The stronger positive correlations for health-enhancing long-chain PUFAs and the health-deteriorating trans-FA that are not endogenously produced are valuable for future cancer prevention public health interventions.

Abstract Background Unhealthy food environments may contribute to unhealthy diets and risk of overweight and obesity through increased consumption of fast-food. Therefore, we aimed to study the association of relative exposure to fast-food restaurants (FFR) with overall diet quality and risk of overweight and obesity in a sample of older adults. Methods We analyzed cross-sectional data of the EPIC-NL cohort (n = 8,231). Data on relative FFR exposure was obtained through linkage of home address in 2015 with a retail outlet database. We calculated relative exposure to FFR by dividing the densities of FFR in street-network buffers of 400, 1000, and 1500 m around the home of residence by the density of all food retailers in the corresponding buffer. We calculated scores on the Dutch Healthy Diet 2015 (DHD15) index using data from a validated food-frequency questionnaire. BMI was categorized into normal weight (BMI

Background: The majority of studies have shown higher greenness exposure associated with reduced mortality risks, but few controlled for spatially correlated air pollution and traffic noise exposures. We aim to address this research gap in the ELAPSE pooled cohort. Methods: Mean Normalized Difference Vegetation Index (NDVI) in a 300-m grid cell and 1-km radius were assigned to participants’ baseline home addresses as a measure of surrounding greenness exposure. We used Cox proportional hazards models to estimate the association of NDVI exposure with natural-cause and cause-specific mortality, adjusting for a number of potential confounders including socioeconomic status and lifestyle factors at individual and area-levels. We further assessed the associations between greenness exposure and mortality after adjusting for fine particulate matter (PM2.5), nitrogen dioxide (NO2) and road traffic noise. Results: The pooled study population comprised 327,388 individuals who experienced 47,179 natural-cause deaths during 6,374,370 person-years of follow-up. The mean NDVI in the pooled cohort was 0.33 (SD 0.1) and 0.34 (SD 0.1) in the 300-m grid and 1-km buffer. In the main fully adjusted model, 0.1 unit increment of NDVI inside 300-m grid was associated with 5% lower risk of natural-cause mortality (Hazard Ratio (HR) 0.95 (95% CI: 0.94, 0.96)). The associations attenuated after adjustment for air pollution [HR (95% CI): 0.97 (0.96, 0.98) adjusted for PM2.5; 0.98 (0.96, 0.99) adjusted for NO2]. Additional adjustment for traffic noise hardly affected the associations. Consistent results were observed for NDVI within 1-km buffer. After adjustment for air pollution, NDVI was inversely associated with diabetes, respiratory and lung cancer mortality, yet with wider 95% confidence intervals. No association with cardiovascular mortality was found. Conclusions: We found a significant inverse association between surrounding greenness and natural-cause mortality, which remained after adjusting for spatially correlated air pollution and traffic noise.

Abstract Background Adults with a low socioeconomic position (SEP) are more likely to engage in unhealthy diets as compared to adults with high SEP. However, individual-level educational interventions aiming to improve food choices have shown limited effectiveness in adults with low SEP. Environmental-level interventions such as nudging strategies however, may be more likely to benefit low SEP groups. We aimed to review the evidence for the effectiveness of nudges as classified according to interventions in proximal physical micro-environments typology (TIPPME) to promote healthy purchases, food choice, or affecting energy intake or content of purchases, within real-life food purchasing environments. Second, we aimed to investigate the potentially moderating role of SEP. Methods We systematically searched PubMed, EMBASE, and PsycINFO until 31 January 2018. Studies were considered eligible for inclusion when they i) complied with TIPPME intervention definitions; ii) studied actual purchases, food choice, or energy intake or content of purchases, iii) and were situated in real-life food purchasing environments. Risk of bias was assessed using a quality assessment tool and evidence was synthesized using harvest plots. Results From the 9210 references identified, 75 studies were included. Studies were generally of weak to moderate quality. The most frequently studied nudges were information (56%), mixed (24%), and position nudges (13%). Harvest plots showed modest tendencies towards beneficial effects on outcomes for information and position nudges. Less evidence was available for other TIPPME nudging interventions for which the harvest plots did not show compelling patterns. Only six studies evaluated the effects of nudges across levels of SEP (e.g., educational level, food security status, job type). Although there were some indications that nudges were more effective in low SEP groups, the limited amount of evidence and different proxies of SEP used warrant caution in the interpretation of findings. Conclusions Information and position nudges may contribute to improving population dietary behaviours. Evidence investigating the moderating role of SEP was limited, although some studies reported greater effects in low SEP subgroups. We conclude that more high-quality studies obtaining detailed data on participant’s SEP are needed. Registration This systematic review is registered in the PROSPERO database ( CRD42018086983 ).

Background There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. Methods and Results We conducted a case‐cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country‐specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice‐weighted Cox regression models and pooled results using random‐effects meta‐analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). Conclusions This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.

Abstract Background Low socio-economic position is associated with consumption of lower quality diets, which may be partly explained by the cost of healthier diets. Therefore, we aimed to investigate the mediating role of dietary costs in the association between educational level and diet quality. Methods We used cross-sectional data from Dutch older adults (N = 9399) in the EPIC-NL cohort. Participants provided information about their own and their partners’ highest attained educational level (as proxy for socio-economic position). Dietary behavior was assessed using a food frequency questionnaire from which we derived two diet-quality scores, including the Dutch Healthy Diet index 2015 (DHD15-index) and the Dietary Approaches to Stop Hypertension (DASH) diet. Dietary cost estimates were based on food price data from food stores, and linked to reported consumption of food items. Multiple regression analyses and bootstrapping were used examine the mediating role of dietary cost in the association between educational level and diet quality. Results Mean age of participants was 70 (SD: 10) years and 77% were women. Dietary costs significantly mediated the association between educational level and diet quality, except for high versus middle individual educational level and the DHD15-index. Depending on the dietary and educational indicator, dietary costs explained between 2 and 7% of the association between educational level and diet quality. Furthermore, associations were found to be modified by sex and age. For the DHD15-index, mediation effects were only present in females and adults older than 65 years, and for the DASH diet mediation effects were only present in females and strongest amongst adults older than 65 years compared to adults younger than 65 years. Conclusion Dietary costs seems to play a modest role in explaining educational differences in diet quality in an older Dutch population. Further research is needed to investigate which other factors may explain SEP differences in diet quality.

Abstract Background Unhealthy lifestyle behaviours such as unhealthy dietary intake and insufficient physical activity (PA) tend to cluster in adults with a low socioeconomic position (SEP), putting them at high cardiometabolic disease risk. Educational approaches aiming to improve lifestyle behaviours show limited effect in this population. Using environmental and context-specific interventions may create opportunities for sustainable behaviour change. In this study protocol, we describe the design of a real-life supermarket trial combining nudging, pricing and a mobile PA app with the aim to improve lifestyle behaviours and lower cardiometabolic disease risk in adults with a low SEP. Methods The Supreme Nudge trial includes nudging and pricing strategies cluster-randomised on the supermarket level, with: i) control group receiving no intervention; ii) group 1 receiving healthy food nudges (e.g., product placement or promotion); iii) group 2 receiving nudges and pricing strategies (taxing of unhealthy foods and subsidizing healthy foods). In collaboration with a Dutch supermarket chain we will select nine stores located in low SEP neighbourhoods, with the nearest competitor store at > 1 km distance and managed by a committed store manager. Across the clusters, a personalized mobile coaching app targeting walking behaviour will be randomised at the individual level, with: i) control group; ii) a group receiving the mobile PA app. All participants (target n = 1485) should be Dutch-speaking, aged 45–75 years with a low SEP and purchase more than half of their household grocery shopping at the selected supermarkets. Participants will be recruited via advertisements and mail-invitations followed by community-outreach methods. Primary outcomes are changes in systolic blood pressure, LDL-cholesterol, HbA1c and dietary intake after 12 months follow-up. Secondary outcomes are changes in diastolic blood pressure, blood lipid markers, waist circumference, steps per day, and behavioural factors including healthy food purchasing, food decision style, social cognitive factors related to nudges and to walking behaviours and customer satisfaction after 12 months follow-up. The trial will be reflexively monitored to support current and future implementation. Discussion The findings can guide future research and public health policies on reducing lifestyle-related health inequalities, and contribute to a supermarket-based health promotion intervention implementation roadmap. Trial registration Dutch Trial Register ID NL7064 , 30th of May, 2018

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Background: Higher age-specific circulating anti-Müllerian hormone (AMH) levels have been linked to a lower risk of cardiometabolic outcomes. However, whether AMH has a casual role in the etiology of these diseases is unknown. The objective of this study was therefore to explore if circulating AMH levels have a causal effect on risk of coronary artery disease (CAD), ischemic stroke and type 2 diabetes (T2D) in women, using a two-sample Mendelian randomization (MR) approach. Methods: We used four single nucleotide polymorphisms (SNPs) from the most recent AMH GWAS meta-analysis as instrumental variables. Summary-level data for CAD (n = 149,752; 11,802 cases), ischemic stroke (n = 17,541; 4678 cases) and T2D (n = 464,389; 30,052 cases) were extracted from the UK Biobank, the Stroke Genetics Network, and DIAMANTE consortia, respectively. To assess the presence of potential pleiotropy we tested the association of the four AMH SNPs, both individually and combined in a weighted genetic risk score, with a range of cardiovascular risk factors and intermediate traits using UK Biobank data. Results: MR estimates, i.e., inverse variance-weighted odds ratios (ORIVW), did not support a causal effect of circulating AMH levels on CAD (ORIVW = 1.13, 95% CI: 0.95–1.35), ischemic stroke (ORIVW = 1.11, 95% CI: 0.83–1.49), and T2D (ORIVW = 0.98, 95% CI: 0.87–1.10). After adjustment for multiple testing, we observed associations between genetically predicted AMH and age at menopause, and age at menarche, but not with intermediate traits on the causal pathway between AMH and cardiometabolic health, such as atherosclerosis or glucose levels. Conclusions: This study does not provide evidence for a causal effect of circulating AMH levels on CAD, ischemic stroke and T2D in women, although weak instrument bias cannot be excluded.

Epidemiologic studies have indicated that cruciferous vegetables can influence the cancer risk; therefore, we examined with a cross-sectional approach the correlation between the frequent consumption of the total cruciferous vegetables and the formation of bulky DNA damage, a biomarker of carcinogen exposure and cancer risk, in the Gen-Air study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. DNA damage measurements were performed in the peripheral blood of 696 of those apparently healthy without cancer controls, including 379 never-smokers and 317 former smokers from seven European countries by the 32P-postlabeling assay. In the Gen-Air controls, the median intake of cruciferous vegetables was 6.16 (IQR 1.16–13.66) g/day, ranging from 0.37 (IQR 0–6.00) g/day in Spain to 11.34 (IQR 6.02–16.07) g/day in the UK. Based on this information, participants were grouped into: (a) high consumers (>20 g/day), (b) medium consumers (3–20 g/day) and (c) low consumers (p = 0.032); this was particularly evident in former smokers (up to a 40% change, p = 0.008). The Generalized Linear Regression models indicated an overall Mean Ratio between the high and the low consumers of 0.78 (95% confidence interval, 0.64–0.97). The current study suggests that a higher intake of cruciferous vegetables is associated with a lower level of bulky DNA adducts and supports the potential for cancer prevention strategies through dietary habit changes aimed at increasing the consumption of cruciferous vegetables.

Abstract Background Initiating and maintaining a healthy lifestyle -including healthy eating and sufficient physical activity- is key for cardiometabolic health. A health-promoting environment can facilitate a healthy lifestyle, and may be especially helpful to reach individuals with a lower socio-economic status (SES). In the Supreme Nudge project, we will study the effects of pricing and nudging strategies in the supermarket – one of the most important point-of-choice settings for food choices – and of a context-specific mobile physical activity promotion app. This paper describes the stepwise and theory-based design of Supreme Nudge, which aims to develop, implement and evaluate environmental changes for a sustained impact on lifestyle behaviours and cardiometabolic health in low SES adults. Methods Supreme Nudge uses a multi-disciplinary and mixed methods approach, integrating participatory action research, qualitative interviews, experimental pilot studies, and a randomized controlled trial in a real-life (supermarket) setting. First, we will identify the needs, characteristics and preferences of the target group as well as of the participating supermarket chain. Second, we will conduct a series of pilot studies to test novel, promising and feasible intervention components. Third, a final selection of intervention components will be implemented in a full-scale randomised controlled supermarket trial. Approximately 1000 low SES adults will be recruited across 8–12 supermarkets and randomised at supermarket level to receive 1) no intervention (control); 2) environmental nudges such as food product placement or promotion; 3) nudges and a tailored physical activity app that provides time- and context specific feedback; 4) pricing interventions, nudges, and the physical activity app. The effects on dietary behaviours and physical activity will be evaluated at 3, 6 and 12 months, and on cardiometabolic health at 6 and 12 months. Finally, we will evaluate the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) of the intervention, and we will use insights from System Innovation and Transition Management theories to define the best strategies for implementation and upscaling beyond the study period. Discussion The Supreme Nudge project is likely to generate thorough evidence relevant for policy and practice on the effects of a mixed method and multi-disciplinary intervention targeting dietary behaviours and physical activity. Trial registration The real-life trial has been registered on 30 May 2018, NTR7302.

Abstract Background Vascular calcifications are associated with a three- to fourfold increased risk of cardiovascular disease (CVD) and are highly prevalent in type 2 diabetes patients. Emerging evidence indicates that vascular calcification is a process of active bone formation regulated by stimulators and inhibitors of calcification. Therefore, this study aimed to evaluate whether six bone markers are associated with CVD risk in patients with type 2 diabetes. Methods We used data of a case-cohort study, nested in the EPIC-NL cohort, comprising 134 CVD cases and a random subcohort of 218 participants, all with type 2 diabetes at baseline. Six bone markers (osteocalcin, osteopontin, osteonectin, osteoprotegerin, alkaline phosphatase and sclerostin) were measured in baseline plasma samples with multiplex assays and information on CVD events was obtained. The association of bone makers with CVD risk was evaluated using Cox proportional hazard analyses. Results Higher concentrations of plasma osteopontin were associated (ptrend

Abstract Background Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. Methods We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. Results Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. Conclusions Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.

Abstract Background The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Results Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p

BackgroundWe evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors. Methods and ResultsWe used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition‐NL (EPIC‐NL). The associations of 23 biomarkers (adiponectin, C‐reactive protein, epidermal‐type fatty acid binding protein, heart‐type fatty acid binding protein, basic fibroblast growth factor, soluble FMS‐like tyrosine kinase‐1, soluble intercellular adhesion molecule‐1 and ‐3, matrix metalloproteinase [MMP]‐1, MMP‐3, MMP‐9, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E‐selectin, P‐selectin, tissue inhibitor of MMP‐1, thrombomodulin, soluble vascular cell adhesion molecule‐1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c‐statistic and net reclassification index (NRI; continuous and based on 10‐year risk strata 0–10%, 10–20%, 20–30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, and MMP‐3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c‐statistic with 0.03 (95% CI 0.01–0.05), and the continuous NRI was 0.37 (95% CI 0.21–0.52). In EPIC‐NL, the multimarker model increased the c‐statistic with 0.03 (95% CI 0.00–0.03), and the continuous NRI was 0.44 (95% CI 0.23–0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03–0.21) in SMART and 0.07 (95% CI −0.04–0.17) in EPIC‐NL. ConclusionsOf the 23 evaluated biomarkers from different pathophysiological pathways, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, MMP‐3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited.

BackgroundThe associations between overall lifestyle profile and cardiovascular disease (CVD) and death have been mainly investigated in cross‐sectional studies. The full benefits of a healthy lifestyle may therefore be underestimated, and the magnitude of benefits associated with changes in lifestyle remains unclear. We quantified the association of changes in lifestyle profiles over 5 years with risk of CVD and all‐cause mortality. Methods and ResultsLifestyle factors (ie, diet, physical activity, smoking, alcohol consumption) and body mass index were assessed and dichotomized as healthy/unhealthy among 5263 adults ages 26 to 66 in 1993–1997 and 5 years later (1998–2002). Multivariable‐adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated to quantify associations of change in lifestyle with fatal/nonfatal CVD and all‐cause mortality that occurred 8 to 15 years after 1998–2002. Independent of baseline lifestyles, each decrement in number of healthy lifestyle factors was, on average, associated with 35% higher risk of CVD (HR, 1.35; 95% CI, 1.12–1.63) and 37% higher risk of all‐cause mortality (HR, 1.37; 95% CI, 1.10–1.70); no association was noted with increase in the number of healthy lifestyle factors (P>0.5). Individuals who maintained 4 to 5 healthy lifestyle factors had 2.5 times lower risk of CVD (HR, 0.43; 95% CI, 0.25–0.63) and all‐cause mortality (HR, 0.40; 95% CI, 0.22–0.73) than those who maintained only 0 to 1 healthy lifestyle factor. ConclusionsOur findings suggest that the benefits of healthy lifestyles may be easier lost than gained over a 5‐year period. This underscores the need for efforts to promote maintenance of healthy lifestyles throughout the life course.

Intra-ocular straylight can cause decreased visual functioning, and it may cause diminished vision-related quality of life (VRQOL). This cross-sectional population-based study investigates the association between straylight and VRQOL in middle-aged and elderly individuals. Multivariable linear regression analyses were used to assess the association between straylight modeled continuously and cutoff at the recommended fitness-to-drive value, straylight ≥ 1.4 log(s), and VRQOL. The study showed that participants with normal straylight values, straylight ≤ 1.4 log(s), rated their VRQOL slightly better than those with high straylight values (straylight ≥ 1.4 log(s)). Furthermore, multivariable regression analysis revealed a borderline statistical significant association ( p = .06) between intra-ocular straylight and self-reported VRQOL in middle-aged and elderly individuals. The association between straylight and self-reported VRQOL was not influenced by the status of the intra-ocular lens (natural vs. artificial intra-ocular lens after cataract extraction) or the number of (instrumental) activities of daily living that were reported as difficult for the elderly individuals.

Objective. To examine the association between undernutrition during postnatal periods of development and the risk of overweight in adulthood. Methods. We studied 8,091 women from Prospect-EPIC, exposed to the Dutch famine at ages between 0 and 21 years, recruited at ages between 49 and 70 years. We used linear and logistic regression models to explore the effect of famine on BMI, waist circumference, and the risk of overweight. Results. Overall, postnatal famine exposure was associated with increased BMI and waist circumference in a dose-dependent manner (𝑃fortrend