Importance Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes. Objective To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality. Design, Setting, and Participants This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020. Exposures The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination. Main Outcomes and Measures The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors. Results Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality. Conclusion and Relevance In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.

Background and aims: Studies in children and adolescents suggest that higher dairy consumption may exert a protective effect on adiposity. However, only few studies examined the association between dietary calcium intake and body mass measures with conflicting results. We evaluated the association between total dietary calcium, calcium from dairy and non-dairy sources and anthropometric indices in a large European cohort of children and adolescents. Methods and Results: As many as 6,696 children belonging to the IDEFICS study were eligible for the cross-sectional analysis (Boys = 51%; age 6.0 +/- 1.8 years; mean +/- SD). Of these, 2,744 were re-examined six years later (Boys = 49.6%; age = 11.7 +/- 1.8 years) in the framework of the I.Family study. The exposures were the baseline energy-adjusted total, dairy and non-dairy calcium intakes measured by a validated 24-h dietary recall. Multivariable linear regression was used to determine the association between calcium intake and z-scores of anthropometric indices (body mass index, BMI; waist circumference, WC; sum of skinfolds, SS; fat mass index, FMI) at baseline, and their variation over the 6 years follow-up. The association of dietary calcium with the incidence of overweight/obesity was also assessed. At baseline, an inverse association between total calcium intake and all the adiposity indices was consistently observed in boys, while only SS and FMI were significant in girls. The prevalence of overweight/obesity decreased significantly (P < 0.0001) across tertiles of calcium intake, in both sexes. Over the follow-up, boys with higher baseline calcium intake value showed significantly lower increase in BMI, WC and FMI z-scores, while in girls only a lower increase in WC zscore was observed. Only in boys, the risk to become overweight/obese decreased significantly across tertiles of calcium intake. Similar results were observed by analyzing only dietary calcium from dairy, while no association was observed between non-dairy calcium and adiposity indices. Conclusions: We showed in a large cohort of European children and adolescents that dietary calcium intake may play a role in the modulation of body fat in developmental age. The association between dietary calcium and adiposity indices was driven by dairy calcium, while no effect was observed for non-dairy calcium intake. The existence of a sex-related difference in the association deserves further investigations. (C) 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling,we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP- 1 , IGFBP- 2 and IGFBP- 3 ). The Endogenous Hormones, Nutritional Biomarkersand Prostate Cancer Collaborative Group dataset includes individual participant data from 16 , 024 male controls (i.e. without prostate cancer) aged 22 – 89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age wasassociated with higher concentrations of IGFBP- 1 and IGFBP- 2 and lower concentrations of IGF-I, IGF-II and IGFBP- 3 . Higher body mass index wasassociated withlower concentrations of IGFBP- 1 and IGFBP- 2 . Taller height was associated with higher concentrations of IGF-I and IGFBP- 3 and lower concentrations of IGFBP- 1 . Smokers had higher concentrations of IGFBP- 1 and IGFBP- 2 and lower concentrations of IGFBP- 3 than nonsmokers. Higher alcohol consumption wasassociated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP- 2 . African Americans had lower concentrations of IGF-II,IGFBP- 1 , IGFBP- 2 and IGFBP- 3 and Hispanics had lower IGF-I, IGF-II and IGFBP- 3 than non-Hispanic whites. These fi ndings indicate that a range of anthropometric, behavioural and sociodemographic factorsare associated with circulating concentrations of IGFsand IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors in fl uence cancer risk. obtained data from 16 , 000 cancer-free males ranging in age from 22 to 89 years. Their analysis con fi rmed associations between circulating IGFs and IGFBPs and age, race/ethnicity and BMI. They also uncovered some new associations, including with height, drinking alcohol and smoking. IGFs and their binding proteins, they suggest, may be part of the mechanism by which these factors in fl uence cancer risk. Studies suggest that IGF-I has acceptable temporal reproducibility over 1- to 5-year period

Background and aims: By investigating differences in lifestyle behaviours and BMI in sibling pairs, family-level confounding is minimized and causal inference is improved, compared to cross-sectional studies of unrelated children. Thus, we aimed to investigate within-sibling pair differences in different lifestyle behaviours and differences in BMI z-scores in children and adolesents. Methods and results: We examined three groups of sibling pairs 1) all same-sex sibling pairs with maximum 4 years age difference (n = 1209 pairs from 1072 families in 8 countries, mean age 10.7 years, standard deviation 2.4 years), 2) sibling pairs discordant for overweight (n = 262) and 3) twin pairs (n = 85). Usual dietary intake was estimated by 24-h recalls and time spent in light (LPA) and moderate-to-vigorous physical activity (MVPA) was measured by accelerometers. Screen time, sleep and dieting for weight loss were assessed by questionnaires. Within all 3 groups of sibling pairs, more time in MVPA was associated with lower BMI z-score. Higher energy intake was associated with higher BMI z-score within twin pairs and within all sibling pairs who were not currently dieting for weight loss. Regarding LPA, screen time or sleep duration, no or inconsistent associations were observed for the three groups of sibling pairs. Conclusions: MVPA and energy intake were associated with BMI differences within sibling and twin pairs growing up in the same home, thus independent of family-level confounding factors. Future studies should explore whether genetic variants regulating appetite or energy expenditure behaviours account for weight differences in sibling pairs. (C) 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

To report dietary free sugars consumption and their different types and food sources in European children. The present study is based on the IDEFICS study, a European multicenter cohort study in children (2–9 years old) from eight countries, comprising 8308 children (51.4% males). Dietary intake of the previous 24 h was assessed using a computer-assisted 24-h dietary recalls (24-HDR) and the different types of sugars were assessed using the German food composition database. Mean total energy intake was 1720 (SD 477) kcal/d for boys and 1631 (SD 451) kcal/d for girls. Total sugars intake was 98 (SD 52) g/day for boys and 93 (SD 49) g/day for girls. Free sugars intake was 81 (SD 49) g/day for boys and 77 (SD 47) g/day for girls. Girls had significantly lower intakes of energy, total and free sugars compared with than boys but did not differ in terms of percent of energy from total (23%) or free sugars (18%). There were large variations between countries in average % energy from free sugars (ranging from 13% in Italy to 27% in Germany). Less than 20% of children were within the recommended intake of 10% of energy from free sugars. The food groups that contributed substantially to free sugars intakes were “Fruit juices”, “Soft drinks”, “Dairy” and “Sweets and candies”. The contribution of free sugars to total energy intake in European children is higher than recommendations. The main food contributors to free sugars intake are sweetened beverages (“Fruit juices” and “Soft drinks”). It is especially important to reduce children’s intake of free sugars, focusing in target population on certain foods and food groups.

Corresponding author: Vittorio Krogh, MD MS, Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy Tel: +390223903508; Fax: +390223903510; email: vittorio.krogh@istitutotumori.mi.it PubMed indexing: Agnoli, Grioni, Krogh, Pala, Allione, Matullo, Di Gaetano, Tagliabue, Pedraglio, Garrone, Cancarini, Cavalleri, Sieri Word count: 5154; Number of tables: 3. Running title: B vitamins and homocysteine in breast cancer risk.

Factors linked to glucose metabolism are involved in the etiology of several cancers. High glycemic index (GI) or high glycemic load (GL) diets, which chronically raise postprandial blood glucose, may increase cancer risk by affecting insulin-like growth factor. We prospectively investigated cancer risk and dietary GI/GL in the EPIC-Italy cohort. After a median 14.9 years, 5112 incident cancers and 2460 deaths were identified among 45,148 recruited adults. High GI was associated with increased risk of colon and bladder cancer. High GL was associated with: increased risk of colon cancer; increased risk of diabetes-related cancers; and decreased risk of rectal cancer. High intake of carbohydrate from high GI foods was significantly associated with increased risk of colon and diabetes-related cancers, but decreased risk of stomach cancer; whereas high intake of carbohydrates from low GI foods was associated with reduced colon cancer risk. In a Mediterranean population with high and varied carbohydrate intake, carbohydrates that strongly raise postprandial blood glucose may increase colon and bladder cancer risk, while the quantity of carbohydrate consumed may be involved in diabetes-related cancers. Further studies are needed to confirm the opposing effects of high dietary GL on risks of colon and rectal cancers.

BackgroundIntakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.Materials and methodsWe assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours.ResultsA high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4-Q1) 1.37; 95% confidence interval (CI), 1.14-1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI16) (16:1n-7/16:0) [OR (Q4-Q1), 1.28; 95% C, 1.07-1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3-T1)=2.01; 95% CI, 1.03-3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.ConclusionThese findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35-70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00-1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01-1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03-2.40) compared to those reporting moderate intakes (<6 g/day), but no dose-response relationship emerged. In men, an increased risk of aggressive forms of UCC was observed even at lower doses (>6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits > 24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01-1.91) and smokers (1.39; 95% CI 1.01-1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking.

Background/objectives: Blood polyunsaturated fatty acids (PUFA) are involved in allergy development, but the etiological role of n-6 and n-3 PUFA is still controversial. A European multicenter study of children (IDEFICS) provided the opportunity to explore the cross-sectional association between fatty acids (FA) and allergy. Subjects/methods: Blood FA levels were measured in 2600 children aged 2–9 years and were recorded as the percentage of weight of all FA detected. Logistic regression of allergy status on FA components was adjusted for age, sex, country, body mass index, family history of allergic disease, breast-feeding, and number of siblings. The results were given as odds ratios (OR) for current vs no allergy ever and an increase in FA by 1 s.d. Results: Overall, higher proportions of n-6 PUFA were associated with higher odds of allergy (OR=1.21 (1.05, 1.40)). Monounsaturated FA (MUFA) were associated with reduced risk for allergy (OR=0.75 (0.65, 0.87)), whereas saturated FA did not differ by allergy status. The strongest associations were observed in children <4 years old, with ORs of allergy given as 1.62 (1.15, 2.29) for n-3 PUFA and 0.63 (0.42, 0.95) for MUFA. With regard to individual FA, these associations were independently observed for docosapentaenoic acid (22:5 n-3) and oleic acid (18:1 n-9). Conclusions: Both PUFA subtypes were positively associated with allergy in an age-dependent manner, whereas MUFA was associated with less allergy. The observation of high proportions of n-3 PUFA in allergic children younger than 4 years might help to understand the nature of early onset of atopic disease.

Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. A R T IC LE Received: February 4, 2016; Revised: April 15, 2016; Accepted: May 17, 2016 © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 of 8 JNCI J Natl Cancer Inst (2016) 108(11): djw153 doi: 10.1093/jnci/djw153 First published online July 6, 2016

71 Background: Meat and fish intake have been associated with various chronic 72 diseases. The use of specific biomarkers may help assessing meat and fish intake 73 and improving subject classification according to their level and type of meat or fish 74 consumed. 75 Objective: A metabolomic approach was applied to search for biomarkers of meat 76 and fish intake in a dietary intervention study and in free-living subjects from the 77 European Prospective Investigation into Cancer and Nutrition (EPIC) study. 78 Design: In the dietary intervention study, four groups of 10 subjects consumed 79 increasing quantities of chicken, red meat, processed meat and fish over three 80 successive weeks. 24-Hour urine samples were collected during each period and 81 analysed by high-resolution liquid chromatography-mass spectrometry. Signals 82 showing an increase in intensity with the amount of food consumed were replicated 83 in 50 EPIC subjects for whom a 24-hour urine sample and 24-h dietary recall 84 collected on a same day were available and selected for their exclusive or no intake 85 of any of the four same foods. 86 Results: 249 mass spectrometric features showed a positive dose-dependent 87 response to meat or fish intake in the intervention study. Eighteen of these features 88 best predicted intake of the four food groups in the EPIC urine samples based on 89 pROC analyses with permutation testing (AUC ranging between 0.61 and 1.0). Out of 90 these signals, eight metabolites were identified. Anserine was found to be specific for 91 chicken intake whereas trimethylamine-N-oxide showed good specificity for fish. 92 Carnosine and three acylcarnitines (acetyl-, propionyland 2-methylbutyrylcarnitine) 93 appeared to be more generic indicators of meat and meat and fish intake, 94 respectively. 95 The American Journal of Clinical Nutrition AJCN/2016/146639 Version 2

Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC.

BACKGROUND:Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors.PATIENTS AND METHODS:Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects.RESULTS:Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor.CONCLUSION:Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.

Background/objectives: To address behaviours associated with childhood obesity, certain target values are recommended that should be met to improve children’s health. In the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS) study such lifestyle recommendations were conveyed as six key messages. Here, we investigate the adherence of European children to these messages. Methods: The IDEFICS intervention was based on the intervention mapping approach with the following six targets: increase water consumption (to replace sugar-containing beverages), increase fruit/vegetable consumption, reduce daily screen time, increase daily physical activity, improve the quality of family life and ensure adequate sleep duration. Internationally recommended target values were applied to determine the prevalence of children meeting these targets. Results: In a cohort of 18 745 children participating in the IDEFICS baseline survey or newly recruited during follow-up, data on the above lifestyle behaviours were collected for a varying number of 8302 to 17 212 children. Information on all six behaviours was available for 5140 children. Although 52.5% of the cohort was classified in the highest category of water consumption, only 8.8% met the target of an intake of fruits/vegetables five times a day. The prevalence of children adhering to the recommendation regarding total screen time—below 1 h for pre-school children and 2 h for school children—was 51.1%. The recommended amount of at least 60 min of moderate-to-vigorous physical activity per day was fulfilled by 15.2%. Family life of the child measured by various indicators was considered as satisfactory in 22.8%. Nocturnal sleep duration of 11 (10) hours or more in pre-school (school) children was achieved by 37.9%. In general, children in northern countries and younger children showed better adherence to the recommendations. Only 1.1% of the children adhered to at least five of these recommendations. Conclusions: Current adherence of children to lifestyle recommendations to prevent childhood obesity is low where observed differences with respect to country, age and gender call for targeted intervention.

Children from lower socioeconomic status (SES) may be at higher risk of unhealthy eating. We described country-specific dietary patterns among children aged 2–9 years from eight European countries participating in the IDEFICS study and assessed the association of dietary patterns with an additive SES indicator. Children aged 2–9 years from eight European countries were recruited in 2007–2008. Principal component analysis was applied to identify dietary country-specific patterns. Linear regression analyses were applied to assess their association with SES. Two to four dietary patterns were identified in the participating regions. The existence of a ‘processed’ pattern was found in the eight regions. Also, a ‘healthy’ pattern was identified in seven of the eight regions. In addition, region-specific patterns were identified, reflecting the existing gastronomic and cultural differences in Europe. The ‘processed’ pattern was significantly inversely associated with the SES additive indicator in all countries except Sweden, whereas the ‘healthy’ pattern was positively associated with SES in the Belgian, Estonian, German and Hungarian regions, but was not significant in the Italian, Spanish and Swedish regions. A ‘processed’ pattern and a ‘healthy‘ pattern were found in most of the participating countries in the IDEFICS study, with comparable food item profiles. The results showed a strong inverse association of SES with the ‘processed’ pattern, suggesting that children of parents with lower SES may be at higher risk of unhealthy eating. Therefore, special focus should be given to parents and their children from lower SES levels when developing healthy eating promotion strategies.