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PDF file - 58K, Median concentrations of leptin and sOB-R by tumor stage and cancer location, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 127K, Relative risks (RR-s)* and 95% confidence intervals (CI-s) of colorectal cancer associated with a doubling in leptin and sOB-R concentrations, by subgroups, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 101K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to sex-specific quintiles of baseline soluble leptin receptor (sOB-R) concentrations, in men and women, the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 100K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to sex-specific quintiles of baseline leptin concentrations, in men and women , the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

PDF file - 80K, Relative risks (RR-s) and 95% confidence intervals (CI-s) of colon, rectal and colorectal cancer according to quintiles of free leptin index (FLI), the European Prospective Investigation into Cancer and Nutrition (EPIC), 1992-2003

Purpose 1. To determine the effect of vitamin D supplementation on bone age (BA), a marker of skeletal maturity, and Bone Health Index (BHI), a surrogate marker of bone density. 2. To characterise the differences in nutritional intake and anthropometry between children with advanced vs. delayed BA. Methods The current study is a post hoc analysis of radiographs obtained as part of a randomised controlled trial. In this double-blind, placebo-controlled trial, deprived Afghan children (n = 3046) aged 1–11 months were randomised to receive six doses of oral placebo or vitamin D3 (100,000 IU) every 3 months for 18 months. Dietary intake was assessed through semi-quantitative food frequency questionnaires at two time points. Anthropometric measurements were undertaken at baseline and 18 months. Serum 25OHD was measured at five time points on a random subset of 632 children. Knee and wrist radiographs were obtained from a random subset (n = 641), of which 565 wrist radiographs were digitised for post-hoc analysis of BA and BHI using BoneXpert version 3.1. Results Nearly 93% (522, male = 291) of the images were analysable. The placebo (n = 258) and vitamin D (n = 264) groups were comparable at baseline. The mean (± SD) age of the cohort was 2 (± 0.3) years. At study completion, there was no difference in mean 25-hydroxy vitamin D concentrations [47 (95% CI 41, 56) vs. 55 (95% CI 45, 57) nmol/L, p = 0.2], mean (± SD) BA SDS [− 1.04 (1.36) vs. − 1.14 (1.26) years, p = 0.3] or mean (± SD) BHI SDS [− 0.30 (0.86) vs. − 0.31 (0.80), p = 0.8] between the placebo and vitamin D groups, respectively. Children with advanced skeletal maturity (BA SDS ≥ 0) when compared to children with delayed skeletal maturity (BA SDS p p p Conclusion Deprived children have significant delay in skeletal maturation but no substantial impairment in bone health as assessed by BHI. BA delay was influenced by total calorie intake, but not bolus vitamin D supplementation.

Background The Gambia has high rates of under-5 mortality from diarrhoea and pneumonia, peaking during complementary-feeding age. Community-based interventions may reduce complementary-food contamination and disease rates. Methods and findings A public health intervention using critical control points and motivational drivers, delivered February–April 2015 in The Gambia, was evaluated in a cluster randomised controlled trial at 6- and 32-month follow-up in September–October 2015 and October–December 2017, respectively. After consent for trial participation and baseline data were collected, 30 villages (clusters) were randomly assigned to intervention or control, stratified by population size and geography. The intervention included a community-wide campaign on days 1, 2, 17, and 25, a reminder visit at 5 months, plus informal community-volunteer home visits. It promoted 5 key complementary-food and 1 key drinking-water safety and hygiene behaviours through performing arts, public meetings, and certifications delivered by a team from local health and village structures to all villagers who attended the activities, to which mothers of 6- to 24-month-old children were specifically invited. Control villages received a 1-day campaign on domestic-garden water use. The background characteristics of mother and clusters (villages) were balanced between the trial arms. Outcomes were measured at 6 and 32 months in a random sample of 21–26 mothers per cluster. There were no intervention or research team visits to villages between 6 and 32 months. The primary outcome was a composite outcome of the number of times key complementary-food behaviours were observed as a proportion of the number of opportunities to perform the behaviours during the observation period at 6 months. Secondary outcomes included the rate of each recommended behaviour; microbiological growth from complementary food and drinking water (6 months only); and reported acute respiratory infections, diarrhoea, and diarrhoea hospitalisation. Analysis was by intention-to-treat analysis adjusted by clustering. (Registration: PACTR201410000859336). We found that 394/571 (69%) of mothers with complementary-feeding children in the intervention villages were actively involved in the campaign. No villages withdrew, and there were no changes in the implementation of the intervention. The intervention improved behaviour adoption significantly. For the primary outcome, the rate was 662/4,351(incidence rate [IR] = 0.15) in control villages versus 2,861/4,378 (IR = 0.65) in intervention villages (adjusted incidence rate ratio [aIRR] = 4.44, 95% CI 3.62–5.44, p < 0.001), and at 32 months the aIRR was 1.17 (95% CI 1.07–1.29, p = 0.001). Secondary health outcomes also improved with the intervention: (1) mother-reported diarrhoea at 6 months, with adjusted relative risk (aRR) = 0.39 (95% CI 0.32–0.48, p < 0.001), and at 32 months, with aRR = 0.68 (95% CI 0.48–0.96, p = 0.027); (2) mother-reported diarrhoea hospitalisation at 6 months, with aRR = 0.35 (95% CI 0.19–0.66, p = 0.001), and at 32 months, with aRR = 0.38 (95% CI 0.18–0.80, p = 0.011); and (3) mother-reported acute respiratory tract infections at 6 months, with aRR = 0.67 (95% CI 0.53–0.86, p = 0.001), though at 32 months improvement was not significant (p = 0.200). No adverse events were reported. The main limitations were that only medium to small rural villages were involved. Obtaining laboratory cultures from food at 32 months was not possible, and no stool microorganisms were investigated. Conclusions We found that low-cost and culturally embedded behaviour change interventions were acceptable to communities and led to short- and long-term improvements in complementary-food safety and hygiene practices, and reported diarrhoea and acute respiratory tract infections. Trial registration The trial was registered on the 17th October 2014 with the Pan African Clinical Trial Registry in South Africa with number (PACTR201410000859336) and 32-month follow-up as an amendment to the trial., Semira Manaseki-Holland and co-workers evaluate a behaviour-change intervention aimed at improving food hygiene for infants in West Africa., Author summary Why was this study done? Children aged 0–2 years are fed complementary foods and have the highest rates of diarrhoea and food-borne illnesses. Most hygiene or child nutrition programmes do not directly address complementary-food safety and hygiene. We performed a large cluster randomised controlled trial (RCT) of a community-level complementary-food safety and hygiene intervention in which medium- and long-term health outcomes were measured. What did the researchers do and find? We used a cluster RCT study to test a novel community-level campaign-like intervention in 15 intervention and 15 control villages in rural Gambia and evaluated outcomes at 6 and 32 months post-intervention. Target behaviours were identified through systematic assessment of motivational drivers for behaviour change and critical control points (CCPs) for contamination in complementary-food preparation and handling practices identified through a hazard analysis assessment. The intervention was implemented at the community level and focussed on mothers of young children; it was delivered by a combination of performing arts, public meetings, household visits, commitment ceremonies, and certifications of mothers and communities. Sixty-nine percent of mothers with complementary-feeding-age children were actively involved in the campaign. At 6 months post-intervention, adoption of behaviours was high; child’s reported diarrhoea, hospital admission for diarrhoea, and respiratory disease were reduced by 60%, 60%, and 30%, respectively. At 32 months post-intervention, mothers in control villages had adopted some of the behaviours promoted by the intervention (intervention ‘cross-contamination’), but practice of the behaviours in the intervention villages remained significantly higher, with a 30% reduction in reported diarrhoea and a 40% reduction in hospital admissions for diarrhoea. Clinic data collected by another research team confirmed reduced diarrhoea visits. These outcomes were achieved without further programmatic input after 5 months. Mothers without babies at the time of the programme were subsequently engaged by community members and adopted the behaviours. The intervention adds further value as it was delivered by a team from the public health and village structures, and was low intensity and low cost. What do these findings mean? We demonstrate that these low-cost, culturally embedded interventions are acceptable, adopted, and sustained at the community level, with high levels of behaviour change and reported reduction in diarrhoea and acute respiratory infection outcomes in the short term, and significant long-term effects. Interventions of this form could make an invaluable contribution to diarrhoea prevention; although our findings are limited to small rural villages, these are nonetheless common in low- and middle-income countries. Our conclusions need to be tested in urban and peri-urban settings. To date, insufficient attention has been devoted to food safety and food hygiene practices aimed at preparing, handling, and feeding complementary food. There have also been insufficient assessments of programmes with cultural performing arts that can engage whole communities to support mothers with behaviour change.

BACKGROUND AND OBJECTIVES: Vitamin D is essential for healthy development of bones, but little is known about the effects of supplementation in young stunted children. Our objective was to assess the effect of vitamin D supplementation on risk of rickets and linear growth among Afghan children. METHODS: In this double-blind, placebo-controlled trial, 3046 children ages 1 to 11 months from inner-city Kabul were randomly assigned to receive oral vitamin D3 (100 000 IU) or placebo every 3 months for 18 months. Rickets Severity Score was calculated by using wrist and knee radiographs for 631 randomly selected infants at 18 months, and rickets was defined as a score >1.5. Weight and length were measured at baseline and 18 months by using standard techniques, and z scores were calculated. RESULTS: Mean (95% confidence interval [CI]) serum 25-hydroxyvitamin D (seasonally corrected) and dietary calcium intake were insufficient at 37 (35–39) nmol/L and 372 (327–418) mg/day, respectively. Prevalence of rickets was 5.5% (placebo) and 5.3% (vitamin D): odds ratio 0.96 (95% CI: 0.48 to 1.92); P = .9. The mean difference in height-for-age z score was 0.05 (95% CI: −0.05 to 0.15), P = .3, although the effect of vitamin D was greater for those consuming >300 mg/day of dietary calcium (0.14 [95% CI: 0 to 0.29]; P = .05). There were no between-group differences in weight-for-age or weight-for-height z scores. CONCLUSIONS: Except in those with higher calcium intake, vitamin D supplementation had no effect on rickets or growth.

Background: China witnessed a dramatic growth in the prevalence of obesity in children due to a shift in dietary behavior during the last two decades. The aim is to systematically review the evidence among the eligible primary studies in which the relationship between dietary patterns and risk of obesity/overweight in children and/or adolescents aged 3-17 years in China was assessed. Methods: Bibliographic databases such as Medline, Embase, were searched. The quality of included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for cross-sectional studies and the Newcastle-Ottawa Scale (NOS) for retrospective cohort studies. The adjusted ORs compared the highest quartile with the lowest quartile of Chinese traditional dietary pattern and western pattern were pooled in forest plots to visualize results. Findings: Among 7 studies included for final analysis, four indicate that greater adherence to a western dietary pattern were significantly positively associated with obesity in children/adolescents aged 3-17 years in China after adjustment of confounding factors. The magnitude of effect varied from study to study: the odds ratios and 95%CIs ranged from (Q4 vs Q1) OR=1.49, 95% CI: 1.21,1.84 to (Q4 vs Q1) OR = 3.10, 95% CI:1.52, 6.32. This positive association is demonstrated in the animal foods, fats, and condiments dominated pattern in a borderline trend (Q4 vs Q1) OR=5.88, 95% CI 1.39, 24.80). One study suggested that greater adherence to the Chinese traditional dietary pattern was significantly associated with a lower risk of obesity (Q4 vs Q1) OR = 0.19, 95%CI: 0.09, 0.40. Interpretation: This systematic review demonstrates western dietary patterns characterized by high fat, energy-dense, low dietary fiber, had a potential higher risk in obesity in children and adolescents aged 3-17 years in China. Fruits and vegetables dominated dietary patterns were less likely to cause obesity in children and adolescents aged 3-17 years. Funding: None to declare. Declaration of Interest: None to declare.

IntroductionThere is evidence that plant-based diets might be associated with a lower risk of IHD; however, previous studies have not reported on intake of subtypes of fruit and vegetables and sources of dietary fibre. This study aims to assess the associations of major plant foods, their subtypes and dietary fibre with risk of ischaemic heart disease (IHD) in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD Consortium.Material and methodsWe conducted a prospective analysis of 490,311 men and women in ten European countries without a history of myocardial infarction or stroke at recruitment. Dietary intake was assessed using validated questionnaires and calibrated with 24-hour recall data. Cox regression models, adjusted for IHD risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring a mean of 12.6 years follow-up, we documented 8504 myocardial infarction cases or deaths from IHD. Participants consuming at least eight portions (80 grams each) of fruits and vegetables a day had a 10% lower risk of IHD (HR 0.90, 95% CI: 0.82–0.98) compared with those consuming fewer than three portions a day. The risk of IHD was 6% (95% CI 0.90–0.99; P-trend = 0.009) lower for a 200 g/day higher intake of fruit and vegetables combined, 3% (0.95–1.00; P-trend = 0.021) lower for a 100 g/ day higher fruit intake, and 8% (0.86–0.97; P-trend = 0.006) lower for a 50 g/ day higher intake of bananas. Moreover, risk of IHD was 9% (0.83–0.99; P-trend = 0.032) lower for a 10g/ day higher intake of nuts and seeds, and 10% (0.82–0.98; P-trend = 0.020) lower for a 10g/ day higher intake of total dietary fibre. No associations were observed between legumes, total vegetables and other subtypes of fruit and vegetables and IHD risk.DiscussionThe results from this large prospective study suggest that higher intakes of fruit and vegetables combined, total fruit, bananas, nuts and seeds, and total fibre are associated with a lower risk of IHD. Given the observational design of this study, causality and potential mechanisms should be further investigated.

Analyses were supported by the UK Medical Research Council (MR/M012190/1), Cancer Research UK (C8221/A19170 and 570/A16491) and the Wellcome Trust (Our Planet Our Health, Livestock Environment and People 205212/Z/16/Z). A.P.C. is supported by a Cancer Research UK Population Research Fellowship (C60192/A28516) and by the World Cancer Research Fund (WCRF UK), as part of the Word Cancer Research Fund International grant programme (2019/1953). EPIC-CVD has been supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270 and MR/L003120/1), the British Heart Foundation (SP/09/002 and RG/08/014 and RG13/13/30194) and the UK National Institute of Health Research. The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge ' ne ' rale de l'Education Nationale, Institut National de la Sante ' et de la Recherche Me ' dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluci ' a, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska degrees ne and Va sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), UK Medical Research Council [1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford, MC_UU_12015/1 (N.J.W.), MC_UU_12015/5 (NGF), and MC_UU_12015/520], and NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) to the MRC Epidemiology Unit Cambridge (N.J.W., N.G.F.). J.D. holds a British Heart Foundation Chair and an NIHR Senior Investigator Award. K.E.B. holds a Girdlers' New Zealand Health Research Council Fellowship. J.D. is funded by the National Institute for Health Research [Senior Investigator Award] [*]. A.W is supported by a BHF-Turing Cardiovascular Data Science Award and by the ECInnovative Medicines Initiative (BigData@Heart).M.S.reports funding from the Alpro Foundation whilst at the Cardiovascular Epidemiology Unit (up to 15-08-2016), and Core MRC Unit support through the Nutritional Epidemiology Programme (MC_UU_12015/5) whilst at the MRC Epidemiology Unit (15-08-2016 until now), during the conduct of the study., The authors thank all participants in the EPIC cohort for their invaluable contribution to the study., Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD. Results There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90–0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95–1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82–0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85–0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91–0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95–1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk. Conclusions In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear., UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M012190/1 G0800270 MR/L003120/1 1000143 MC_UU_12015/1 MC_UU_12015/5 MC_UU_12015/520, Cancer Research UK C8221/A19170 570/A16491 14136 C570/A16491, Wellcome Trust (Our Planet Our Health, Livestock Environment and People) 205212/Z/16/Z, Cancer Research UK Population Research Fellowship C60192/A28516, World Cancer Research Fund (WCRF UK), as part of the Word Cancer Research Fund International grant programme 2019/1953, European Commission HEALTH-F2-2012-279233, European Research Council (ERC) European Commission 268834, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), European Commission LSHM_CT_2006_037197, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) 6236, Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, NIHR Senior Investigator Award, Girdlers' New Zealand Health Research Council Fellowship, BHF-Turing Cardiovascular Data Science Award, ECInnovative Medicines Initiative (BigData@Heart), Alpro Foundation 15-08-2016, Core MRC Unit support through the Nutritional Epidemiology Programme MC_UU_12015/5

Background Although maternal death is rare in the UK, 90% (510 of 566 deaths) of women who died during or within a year after pregnancy in 2016–18 had multiple health and social problems (MBRRACE-UK). This study aims to estimate the prevalence of pre-existing multimorbidity in pregnant women in the UK. Methods Pregnant women aged 15–49 years with a conception date between Jan 1 and Dec 31, 2018, were included in this cross-sectional study, using routine health-care datasets: Clinical Practice Research Datalink (CPRD) GOLD (UK, n=37 641), Secure Anonymised Information Linkage (SAIL) databank (Wales, n=27 782), and Scottish Morbidity Records (SMR, secondary care) with linked community prescribing data (Tayside and Fife, n=6099). We defined pre-existing multimorbidity (two or more morbidities) preconception from 79 long-term physical and mental health conditions. This definition was identified from the literature and prioritised by the multidisciplinary research advisory group, including patient representatives. The association of women's characteristics preconception with multimorbidity was examined with logistic regression. The University of St Andrews School of Medicine Ethics Committee approved this project. Participant consent was not required as the data used are anonymised. Interpretation Prevalence of multimorbidity was 44·2% (95% CI 43·7–44·7) in CPRD, 46·2% (45·6–46·8) in SAIL, and 19·8% (18·8–20·8) in SMR. Mental health conditions were highly prevalent and involved 70% of multimorbidity (CPRD: prevalence of multimorbidity with one or more mental health conditions 31·3% [30·8–31·8]). Pregnant women with conditions that were leading causes of maternal deaths had a high prevalence of multimorbidity (CPRD: 745 [2·0%] of 37 641 women had cardiovascular disease, of whom 597 [80·1%] had multimorbidity). Higher maternal age (CPRD: adjusted odds ratio 1·81 [95% CI 1·04–3·17] for 45–49 years vs 15–19 years), gravidity (1·68 [1·50–1·89] for ≥5 vs 1), BMI (1·59 [1·44–1·76], for ≥30 vs 18·5–24·9) and smoking (1·61 [1·46–1·77] for smoker vs non-smoker) were significantly associated with multimorbidity. Ethnicity and deprivation were not significantly associated with multimorbidity. Interpretation A significant proportion of women enter pregnancy with pre-existing multimorbidity, especially mental health conditions. Pregnant women with multimorbidity were more likely to smoke and have a raised BMI and support may be required to address this. There may be health-care access inequalities for some health conditions, especially mental health conditions in pregnant women from deprived or ethnic minority groups. Secondary care and linked community prescription dataset captured severe conditions and might underestimate the prevalence of multimorbidity. Urgent research is needed to quantify the consequences of maternal multimorbidity for mother and child. Funding This work was supported by the joint UKRI-NIHR Strategic Priorities Fund consolidator grant (grant number MR/V005243/1). BT was funded by the National Institute for Health Research (NIHR) West Midlands Applied Research Collaboration. AA and SIL were funded as NIHR Academic Clinical Fellows. The views expressed are those of the author and not necessarily those of the funders, the NIHR or the UK Department of Health and Social Care.

Background: Folate deficiency may increase the risk of peripheral neuropathy but there is a paucity of data from large prospective studies examining this association. Methods: Longitudinal analysis of electronic health records in The Health Improvement Network (THIN), a U.K. primary care database including 594,338 patients aged 18&ndash, 70 years with a folate measurement and without a history of peripheral neuropathy. Results: After a mean follow-up of 3.71 (standard deviation (SD) = 3.14) years, 1949 patients were diagnosed with peripheral neuropathy and 20,679 patients died. In those &lt, 40 years, compared to patients with folate &ge, 13.6 nmol/L, those with folate &lt, 6.8 (deficient) and 6.8&ndash, 13.5 nmol/L (insufficient) had a hazard ratio (HR) for peripheral neuropathy of 1.83 (95% confidence intervals (CI) = 1.16&ndash, 2.91) and 1.48 (95% CI = 1.04&ndash, 2.08), respectively. There was no significant association between folate and peripheral neuropathy among those aged 41&ndash, 70 years. Compared to patients with folate &ge, 13.6 nmol/L, folate &lt, 6.8 nmol/L was associated with a greater risk of death among all ages. Conclusion: Folate deficiency and insufficiency was associated with a greater risk of peripheral neuropathy among younger patients. This investigation should be replicated in other large datasets and it may be important to monitor peripheral neuropathy incidence after the introduction of mandatory folic acid fortification of flour in the U.K.

ObjectivesThe objective of this study is to use latent class analysis of up to 20 comorbidities in patients with a diagnosis of ischaemic heart disease (IHD) to identify clusters of comorbidities and to examine the associations between these clusters and mortality.MethodsLongitudinal analysis of electronic health records in the health improvement network (THIN), a UK primary care database including 92 186 men and women aged ≥18 years with IHD and a median of 2 (IQR 1–3) comorbidities.ResultsLatent class analysis revealed five clusters with half categorised as a low-burden comorbidity group. After a median follow-up of 3.2 (IQR 1.4–5.8) years, 17 645 patients died. Compared with the low-burden comorbidity group, two groups of patients with a high-burden of comorbidities had the highest adjusted HR for mortality: those with vascular and musculoskeletal conditions, HR 2.38 (95% CI 2.28 to 2.49) and those with respiratory and musculoskeletal conditions, HR 2.62 (95% CI 2.45 to 2.79). Hazards of mortality in two other groups of patients characterised by cardiometabolic and mental health comorbidities were also higher than the low-burden comorbidity group; HR 1.46 (95% CI 1.39 to 1.52) and 1.55 (95% CI 1.46 to 1.64), respectively.ConclusionsThis analysis has identified five distinct comorbidity clusters in patients with IHD that were differentially associated with risk of mortality. These analyses should be replicated in other large datasets, and this may help shape the development of future interventions or health services that take into account the impact of these comorbidity clusters.

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

There is increasing evidence that vitamin D supplementation may only be beneficial in people with vitamin D deficiency, and the lack of sufficient people with very low vitamin D levels could explain the lack of protection against cardiovascular disease (CVD) reported in recent clinical trials of vitamin D supplementation. The aim of this study was to assess associations of low to moderate circulating concentrations of 25-hydroxyvitamin D (25(OH)D with risk of incident CVD and all-cause mortality, as well as the risk of ischaemic heart disease (IHD), cerebrovascular disease, and heart failure separately.Longitudinal analysis of electronic health records in The Health Improvement Network (THIN), a UK primary care database. The analysis included 180,263 patients age 18 years and older without a history of CVD and with circulating concentrations of 25(OH)D. After a mean follow-up of 2.2 (SD 1.7) years, there were 3747 patients diagnosed with CVD and 3912 patients died. Compared to patients in the highest quintile of 25(OHD) (≥ 67.5 nmol/L), those in the lowest 25(OH)D quintile (23.1 nmol/L) had a hazard ratio (HR) of 1.24 (95% CI 1.12-1.38, P 0.001) for CVD and 1.71 (1.55-1.88, P 0.001) for mortality. The HR for both outcomes associated with 25(OH)D concentration was non-linear, being significantly increased in patients with 25(OH)D35 nmol/L, and highest in those with 25(OH)D25 nmol/L, although increased for mortality at 25(OH)D ≥100 nmol/L. The increased CVD HR in the lowest 25(OH)D quintile was more from IHD (1.35, 95% CI 1.13-1.60) and heart failure (1.38, 95% CI 1.08-1.77), than from cerebrovascular disease (1.13, 95% CI 0.97-1.31).Low 25(OH)D are associated with highest risk of CVD and mortality, and are consistent with accumulating evidence that increased risk of these diseases occurs primarily in people with vitamin D deficiency.

ObjectiveTo investigate trends in the incidence of testing for vitamin D deficiency and the prevalence of patients with circulating concentrations of 25-hydroxyvitamin D (25(OH)D) indicative of deficiency (DesignLongitudinal analysis of electronic health records in The Health Improvement Network primary care database.SettingUK primary care.InterventionNone.ParticipantsThe analysis included 6 416 709 participants aged 18 years and older.Primary outcomesIncidence of having a blood test for vitamin D deficiency between 2005 and 2015, the prevalence with blood 25(OH)D ResultsAfter a mean follow-up time of 5.4 (SD 3.7) years, there were 210 502 patients tested for vitamin D deficiency. The incidence of vitamin D testing rose from 0.29 per 1000 person-years at risk (PYAR) (95% CI 0.27 to 0.31) in 2005 to 16.1 per 1000 PYAR (95% CI 15.9 to 16.2) in 2015. Being female, older, non-white ethnicity and more economically deprived were all strongly associated with being tested. One-third (n=69 515) had 25(OH)D ConclusionsTesting for vitamin D deficiency increased over the past decade among adults in the UK. One-third of UK adults who had a vitamin D test performed in primary care were vitamin D deficient, and deficiency was much higher among ethnic minority patients. Future research should focus on strategies to ensure population intake of vitamin D, particularly in at-risk groups, meets recommendations to reduce the risk of deficiency and need for testing.

Aims Previous research has shown that young children from lower-income countries who play on soil contaminated with faecal bacteria may have an increased risk of diarrhoea. We describe the directly observed activities of young children in rural Gambia and assess whether exposure to the ground outside and factors such as who cares for the child are associated with the child’s risk of diarrhoea. Methods This was a cross-sectional analysis of secondary data from 735 randomly selected households with a child aged 6–36 months from 30 rural villages in The Gambia. Fieldworkers observed the children’s activities and the presence of livestock in the compound, and caregivers reported diarrhoea in the children over the past week. The predictors of diarrhoea were assessed by using a mixed effects multivariate logistic regression model, adjusted for demographic, socio-economic and behavioural factors. Results The majority (87.1%) of children were observed on the ground outside and 84.4% of children were in compounds that contained livestock. Some children (15.6%) were observed on the ground on multiple occasions but the longest period the children were observed on the ground was a median (IQR) of 93 (46–195) minutes. For every hour a child spent on the ground outside during the longest observed period, their risk of diarrhoea increased by 12.4% (adjusted OR=1.124, 95% CI=1.000–1.264, p=0.049). Having an older child, compared to an adult supervising the child reduced the risk of diarrhoea by nearly half (adjusted OR=0.523, 95% CI=0.344–0.794, p=0.002). Conclusion This is the first study from rural Gambia to explore the activities of young children and quantify their exposure to soil on the ground and nearby livestock. The length of the longest period the child spent on the ground outside was positively associated with the risk of diarrhoea. This study highlights the need for interventions that will reduce young children’s exposure to contaminated soil in compounds and suggests that older children as carers could play a part.

OBJECTIVE: To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. DESIGN: Systematic review and meta-analysis of observational studies and randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. STUDY SELECTION: Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. DATA EXTRACTION: Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. RESULTS: In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. CONCLUSIONS: Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

Although assumed, it remains unclear that fatty acid (FA) biomarkers of n-3 long-chain PUFA reflect wide ranges of intake. However, to be utilised as biomarkers, to predict dietary intake, dose-response curves that cover a spectrum of intakes are required. The aim of the study was to investigate whether the FA composition of plasma phosphatidylcholine (PC) is a sensitive biomarker of n-3 FAs from fish oil, across a range of supplementation doses, and alpha-linolenic acid (ALA) supplementation, in young, healthy women.A total of 303 young women were randomised to intakes ranging between 0.33 and 4.50 g EPA+DHA/day from fish oil (not all doses used in each year) or flaxseed oil (5.90-6.60 g/d) daily for 14 days in a series of trials, over 5 years. Fasting blood was collected at baseline (day 0) and day 14 and plasma PC FA composition, total and HDL-cholesterol and triglyceride concentrations measured.Fourteen days supplementation with fish oil significantly (P 0.01) increased, in a dose-dependent fashion, plasma PC EPA, DPA and DHA at all doses except 1 and 3 mL/day. For the combined group of women who consumed any fish oil there was a 16% (P 0.01) decrease in plasma triacylglycerol concentrations after 14 days supplementation. Flaxseed oil supplementation for 14 day resulted in significant (P 0.01) increases in ALA, EPA and DPA, whilst DHA remained unchanged.Our data demonstrate plasma PC is a sensitive biomarker of n-3 FA intake and reflects changes within 14 days across a range of intakes.

Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (- and -carotene, lycopene, -cryptoxanthin, canthaxanthin, zeaxanthin and lutein), - and -tocopherol and retinol were measured by reverse phase high-performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma -carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31-0.88, p for trend=0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30-0.94, p for trend=0.06) and -tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39-0.99, p for trend=0.08. For - and -carotene, lutein, sum of carotenoids and -tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of -carotene, zeaxanthin and -tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted. What's new? Fruits and vegetables may play a role in the prevention of pancreatic cancer, but associations between the antioxidants those foods contain and disease risk remain unclear. In this study, pancreatic cancer risk was inversely associated with increased prediagnostic plasma concentrations of the antioxidants -carotene, zeaxanthin, and -tocopherol. Geographic variations were also detected. In Northern European countries, inverse associations with risk were found for blood levels of several carotenoids, whereas the association was strongest for -tocopherol in Southern European countries. The role of carotenoids and vitamins should be considered in subsequent investigations of the etiology of pancreatic cancer.

Birth weight and height are correlated and likely to be markers of some aspect of growth that affects cancer risk in adulthood. However, birth weight adds little, if any, additional information to adult height as a predictor of cancer incidence in women., Background Most evidence about associations between birth weight and adult cancer risk comes from studies linking birth records to cancer registration data, where information on known risk factors for cancer is generally lacking. Here, we report on associations between birth weight and cause-specific cancer risk in a large cohort of UK women, and investigate how observed associations are affected by other factors. Methods A total of 453 023 women, born in the 1930s and 1940s, reported their birth weight, maternal smoking, parental heights, age at menarche, adult height, adult smoking, and many other personal characteristics. They were followed for incident cancer. Using Cox regression, relative risks by birth weight were estimated for cancers with more than 1500 incident cases, adjusting for 17 potential confounding factors, individually and simultaneously. Results Birth weight reported in adulthood was strongly correlated with that recorded at birth (correlation coefficient = 0.78, P < 0.0001). Reported birth weight was associated with most of the potential confounding factors examined, the strongest association being with adult height. After 9.2 years follow-up per woman, 39 060 incident cancers were registered (4414 colorectal, 3175 lung, 1795 malignant melanoma, 14 542 breast, 2623 endometrial, 2009 ovarian, 1565 non-Hodgkin lymphoma, and 8937 other cancers). Associations with birth weight were null or weak and reduced after adjustment by adult height (P[trend] > 0.01 for every cancer, after adjustment). In contrast, adult height was strongly related to the risk of every cancer except lung cancer, after adjusting for birth weight and other factors (P[trend] < 0.0001 for most cancers). For lung cancer, adjusting for smoking reduced the association with birth weight. Meta-analyses were dominated by our findings. Conclusion Birth weight and adult height are correlated and likely to be markers of some aspect of growth that affects cancer risk in adulthood. However, birth weight adds little, if any, additional information to adult height as a predictor of cancer incidence in women.

Limited epidemiological evidence suggests a protective role for plant foods rich in flavonoids and antioxidants in hepatocellular cancer (HCC) etiology. Our aim was to prospectively investigate the association between dietary intake of flavonoids, lignans and nonenzymatic antioxidant capacity (NEAC) and HCC risk. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 477,206 subjects (29.8% male) recruited from ten Western European countries, was analyzed. Flavonoid, lignan and NEAC intakes were calculated using a compilation of existing food composition databases linked to dietary information from validated dietary questionnaires. Dietary NEAC was based on ferric reducing antioxidant capacity (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hepatitis B/C status was measured in a nested case-control subset. During a mean follow-up of 11-years, 191 incident HCC cases (66.5% men) were identified. Using Cox regression, multivariable adjusted models showed a borderline nonsignificant association of HCC with total flavonoid intake (highest versus lowest tertile, HR = 0.65, 95% CI: 0.40-1.04; p(trend) = 0.065), but not with lignans. Among flavonoid subclasses, flavanols were inversely associated with HCC risk (HR = 0.62, 95% CI: 0.39-0.99; p(trend) = 0.06). Dietary NEAC was inversely associated with HCC (FRAP: HR 0.50, 95% CI: 0.31-0.81; p(trend) = 0.001; TRAP: HR 0.49, 95% CI: 0.31-0.79; p(trend) = 0.002), but statistical significance was lost after exclusion of the first 2 years of follow-up. This study suggests that higher intake of dietary flavanols and antioxidants may be associated with a reduced HCC risk.

Background: In 2007, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) issued recommendations on diet, physical activity, and weight management for cancer prevention on the basis of the most comprehensive collection of available evidence. Objective: We investigated whether concordance with WCRF/AICR recommendations is related to risk of death. Design: The current study included 378,864 participants from 9 European countries enrolled in the European Prospective Investigation into Cancer and Nutrition study. At recruitment (1992-1998), dietary, anthropometric, and lifestyle information was collected. A WCRF/AICR score, which incorporated 6 of the WCRF/AICR recommendations for men [regarding body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, and alcoholic drinks (score range: 0-6)] and 7 WCRF/AICR recommendations for women [plus breastfeeding (score range: 0-7)], was constructed. Higher scores indicated greater concordance with WCRF/AICR recommendations. Associations between the WCRF/AICR score and risks of total and cause-specific death were estimated by using Cox regression analysis. Results: After a median follow-up time of 12.8 y, 23,828 deaths were identified. Participants within the highest category of the WCRF/AICR score (5-6 points in men; 6-7 points in women) had a 34% lower hazard of death (95% CI: 0.59, 0.75) compared with participants within the lowest category of the WCRF/AICR score (0-2 points in men; 0-3 points in women). Significant inverse associations were observed in all countries. The WCRF/AICR score was also significantly associated with a lower hazard of dying from cancer, circulatory disease, and respiratory disease. Conclusion: Results of this study suggest that following WCRF/AICR recommendations could significantly increase longevity. Am J Clin Nutr 2013;97:1107-20.

In this study, the relation between fruit and vegetable consumption and mortality was investigated within the European Prospective Investigation Into Cancer and Nutrition. Survival analyses were performed, including 451,151 participants from 10 European countries, recruited between 1992 and 2000 and followed until 2010. Hazard ratios, rate advancement periods, and preventable proportions to respectively compare risk of death between quartiles of consumption, to estimate the period by which the risk of death was postponed among high consumers, and to estimate proportions of deaths that could be prevented if all participants would shift their consumption 1 quartile upward. Consumption of fruits and vegetables was inversely associated with all-cause mortality (for the highest quartile, hazard ratio = 0.90, 95% confidence interval (CI): 0.86, 0.94), with a rate advancement period of 1.12 years (95% CI: 0.70, 1.54), and with a preventable proportion of 2.95%. This association was driven mainly by cardiovascular disease mortality (for the highest quartile, hazard ratio = 0.85, 95% CI: 0.77, 0.93). Stronger inverse associations were observed for participants with high alcohol consumption or high body mass index and suggested in smokers. Inverse associations were stronger for raw than for cooked vegetable consumption. These results support the evidence that fruit and vegetable consumption is associated with a lower risk of death.

OBJECTIVES: Obesity is associated with a proinflammatory state that may be involved in the etiology of inflammatory bowel disease (IBD), for which there are plausible biological mechanisms. Our aim was to perform the first prospective cohort study investigating if there is an association between obesity and the development of incident IBD. METHODS: A total of 300,724 participants were recruited into the European Prospective Investigation into Cancer and Nutrition study. At recruitment, anthropometric measurements of height and weight plus physical activity and total energy intake from validated questionnaires were recorded. The cohort was monitored identifying participants who developed either Crohn's disease (CD) or ulcerative colitis (UC). Each case was matched with four controls and conditional logistic regression used to calculate odds ratios (ORs) for body mass index (BMI) adjusted for smoking, energy intake, and physical activity. RESULTS: In the cohort, 177 participants developed incident UC and 75 participants developed incident CD. There were no associations with the four higher categories of BMI compared with a normal BMI for UC (P-trend = 0.36) or CD (P-trend = 0.83). The lack of associations was consistent when BMI was analyzed as a continuous or binary variable (BMI 18.5 = 25 kg/m(2)). Physical activity and total energy intake, factors that influence BMI, did not show any association with UC (physical activity, P-trend = 0.79; total energy intake, P-trend = 0.18) or CD (physical activity, P-trend = 0.42; total energy, P-trend = 0.11). CONCLUSIONS: Obesity as measured by BMI is not associated with the development of incident UC or CD. Alternative measures of obesity are required to further investigate the role of obesity in the development of incident IBD.

OBJECTIVE Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODS Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTS Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages 0.05). CONCLUSIONS Early menopause is associated with a greater risk of type 2 diabetes.

Background: Acrylamide is a chemical compound present in tobacco smoke and food, classified as a probable human carcinogen and a known human neurotoxin. Acrylamide is formed in foods, typically carbohydrate-rich and protein-poor plant foods, during high-temperature cooking or other thermal processing. The objectives of this study were to compare dietary estimates of acrylamide from questionnaires (DQ) and 24-h recalls (R) with levels of acrylamide adduct (AA) in haemoglobin. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, acrylamide exposure was assessed in 510 participants from 9 European countries, randomly selected and stratified by age, sex, with equal numbers of never and current smokers. After adjusting for country, alcohol intake, smoking status, number of cigarettes and energy intake, correlation coefficients between various acrylamide measurements were computed, both at the individual and at the aggregate (centre) level. Results: Individual level correlation coefficient between DQ and R measurements (r DQ,R) was 0.17, while r DQ,AA and r R,AA were 0.08 and 0.06, respectively. In never smokers, r DQ,R, r DQ,AA and r R,AA were 0.19, 0.09 and 0.02, respectively. The correlation coefficients between means of DQ, R and AA measurements at the centre level were larger (r > 0.4). Conclusions: These findings suggest that estimates of total acrylamide intake based on self-reported diet correlate weakly with biomarker AA Hb levels. Possible explanations are the lack of AA levels to capture dietary acrylamide due to individual differences in the absorption and metabolism of acrylamide, and/or measurement errors in acrylamide from self-reported dietary assessments, thus limiting the possibility to validate acrylamide DQ measurements. © 2012 Springer-Verlag Berlin Heidelberg.

Journal Article; Research Support, Non-U.S. Gov't; OBJECTIVE We investigated the association between the proportion of long-chain n-3 polyunsaturated fatty acids (PUFA) in plasma phospholipids from blood samples drawn at enrollment and subsequent change in body weight. Sex, age, and BMI were considered as potential effect modifiers. METHOD A total of 1,998 women and men participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) were followed for a median of 4.9 years. The associations between the proportion of plasma phospholipid long-chain n-3 PUFA and change in weight were investigated using mixed-effect linear regression. RESULTS The proportion of long-chain n-3 PUFA was not associated with change in weight. Among all participants, the 1-year weight change was -0.7 g per 1% point higher long-chain n-3 PUFA level (95% confidence interval: -20.7 to 19.3). The results when stratified by sex, age, or BMI groups were not systematically different. CONCLUSION The results of this study suggest that the proportion of long-chain n-3 PUFA in plasma phospholipids is not associated with subsequent change in body weight within the range of exposure in the general population. Yes

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp– and oral glucose tolerance test–based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], −0.03 [−0.04, −0.01]; P = 0.004). This score was associated with lower BMI (−0.01 [−0.01, −0.0]; P = 0.02) and gluteofemoral fat mass (−0.03 [−0.05, −0.02; P = 1.4 × 10−6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Background: Fatty acids in blood may be related to the risk of prostate cancer, but epidemiologic evidence is inconsistent. Blood fatty acids are correlated through shared food sources and common endogenous desaturation and elongation pathways. Studies of individual fatty acids cannot take this into account, but pattern analysis can. Treelet transform (TT) is a novel method that uses data correlation structures to derive sparse factors that explain variation. Objective: The objective was to gain further insight in the association between plasma fatty acids and risk of prostate cancer by applying TT to take data correlations into account. Design: We reanalyzed previously published data from a case-control study of prostate cancer nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. TT was used to derive factors explaining the variation in 26 plasma phospholipid fatty acids of 962 incident prostate cancer cases matched to 1061 controls. Multiple imputation was used to deal with missing data in covariates. ORs of prostate cancer according to factor scores were determined by using multivariable conditional logistic regression. Results: Four simple factors explained 38% of the variation in plasma fatty acids. A high score on a factor reflecting a long-chain n-3 PUFA pattern was associated with greater risk of prostate cancer (OR for highest compared with lowest quintile: 1.36; 95% CI: 0.99, 1.86; P-trend = 0.041). Conclusion: Pattern analyses using TT groupings of correlated fatty acids indicate that intake or metabolism of long-chain n-3 PUFAs may be relevant to prostate cancer etiology. Am J Clin Nutr 2012;96:1354-61.

Aims/hypothesis: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis. Methods: Pre-diagnostic levels of HbA1c and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer. Results: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA1c levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [≥6.5%, 48 mmol/mol] vs lowest [≤5.4%, 36 mmol/mol] category), even for individuals with HbA1c levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA1c levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis. Conclusions/interpretation: Our data on HbA1c show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA1c levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.

Pancreatic cancer is the fourth most common cause of cancer death worldwide with large geographical variation, which implies the contribution of diet and lifestyle in its etiology. We examined the association of meat and fish consumption with risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 477,202 EPIC participants from 10 European countries recruited between 1992 and 2000 were included in our analysis. Until 2008, 865 nonendocrine pancreatic cancer cases have been observed. Calibrated relative risks (RRs) and 95% confidence intervals (CIs) were computed using multivariable-adjusted Cox hazard regression models. The consumption of red meat (RR per 50 g increase per day = 1.03, 95% CI = 0.93-1.14) and processed meat (RR per 50 g increase per day = 0.93, 95% CI = 0.71-1.23) were not associated with an increased pancreatic cancer risk. Poultry consumption tended to be associated with an increased pancreatic cancer risk (RR per 50 g increase per day = 1.72, 95% CI = 1.04-2.84); however, there was no association with fish consumption (RR per 50 g increase per day = 1.22, 95% CI = 0.92-1.62). Our results do not support the conclusion of the World Cancer Research Fund that red or processed meat consumption may possibly increase the risk of pancreatic cancer. The positive association of poultry consumption with pancreatic cancer might be a chance finding as it contradicts most previous findings.

Background: Phytanic acid, a fatty acid predominantly obtained from foods high in ruminant fat, may have a biological role in the up-regulation of the protein α-methylacyl-coenzyme A racemase, which is overexpressed in prostate cancer tissue. Objective: This study aimed to examine the association between plasma concentrations of phytanic acid and subsequent risk of prostate cancer. Design: Within the European Prospective Investigation into Cancer and Nutrition cohort, 566 incident prostate cancer cases from Germany, Greece, Italy, the Netherlands, Spain, and the United Kingdom were individually matched to 566 controls by study center, age at recruitment, and time of day and duration of fasting at blood collection. Phytanic acid concentrations were measured by using a gas chromatography-mass spectrometry assay. Results: In controls, plasma phytanic acid concentration was strongly correlated with dairy fat intake (r = 0.49, P < 0.0001), varied significantly by country (P for heterogeneity < 0.0001), and decreased with age (P for trend = 0.02) and duration of fasting at blood collection (P for trend = 0.002). There was no significant association of phytanic acid with prostate cancer risk overall (odds ratio for a doubling in concentration: 1.05; 95% CI: 0.91, 1.21; P for trend = 0.53) or by stage or grade of disease. However, in men who had fasted (>3 h) at blood collection, the odds ratio for prostate cancer was 1.27 (95% CI: 1.01, 1.60; P for trend = 0.04). Conclusion: Plasma phytanic acid concentration is significantly associated with intake of dairy fat but not with overall risk of prostate cancer in this European population. © 2010 American Society for Nutrition.

Results from the majority of studies show little association between circulating concentrations of vitamin D and prostate cancer risk, a finding that has not been demonstrated in a wider European population, however. The authors examined whether vitamin D concentrations were associated with prostate cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (1994-2000). Serum concentrations of 25-hydroxyvitamin D were measured in 652 prostate cancer cases matched to 752 controls from 7 European countries after a median follow-up time of 4.1 years. Conditional logistic regression models were used to calculate odds ratios for prostate cancer risk in relation to serum 25-hydroxyvitamin D after standardizing for month of blood collection and adjusting for covariates. No significant association was found between 25-hydroxyvitamin D and risk of prostate cancer (highest vs. lowest quintile: odds ratio = 1.28, 95% confidence interval: 0.88, 1.88; P for trend = 0.188). Subgroup analyses showed no significant heterogeneity by cancer stage or grade, age at diagnosis, body mass index, time from blood collection to diagnosis, or calcium intake. In summary, the results of this large nested case-control study provide no evidence in support of a protective effect of circulating concentrations of vitamin D on the risk of prostate cancer.

Background: Epidemiologic data suggest that diet is a risk factor in the etiology of gastric cancer. However, the role of dietary fatty acids, a modifiable risk factor, remains relatively unexplored. Objective: The objective of this study was to determine the association of plasma phospholipid fatty acid concentrations, as biomarkers of exogenous and endogenously derived fatty acids, with the risk of gastric adenocarcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition-Europe Gastric Cancer (EPIC-EURGAST). Design: Fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 238 cases matched to 626 controls by age, sex, study center, and date of blood donation. Conditional logistic regression models adjusted for Helicobacter pylori infection status, BMI, smoking, physical activity, education, and energy intake were used to estimate relative cancer risks. Results: Positive risk associations for gastric cancer were observed in the highest compared with the lowest quartiles of plasma oleic acid (OR: 1.72; 95% CI: 1.01, 2.94), di-homo-gamma-linolenic acid (OR: 1.92; 95% CI: 1.10, 3.35), alpha-linolenic acid (OR: 3.20; 95% CI: 1.70, 6.06), and the ratio of MUFAs to saturated fatty acids, as an indicator of stearoyl-CoA desaturase-1 enzyme activity (OR: 1.40; 95% CI: 0.81, 2.43). An inverse risk association was observed with the ratio of linoleic to alpha-linolenic acid (OR: 0.37; 95% CI: 0.20, 0.66). Conclusion: These data suggest that a specific prediagnostic plasma phospholipid fatty acid profile, characterized mainly by high concentrations of oleic acid, alpha-linolenic acid, and di-homo-gamma-linolenic acid, which presumably reflect both a complex dietary pattern and altered fatty acid metabolism, may be related to increased gastric cancer risk. Am J Clin Nutr 2011;94:1304-13. (Less)

BACKGROUND: The use of serum fatty acid biomarkers in nutritional epidemiology is increasingly common; however, there is an absence of scientific evidence to substantiate whether the measurement of fatty acids as molecular percentages (which is the conventional approach) or as absolute concentrations is more informative. OBJECTIVE: To advance understanding about this fundamental concept, we examined the ability of serum myristic acid and linoleic acid, expressed as molecular percentages or as concentrations, to predict dietary fat and serum cholesterol concentrations. DESIGN: A cross-sectional analysis of a population-based survey of New Zealand adults (n = 2732) was undertaken. The association of myristic and linoleic acids in serum cholesterol ester and phospholipid with dietary fat or serum cholesterol was assessed. RESULTS: Intake of saturated fat, dairy fat, and polyunsaturated fat was predicted similarly with the use of both units of measurement. After adjustment for confounders, mean total cholesterol decreased by 0.18 mmol/L from the lowest to the highest quintile of serum cholesteryl-linoleate as a molecular percentage (P = 0.027). In contrast, mean total cholesterol increased by 1.09 mmol/L from the lowest to the highest quintile of serum cholesteryl-linoleate concentration (P < 0.001). The molecular percentage and concentration of serum cholesteryl-myristate were positively associated with total cholesterol (P < 0.001). Results for serum phospholipid fatty acids were similar. CONCLUSION: Serum myristic acid and linoleic acid measured as molecular percentages, but not as concentrations, predict serum total cholesterol in a manner that distinguishes between the differential cholesterolemic effects of dietary saturated and polyunsaturated fats.

Adiponectin-an adipose tissue-derived protein-may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high-molecular weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite them being hypothesized to have differential biological activities, i.e. regulating insulin sensitivity (HMW adiponectin) versus inflammatory response (non-HMW adiponectin). In a prospective, nested case-control study, we investigated whether prediagnostic serum concentrations of total, HMW and non-HMW adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon and 451 rectal) were matched to 1206 controls using incidence-density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53-0.95, P(trend) = 0.03 for total adiponectin and RR = 0.45, 95% CI = 0.34-0.61, P(trend) < 0.0001 for non-HMW adiponectin]. HMW adiponectin concentrations were not associated with CRC risk (RR = 0.91, 95% CI = 0.68-1.22, P(trend) = 0.55). Non-HMW adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR = 0.39, 95% CI = 0.26-0.60, P(trend) < 0.0001), whereas the association with total adiponectin was no longer significant (RR = 0.81, 95% CI = 0.60-1.09, P(trend) = 0.23). When stratified by cancer site, non-HMW adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms.

Folate intake has shown an inverse association with pancreatic cancer; nevertheless, results from plasma measurements were inconsistent. The aim of this study is to examine the association between plasma total homocysteine, methionine, folate, cobalamin, pyridoxal 5'-phosphate, riboflavin, flavin mononucleotide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). We conducted a nested case-control study in the EPIC cohort, which has an average of 9.6 years of follow-up (1992-2006), using 463 incident pancreatic cancer cases. Controls were matched to each case by center, sex, age (+/- 1 year), date (+/- 1 year) and time (+/- 3 h) at blood collection and fasting status. Conditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for education, smoking status, plasma cotinine concentration, alcohol drinking, body mass index and diabetes status. We observed a U-shaped association between plasma folate and pancreatic cancer risk. The ORs for plasma folate 20 nmol/L were 1.58 (95% CI = 0.72-3.46), 1.39 (0.93-2.08), 1.0 (reference), 0.79 (0.52-1.21), and 1.34 (0.89-2.02), respectively. Methionine was associated with an increased risk in men (per quintile increment: OR = 1.17, 95% CI = 1.00-1.38) but not in women (OR = 0.91, 95% CI = 0.78-1.07; p for heterogeneity < 0.01). Our results suggest a U-shaped association between plasma folate and pancreatic cancer risk in both men and women. The positive association that we observed between methionine and pancreatic cancer may be sex dependent and may differ by time of follow-up. However, the mechanisms behind the observed associations warrant further investigation. (C) 2011 Elsevier Ltd. All rights reserved.

We prospectively investigated dietary flavonoid intake and esophageal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,312 adult subjects from 10 European countries. At baseline, country-specific validated dietary questionnaires were used. During a mean follow-up of 11 years (1992-2010), there were 341 incident esophageal cancer cases, of which 142 were esophageal adenocarcinoma (EAC), 176 were esophageal squamous cell carcinoma (ESCC), and 23 were other types of esophageal cancer. In crude models, a doubling in total dietary flavonoid intake was inversely associated with esophageal cancer risk (hazard ratio (HR) (log(2))=0.87, 95% confidence interval (CI): 0.78, 0.98) but not in multi-variable models (HR (log(2))=0.97, 95% CI: 0.86, 1.10). After covariate adjustment, no statistically significant association was found between any flavonoid subclass and esophageal cancer, EAC, or ESCC. However, among current smokers, flavonols were statistically significantly associated with a reduced esophageal cancer risk (HR (log(2)) = 0.72, 95% CI: 0.56, 0.94), whereas total flavonoids, flavanols, and flavan-3-ol monomers tended to be inversely associated with esophageal cancer risk. No associations were found in either never or former smokers. These findings suggest that dietary flavonoid intake was not associated with overall esophageal cancer, EAC, or ESCC risk, although total flavonoids and some flavonoid subclasses, particularly flavonols, may reduce the esophageal cancer risk among current smokers.

Background There is limited evidence for an association between the pattern of lifetime alcohol use and cause-specific risk of death.Methods Multivariable hazard ratios were estimated for different causes of death according to patterns of lifetime alcohol consumption using a competing risks approach: 111 953 men and 268 442 women from eight countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included. Self-reported alcohol consumption at ages 20, 30, 40 or 50 years and at enrolment were used for the analysis; 26 411 deaths were observed during an average of 12.6 years of follow-up.Results The association between lifetime alcohol use and death from cardiovascular diseases was different from the association seen for alcohol-related cancers, digestive, respiratory, external and other causes. Heavy users (>5 drinks/day for men and >2.5 drinks/day for women), regardless of time of cessation, had a 2- to 5-times higher risk of dying due to alcohol-related cancers, compared with subjects with lifetime light use (≤1 and ≤0.5 drink/week for men and women, respectively). Compared with lifetime light users, men who used

Item does not contain fulltext BACKGROUND: Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n = 110) or UC (n = 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking. RESULTS: Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend = 0.19) and 0.63 (95% CI, 0.28-1.42, p trend = 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend = 0.40) and 0.81 (95% CI, 0.49-1.34, p trend = 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47). CONCLUSIONS: Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect.