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Background: Epidemiological studies have demonstrated an association between the degree of food processing in our diet and the risk of various chronic diseases. Much of this evidence is based on the international Nova classification system, which classifies food into four groups based on the type of processing: (1) Unprocessed and minimally processed foods, (2) Processed culinary ingredients, (3) Processed foods, and (4) “Ultra-processed” foods (UPF). The ability of the Nova classification to accurately characterise the degree of food processing across consumption patterns in various European populations has not been investigated so far. Therefore, we applied the Nova coding to data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in order to characterize the degree of food processing in our diet across European populations with diverse cultural and socio-economic backgrounds and to validate this Nova classification through comparison with objective biomarker measurements. Methods: After grouping foods in the EPIC dataset according to the Nova classification, a total of 476,768 participants in the EPIC cohort (71.5% women; mean age 51 [standard deviation (SD) 9.93]; median age 52 [percentile (p)25– p75: 58–66] years) were included in the cross-sectional analysis that characterised consumption patterns based on the Nova classification. The consumption of food products classified as different Nova categories were compared to relevant circulating biomarkers denoting food processing, measured in various subsamples (N between 417 and 9,460) within the EPIC cohort via (partial) correlation analyses (unadjusted and adjusted by sex, age, BMI and country). These biomarkers included an industrial transfatty acid (ITFA) isomer (elaidic acid; exogenous fatty acid generated during oil hydrogenation and heating) and urinary 4-methyl syringol sulfate (an indicator for the consumption of smoked food and a component of liquid smoke used in UPF). Results: Contributions of UPF intake to the overall diet in % grams/day varied across countries from 7% (France) to 23% (Norway) and their contributions to overall % energy intake from 16% (Spain and Italy) to >45% (in the UK and Norway). Differences were also found between sociodemographic groups; participants in the highest fourth of UPF consumption tended to be younger, taller, less educated, current smokers, more physically active, have a higher reported intake of energy and lower reported intake of alcohol. The UPF pattern as defined based on the Nova classification (group 4;% kcal/day) was positively associated with blood levels of industrial elaidic acid (r = 0.54) and 4-methyl syringol sulfate (r = 0.43). Associations for the other 3 Nova groups with these food processing biomarkers were either inverse or non-significant (e.g., for unprocessed and minimally processed foods these correlations were –0.07 and –0.37 for elaidic acid and 4-methyl syringol sulfate, respectively). Conclusion: These results, based on a large pan-European cohort, demonstrate sociodemographic and geographical differences in the consumption of UPF. Furthermore, these results suggest that the Nova classification can accurately capture consumption of UPF, reflected by stronger correlations with circulating levels of industrial elaidic acid and a syringol metabolite compared to diets high in minimally processed foods., International Agency for Research on Cancer (IARC), Imperial College London, NIHR Imperial Biomedical Research Centre (BRC), Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro- AIRC-Italy, Compagnia di SanPaolo 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), Statistics Netherlands (Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom)

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

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

Background and purpose Limited information is available on incidence and outcomes of COVID‐19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS‐CoV‐2 infection and COVID‐19‐related outcomes in patients with MS, and compared these with the general population. Methods A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID‐19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. Results Two‐hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID‐19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease‐modifying treatment and hospitalization risk. Conclusions Patients with MS do not appear to have greater risks of SARS‐CoV‐2 infection or severe COVID‐19 outcomes compared with the general population. The decision to start or continue disease‐modifying treatment should be based on a careful risk–benefit assessment., In this multicenter registry‐based cohort study, patients with multiple sclerosis did not have an increased risk of becoming infected with COVID‐19 compared with the general population, and were not more likely to have a severe outcome of COVID‐19 (i.e., admission to an intensive care unit or death). No relationship was found between the use of any disease‐modifying treatment and the development of severe COVID‐19 disease.

EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award

Purpose Excess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults. Methods Sociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case–control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants. Results Out of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight. Conclusion Obesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991–2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks. Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97–1.09), total soft drinks (HR = 1.01; 95% CI, 0.98–1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94–1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96–1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97–1.16; 1.03, 0.98–1.09; 0.97, 0.89–1.07; and 1.06, 0.99–1.14, respectively). Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity. Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679–0.721]). Our model had slightly improved discrimination (0.714 [0.694–0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.

In this study we aimed to compare patient and graft survival of kidney transplant recipients who received a kidney from a living-related donor (LRD) or living-unrelated donor (LUD). Adult patients in the ERA-EDTA Registry who received their first kidney transplant in 1998-2017 were included. Ten-year patient and graft survival were compared between LRD and LUD transplants using Cox regression analysis. In total, 14 370 patients received a kidney from a living donor. Of those, 9212 (64.1%) grafts were from a LRD, 5063 (35.2%) from a LUD and for 95 (0.7%), the donor type was unknown. Unadjusted five-year risks of death and graft failure (including death as event) were lower for LRD transplants than for LUD grafts: 4.2% (95% confidence interval [CI]: 3.7-4.6) and 10.8% (95% CI: 10.1-11.5) versus 6.5% (95% CI: 5.7-7.4) and 12.2% (95% CI: 11.2-13.3), respectively. However, after adjusting for potential confounders, associations disappeared with hazard ratios of 0.99 (95% CI: 0.87-1.13) for patient survival and 1.03 (95% CI: 0.94-1.14) for graft survival. Unadjusted risk of death-censored graft failure was similar, but after adjustment, it was higher for LUD transplants (1.19; 95% CI: 1.04-1.35). In conclusion, patient and graft survival of LRD and LUD kidney transplant recipients was similar, whereas death-censored graft failure was higher in LUD. These findings confirm the importance of both living kidney donor types.

WOS:000577244700025 PubMed ID: 32897277 Background. This article presents a summary of the 2017 Annual Report of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 37 countries. Methods. The ERA-EDTA Registry received individual patient data on patients undergoing RRT for ESRD in 2017 from 32 national or regional renal registries and aggregated data from 21 registries. The incidence and prevalence of RRT, kidney transplantation activity and survival probabilities of these patients were calculated. Results. In 2017, the ERA-EDTA Registry covered a general population of 694 million people. The incidence of RRT for ESRD was 127 per million population (pmp), ranging from 37 pmp in Ukraine to 252 pmp in Greece. A total of 62% of patients were men, 52% were >= 65 years of age and 23% had diabetes mellitus as the primary renal disease. The treatment modality at the onset of RRT was haemodialysis for 85% of patients. On 31 December 2017, the prevalence of RRT was 854 pmp, ranging from 210 pmp in Ukraine to 1965 pmp in Portugal. The transplant rate in 2017 was 33 pmp, ranging from 3 pmp in Ukraine to 103 pmp in the Spanish region of Catalonia. For patients commencing RRT during 2008-12, the unadjusted 5-year patient survival probability for all RRT modalities combined was 50.8%. ERA-EDTA The ERA-EDTA Registry is funded by the ERA-EDTA. This article was written by Kramer et al. on behalf of the ERAEDTA Registry, which is an official body of the ERA-EDTA. In addition, M.F.S.R. reports personal fees from NxStage outside the submitted work and K.J.J. reports grants from the ERA-EDTA during the conduct of the study and a speaker fee from Fresenius Medical Care outside the submitted work.

Background: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Results: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00–1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19–2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99–1.82), the latter being nonstatistically significant only in the fully adjusted model. Conclusions: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Impact: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence.

Background Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. Methods In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. Results During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. Conclusion Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

Background Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort. Methods Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93–1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73–0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94–1.05). Conclusions While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies.

Background. The incidence of renal replacement therapy (RRT) in the general population >= 75 years of age varies considerably between countries and regions in Europe. Our aim was to study characteristics and survival of elderly RRT patients and to find explanations for differences in RRT incidence. Methods. Patients >= 75 years of age at the onset of RRT in 2010-2013 from 29 national or regional registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry were included. Chi-square and Mann-Whitney U tests were used to assess variation in patient characteristics and linear regression was used to study the association between RRT incidence and various factors. Kaplan-Meier curves and Cox regression were employed for survival analyses. Results. The mean annual incidence of RRT in the age group >= 75 years of age ranged from 157 to 924 per million age-related population. The median age at the start of RRT was higher and comorbidities were less common in areas with higher RRT incidence, but overall the association between patient characteristics and RRT incidence was weak. The unadjusted survival was lower in high-incidence areas due to an older age at onset of RRT, but the adjusted survival was similar [relative risk 1.00 (95% confidence interval, 0.97-1.03)] in patients from low- and high-incidence areas. Conclusions. Variation in the incidence of RRT among the elderly across European countries and regions is remarkable and could not be explained by the available data. However, the survival of patients in low-and high-incidence areas was remarkably similar.

Funder: Centre International de Recherche sur le Cancer; doi: http://dx.doi.org/10.13039/100008700, Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive. Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS). Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS. Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.

Background: Except for a documented increase in osteoprotegerin (OPG) concentrations with older age, data on determinants of soluble Receptor Activator of Nuclear Factor κB (sRANKL) and OPG concentrations in women are limited. We evaluated reproductive and lifestyle factors as potential sources of variation in circulating sRANKL and OPG concentrations in pre- and postmenopausal women. Methods: This study includes 2,016 controls [n = 1,552 (76%) postmenopausal, n = 757 (38%) using postmenopausal hormone therapy (PMH)] from a breast cancer case–control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Serum sRANKL was measured using an ELISA and serum OPG using an electrochemiluminescent assay. Generalized linear models were used to evaluate associations between these analytes and reproductive and lifestyle factors. Results: Older age at blood collection was associated with lower sRANKL concentrations in postmenopausal women (Ptrend ≤ 0.03) and higher OPG concentrations in all women (Ptrend ≤ 0.01). Longer duration of oral contraceptive use among premenopausal women and postmenopausal PMH users was associated with higher OPG (Ptrend ≤ 0.04). In postmenopausal non-PMH users, sRANKL concentrations were lower with longer duration of oral contraceptive use and current (vs. never) smoking (P ≤ 0.01). sRANKL concentrations were higher among women with higher BMI (Ptrend ≤ 0.01). The evaluated factors accounted for 12% of the variation in sRANKL concentrations and 21% of the variation in OPG concentrations. Conclusions: Circulating sRANKL and OPG concentrations are minimally impacted by hormone-related factors in pre- and postmenopausal women. Impact: This study suggests circulating concentrations of sRANKL and OPG are unlikely to be strongly modified by hormone-related reproductive and lifestyle factors.

Publisher's version (útgefin grein), Background: This article summarizes the ERA-EDTA Registry's 2016 Annual Report, by describing the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2016 within 36 countries. Methods: In 2017 and 2018, the ERA-EDTA Registry received data on patients undergoing RRT for ESRD in 2016 from 52 national or regional renal registries. In all, 32 registries provided individual patient data and 20 provided aggregated data. The incidence and prevalence of RRT and the survival probabilities of these patients were determined. Results: In 2016, the incidence of RRT for ESRD was 121 per million population (pmp), ranging from 29 pmp in Ukraine to 251 pmp in Greece. Almost two-thirds of patients were men, over half were aged ≥65 years and almost a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 84% of patients. On 31 December 2016, the prevalence of RRT was 823 pmp, ranging from 188 pmp in Ukraine to 1906 pmp in Portugal. In 2016, the transplant rate was 32 pmp, varying from 3 pmp in Ukraine to 94 pmp in the Spanish region of Catalonia. For patients commencing RRT during 2007-11, the 5-year unadjusted patient survival probability on all RRT modalities combined was 50.5%. For 2016, the incidence and prevalence of RRT were higher among men (187 and 1381 pmp) than women (101 and 827 pmp), and men had a higher rate of kidney transplantation (59 pmp) compared with women (33 pmp). For patients starting dialysis and for patients receiving a kidney transplant during 2007-11, the adjusted patient survival probabilities appeared to be higher for women than for men., The ERA-EDTA Registry is funded by the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA). This article was written by Anneke Kramer et al. on behalf of the ERA-EDTA Registry, which is an official body of the ERA-EDTA. In addition, Dr. Caskey reports funding from the National Health Service during the conduct of the study. Dr. Finne reports personal fees from Baxter, outside the submitted work and Dr. Slon Roblero reports personal fees from NxStage, outside the submitted work.

Publisher's version (útgefin grein), Background This article summarizes the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Registry’s 2015 Annual Report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2015 within 36 countries. Methods In 2016 and 2017, the ERA-EDTA Registry received data on patients who were undergoing RRT for ESRD in 2015, from 52 national or regional renal registries. Thirty-two registries provided individual patient-level data and 20 provided aggregated-level data. The incidence, prevalence and survival probabilities of these patients were determined. Results In 2015, 81 373 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 119 per million population (pmp). The incidence ranged by 10-fold, from 24 pmp in Ukraine to 232 pmp in the Czech Republic. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 85% of the patients, peritoneal dialysis for 11% and a kidney transplant for 4%. By Day 91 of commencing RRT, 82% of patients were receiving haemodialysis, 13% peritoneal dialysis and 5% had a kidney transplant. On 31 December 2015, 546 783 individuals were receiving RRT for ESRD, corresponding to an unadjusted prevalence of 801 pmp. This ranged throughout Europe by more than 10-fold, from 178 pmp in Ukraine to 1824 pmp in Portugal. In 2015, 21 056 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 31 pmp. This varied from 2 pmp in Ukraine to 94 pmp in the Spanish region of Cantabria. For patients commencing RRT during 2006–10, the 5-year unadjusted patient survival probabilities on all RRT modalities combined was 50.0% (95% confidence interval 49.9–50.1)., The ERA-EDTA Registry is funded by the ERA-EDTA. This article was written by Anneke Kramer et al. on behalf of the ERA-EDTA Registry, which is an official body of the ERA-EDTA.

Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D3 (25(OH)D3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimate was attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)(2)), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D3 levels were associated with higher risk of death from any cause among RCC cases.

Background: This article provides a summary of the 2013 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report (available at http://www.era- edta-reg.org), with a focus on patients with diabetes mellitus (DM) as the cause of end-stage renal disease (ESRD). Methods: In 2015, the ERA-EDTA Registry received data on renal replacement therapy (RRT) for ESRD from 49 national or regional renal registries in 34 countries in Europe and bordering the Mediterranean Sea. Individual patient data were provided by 31 registries, while 18 registries provided aggregated data. The total population covered by the participating registries comprised 650 million people. Results: In total, 72 933 patients started RRT for ESRD within the countries and regions reporting to the ERA-EDTA Registry, resulting in an overall incidence of 112 per million population (pmp). The overall prevalence on 31 December 2013 was 738 pmp (n = 478 990). Patients with DM as the cause of ESRD comprised 24% of the incident RRT patients (26 pmp) and 17% of the prevalent RRT patients (122 pmp). When compared with the USA, the incidence of patients starting RRT pmp secondary to DM in Europe was five times lower and the incidence of RRT due to other causes of ESRD was two times lower. Overall, 19 426 kidney transplants were performed (30 pmp). The 5-year adjusted survival for all RRT patients was 60.9% [95% confidence interval (CI) 60.5-61.3] and 50.6% (95% CI 49.9- 51.2) for patients with DM as the cause of ESRD.

Risk stratification of patients with pulmonary embolism (PE) may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy. Nontargeted proteomics may identify biomarkers useful for the risk stratification of patients with acute symptomatic pulmonary embolism (PE). We studied 6 patients presenting with low-risk PE and 6 patients presenting with intermediate (n = 3) or high-risk (n = 3) PE. Two-dimensional difference gel electrophoresis was used to compare their plasma protein abundances. Candidate protein markers were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry. A panel of four biomarkers (haptoglobin, hemopexin, α2-macroglobulin, and Ig α1-chain C region) showed differences in plasma abundance among patients with acute symptomatic PE of different severity. Haptoglobin and hemopexin were decreased, whereas α2-macroglobulin and Ig α1-chain C region were increased, in patients with high or intermediate-risk PE compared with low-risk PE patient. In a separate clinical population consisting of 104 adults with acute PE, serum haptoglobin concentrations had an 85% chance of correctly identifying patients with high-risk PE according to receiving operating characteristics curve analysis. Moreover, serum haptoglobin concentrations ≤1 g/l showed an 80% sensitivity and a 96% specificity for the diagnosis of high-risk PE. Nontargeted proteomics identified protein biomarkers for the severity of PE that are involved in iron metabolism pathways and acute-phase response. Among them, reduced serum haptoglobin concentrations show a high accuracy for the biochemical detection of high-risk PE.