Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study

Objective. To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. Design Nested case-control study. Setting. The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. Participants: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls. Main outcome measures. Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. Results. 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); ≥100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. Conclusions The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&P in Spanish foods was compiled. The study included 40 685 subjects aged 35–64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&P intake were 100 and 933 μg/d respectively. Approximately, 32 % of the population did not consume R&P. The most abundant of the four stilbenes studied was trans-piceid (53·6 %), followed by trans-resveratrol (20·9 %), cis-piceid (19·3 %) and cis-resveratrol (6·2 %). The most important source of R&P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&P was similar to the wine pattern. This is the first time that R&P intake has been estimated in a Mediterranean country.

Bulky DNA adducts, 4-aminobiphenyl-haemoglobin adducts and diet in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study

In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0·02), vitamin E (P = 0·04) and alcohol (P = 0·03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P = 0·03, 0·04, and 0·03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances.

Consumption and portion sizes of tree nuts, peanuts and seeds in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts from 10 European countries

Tree nuts, peanuts and seeds are nutrient dense foods whose intake has been shown to be associated with reduced risk of some chronic diseases. They are regularly consumed in European diets either as whole, in spreads or from hidden sources (e.g. commercial products). However, little is known about their intake profiles or differences in consumption between European countries or geographic regions. The objective of this study was to analyse the population mean intake and average portion sizes in subjects reporting intake of nuts and seeds consumed as whole, derived from hidden sources or from spreads. Data was obtained from standardised 24-hour dietary recalls collected from 36 994 subjects in 10 different countries that are part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Overall, for nuts and seeds consumed as whole, the percentage of subjects reporting intake on the day of the recall was: tree nuts = 4. 4%, peanuts = 2.3 % and seeds = 1.3 %. The data show a clear northern (Sweden: mean intake = 0.15 g/d, average portion size = 15.1 g/d) to southern (Spain: mean intake = 2.99 g/d, average portion size = 34.7 g/d) European gradient of whole tree nut intake. The three most popular tree nuts were walnuts, almonds and hazelnuts, respectively. In general, tree nuts were more widely consumed than peanuts or seeds. In subjects reporting intake, men consumed a significantly higher average portion size of tree nuts (28.5 v. 23.1 g/d, P<0.01) and peanuts (46.1 v. 35.1 g/d, P<0.01) per day than women. These data may be useful in devising research initiatives and health policy strategies based on the intake of this food group.

Variability of indication criteria in knee and hip replacement: an observational study

BACKGROUND. Total knee (TKR) and hip (THR) replacement (arthroplasty) are effective surgical procedures that relieve pain, improve patients' quality of life and increase functional capacity. Studies on variations in medical practice usually place the indications for performing these procedures to be highly variable, because surgeons appear to follow different criteria when recommending surgery in patients with different severity levels. We therefore proposed a study to evaluate inter-hospital variability in arthroplasty indication. METHODS. The pre-surgical condition of 1603 patients included was compared by their personal characteristics, clinical situation and self-perceived health status. Patients were asked to complete two health-related quality of life questionnaires: the generic SF-12 (Short Form) and the specific WOMAC (Western Ontario and Mcmaster Universities) scale. The type of patient undergoing primary arthroplasty was similar in the 15 different hospitals evaluated.The variability in baseline WOMAC score between hospitals in THR and TKR indication was described by range, mean and standard deviation (SD), mean and standard deviation weighted by the number of procedures at each hospital, high/low ratio or extremal quotient (EQ5-95), variation coefficient (CV5-95) and weighted variation coefficient (WCV5-95) for 5-95 percentile range. The variability in subjective and objective signs was evaluated using median, range and WCV5-95. The appropriateness of the procedures performed was calculated using a specific threshold proposed by Quintana et al for assessing pain and functional capacity. RESULTS. The variability expressed as WCV5-95 was very low, between 0.05 and 0.11 for all three dimensions on WOMAC scale for both types of procedure in all participating hospitals. The variability in the physical and mental SF-12 components was very low for both types of procedure (0.08 and 0.07 for hip and 0.03 and 0.07 for knee surgery patients). However, a moderate-high variability was detected in subjective-objective signs. Among all the surgeries performed, approximately a quarter of them could be considered to be inappropriate. CONCLUSIONS. A greater inter-hospital variability was observed for objective than for subjective signs for both procedures, suggesting that the differences in clinical criteria followed by surgeons when indicating arthroplasty are the main responsible factors for the variation in surgery rates.

Diagnostic accuracy, effectiveness and cost for cognitive impairment and dementia screening of three short cognitive tests applicable to illiterates

BACKGROUND Illiteracy, a universal problem, limits the utilization of the most widely used short cognitive tests. Our objective was to assess and compare the effectiveness and cost for cognitive impairment (CI) and dementia (DEM) screening of three short cognitive tests applicable to illiterates. METHODS Phase III diagnostic test evaluation study was performed during one year in four Primary Care centers, prospectively including individuals with suspicion of CI or DEM. All underwent the Eurotest, Memory Alteration Test (M@T), and Phototest, applied in a balanced manner. Clinical, functional, and cognitive studies were independently performed in a blinded fashion in a Cognitive Behavioral Neurology Unit, and the gold standard diagnosis was established by consensus of expert neurologists on the basis of these results. Effectiveness of tests was assessed as the proportion of correct diagnoses (diagnostic accuracy [DA]) and the kappa index of concordance (k) with respect to gold standard diagnoses. Costs were based on public prices at the time and hospital accounts. RESULTS The study included 139 individuals: 47 with DEM, 36 with CI, and 56 without CI. No significant differences in effectiveness were found among the tests. For DEM screening: Eurotest (k = 0.71 [0.59-0.83], DA = 0.87 [0.80-0.92]), M@T (k = 0.72 [0.60-0.84], DA = 0.87 [0.80-0.92]), Phototest (k = 0.70 [0.57-0.82], DA = 0.86 [0.79-0.91]). For CI screening: Eurotest (k = 0.67 [0.55-0.79]; DA = 0.83 [0.76-0.89]), M@T (k = 0.52 [0.37-0.67]; DA = 0.80 [0.72-0.86]), Phototest (k = 0.59 [0.46-0.72]; DA = 0.79 [0.71-0.86]). There were no differences in the cost of DEM screening, but the cost of CI screening was significantly higher with M@T (330.7 ± 177.1 €, mean ± sd) than with Eurotest (294.1 ± 195.0 €) or Phototest (296.0 ± 196. 5 €). Application time was shorter with Phototest (2.8 ± 0.8 min) than with Eurotest (7.1 ± 1.8 min) or M@T (6.8 ± 2.2 min). CONCLUSIONS Eurotest, M@T, and Phototest are equally effective. Eurotest and Phototest are both less expensive options but Phototest is the most efficient, requiring the shortest application time.

Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.

BACKGROUND: One course of antenatal corticosteroids reduces the risk of respiratory distress syndrome and neonatal death. Weekly doses given to women who remain undelivered after a single course may have benefits (less respiratory morbidity) or cause harm (reduced growth in utero). We aimed to find out whether multiple courses of antenatal corticosteroids would reduce neonatal morbidity and mortality without adversely affecting fetal growth. METHODS: 1858 women at 25-32 weeks' gestation who remained undelivered 14-21 days after an initial course of antenatal corticosteroids and continued to be at high risk of preterm birth were randomly assigned to multiple courses of antenatal corticosteroids (n=937) or placebo (n=921), every 14 days until week 33 or delivery, whichever came first. The primary outcome was a composite of perinatal or neonatal mortality, severe respiratory distress syndrome, intraventricular haemorrhage (grade III or IV), periventricular leucomalacia, bronchopulmonary dysplasia, or necrotising enterocolitis. Analysis was by intention to treat. All patients and caregivers were unaware of the treatment given. This trial is registered as number ISRCTN2654148. FINDINGS: Infants exposed to multiple courses of antenatal corticosteroids had similar morbidity and mortality to those exposed to placebo (150 [12.9%] vs 143 [12.5%]). Those receiving multiple doses of corticosteroids also weighed less at birth than those exposed to placebo (2216 g vs 2330 g, p=0.0026), were shorter (44.5 cm vs 45.4 cm, p<0.001), and had a smaller head circumference (31.1 cm vs 31.7 cm, p<0.001). INTERPRETATION: Multiple courses of antenatal corticosteroids, every 14 days, do not improve preterm-birth outcomes, and are associated with a decreased weight, length, and head circumference at birth. Therefore, this treatment schedule is not recommended. FUNDING: Canadian Institutes of Health Research.

Plan estratégico de investigación, desarrollo e innovación en salud (2006-2010)

Documento disponible en inglés: Strategic plan for health research, development and innovation (2006-2010)

Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA₁ receptor knockout mice.

BACKGROUND The lysophosphatidic acid LPA₁ receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA₁ receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory. METHODOLOGY/PRINCIPAL FINDINGS Male LPA₁-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice. CONCLUSIONS/SIGNIFICANCE These results reveal that the absence of the LPA₁ receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA₁ receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology.

Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study

BACKGROUND Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI). METHODS AND FINDINGS The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5-22.4 kg/m(2)) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m(2)) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50-103 per 1,000 person-years in men and 28-74 per 1,000 person-years in women). CONCLUSIONS WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.

Multiple miscarriages are associated with the risk of ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition.

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.

Dietary fibre intake and risks of cancers of the colon and rectum in the European prospective investigation into cancer and nutrition (EPIC).

BACKGROUND Earlier analyses within the EPIC study showed that dietary fibre intake was inversely associated with colorectal cancer risk, but results from some large cohort studies do not support this finding. We explored whether the association remained after longer follow-up with a near threefold increase in colorectal cancer cases, and if the association varied by gender and tumour location. METHODOLOGY/PRINCIPAL FINDINGS After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79-0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals. CONCLUSIONS/SIGNIFICANCE Our results strengthen the evidence for the role of high dietary fibre intake in colorectal cancer prevention.

Tea consumption and incidence of type 2 diabetes in Europe: the EPIC-InterAct case-cohort study.

BACKGROUND In previous meta-analyses, tea consumption has been associated with lower incidence of type 2 diabetes. It is unclear, however, if tea is associated inversely over the entire range of intake. Therefore, we investigated the association between tea consumption and incidence of type 2 diabetes in a European population. METHODOLOGY/PRINCIPAL FINDINGS The EPIC-InterAct case-cohort study was conducted in 26 centers in 8 European countries and consists of a total of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,835 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Country-specific Hazard Ratios (HR) for incidence of type 2 diabetes were obtained after adjustment for lifestyle and dietary factors using a Cox regression adapted for a case-cohort design. Subsequently, country-specific HR were combined using a random effects meta-analysis. Tea consumption was studied as categorical variable (0, >0-<1, 1-<4, ≥ 4 cups/day). The dose-response of the association was further explored by restricted cubic spline regression. Country specific medians of tea consumption ranged from 0 cups/day in Spain to 4 cups/day in United Kingdom. Tea consumption was associated inversely with incidence of type 2 diabetes; the HR was 0.84 [95%CI 0.71, 1.00] when participants who drank ≥ 4 cups of tea per day were compared with non-drinkers (p(linear trend) = 0.04). Incidence of type 2 diabetes already tended to be lower with tea consumption of 1-<4 cups/day (HR = 0.93 [95%CI 0.81, 1.05]). Spline regression did not suggest a non-linear association (p(non-linearity) = 0.20). CONCLUSIONS/SIGNIFICANCE A linear inverse association was observed between tea consumption and incidence of type 2 diabetes. People who drink at least 4 cups of tea per day may have a 16% lower risk of developing type 2 diabetes than non-tea drinkers.

Determinants of non- response to a second assessment of lifestyle factors and body weight in the EPIC-PANACEA study.

BACKGROUND This paper discusses whether baseline demographic, socio-economic, health variables, length of follow-up and method of contacting the participants predict non-response to the invitation for a second assessment of lifestyle factors and body weight in the European multi-center EPIC-PANACEA study. METHODS Over 500.000 participants from several centers in ten European countries recruited between 1992 and 2000 were contacted 2-11 years later to update data on lifestyle and body weight. Length of follow-up as well as the method of approaching differed between the collaborating study centers. Non-responders were compared with responders using multivariate logistic regression analyses. RESULTS Overall response for the second assessment was high (81.6%). Compared to postal surveys, centers where the participants completed the questionnaire by phone attained a higher response. Response was also high in centers with a short follow-up period. Non-response was higher in participants who were male (odds ratio 1.09 (confidence interval 1.07; 1.11), aged under 40 years (1.96 (1.90; 2.02), living alone (1.40 (1.37; 1.43), less educated (1.35 (1.12; 1.19), of poorer health (1.33 (1.27; 1.39), reporting an unhealthy lifestyle and who had either a low (<18.5 kg/m2, 1.16 (1.09; 1.23)) or a high BMI (>25, 1.08 (1.06; 1.10); especially ≥30 kg/m2, 1.26 (1.23; 1.29)). CONCLUSIONS Cohort studies may enhance cohort maintenance by paying particular attention to the subgroups that are most unlikely to respond and by an active recruitment strategy using telephone interviews.

Social inequalities and mortality in Europe-results from a large multi-national cohort

BACKGROUND Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans. METHODS A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model's with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality. RESULTS Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52-0.61); among women by 29% (HR 0.71, 95% C.I. 0.64-0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries. DISCUSSION In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.