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.

Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC.

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies.

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.

1.° Joannis de Rupella, ordinis Fratrum Minorum, summa de anima et viribus ejus. — 2.° S. Augustini liber de spiritu et anima. — 3.° Anonymi libellus de anima, seu de viribus animae. — 4.° Revelationes de locis Purgatorii et patriae coelestis : authore Petro, Abbate Cluniacensi. — 5.° Scholium de S. Elizabetha, Schonaugiensi virgine. — 6.° Scholium de S. Maria de Oignies. — 7.° Revelatio cujusdam sanctae mulieris.

Bigotianus

International recommendations on the diagnosis and treatment of patients with acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P = 0.0001; CD8(+) naïve cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells.

Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

OBJECTIVES: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe. DESIGN: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis. SETTING AND PARTICIPANTS: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998. OUTCOME MEASURES: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models. RESULTS: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours. CONCLUSIONS: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

El clam de la dona enamorada : 'La germana, l'estrangera' de Maria-Mercè Marçal. Interpretació tipològica radical de la paraula poètica

Interpretació del recull poètic 'La germana, l'estrangera' de Maria-Mercè Marçal a partir de la tipologia radical de Dolors Oller. Ens proposem amb aquest treball copsar les actituds interrogatives de Maria-Mercè Marçal subjectivades en clau de dona, d'amant i de mare, situant el lector en un discurs visionari el qual es gestiona a través de la paraula poètica simbolista. El recull és un clam de dona enamorada que reflecteix les interioritats de la pròpia experiència vital de l'autora.

Paraula i poètiques del desig. Tres itineraris del subjecte líric postmodern: alteritat, identitat i escriptura al l’obra de Gabriel Ferrater, Maria-Mercé Marçal i Enric Casasses

La present investigació parteix de la urgència de revisar la poesia catalana contemporània des dels paràmetres de la teoria literària que abracen l’àmbit de la representació del desig. Sota aquest paraigües teòric i la seva estricta vinculació amb les noves formulacions del subjecte líric postmodern, he proposat un estudi comparatiu entre tres grans poètiques que han marcat, cada una d’elles en el seu context socioliterari, un punt d’inflexió: Gabriel Ferrater, Maria-Mercè Marçal i Enric Casasses. Més enllà de la ruptura moderna entre escriptura i exaltació d’una subjectivitat única i monolítica, he investigat i esclarit les variables retòriques (teoria literària ) i ontològiques (discursos filosòfics) que coparticipen en la instal•lació d’un subjecte líric i un quefer poètic postmoderns. Un nou posicionament de la veu lírica que transforma la identitat textural en un procés, en una recerca. Així és que l’alteritat amorosa s’evidencia com el centre de representació i experimentació dels límits del jo líric. A partir de les aproximacions teòriques sobre la representació del desig –que des del postestructuralisme han arribat, mitjançant la crítica literària feminista, fins als nostres dies -, he establert les coordenades metodològiques que justifiquen el triangle comparatiu i m’han permès mostrar com la poesia eròticoamorosa és epicentre de la poesia i la poètica dels tres autors. L’exègesi de les seves obres ha guiat la investigació cap a l’abordatge de les construccions dels “jo” lírics, tot prenent com a centre: a) l’escriptura, obertura cap a l’Altre, b) el subjecte de l’enunciació com a subjecte desitjant, c) les representacions de l’altre/a amorós, d) les retòriques del desig, e) la recerca del plaer textual, i f)moral i poètiques. L’objectiu final ha estat dibuixar un mapa de carreteres per guiar els itineraris de l’escriptura del desig en la nostra poesia i, palesar, a mode de síntesi i d’obertura, com l’obra d’Enric Casasses recull la retòrica de l’alteritat amorosa i funda, des d’ella, la necessitat de la paraula oral i l’acció poètiques.

Plasma Elaidic Acid Level as Biomarker of Industrial Trans Fatty Acids and Risk of Weight Change: Report from the EPIC Study.

BACKGROUND Few epidemiological studies have examined the association between dietary trans fatty acids and weight gain, and the evidence remains inconsistent. The main objective of the study was to investigate the prospective association between biomarker of industrial trans fatty acids and change in weight within the large study European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS Baseline plasma fatty acid concentrations were determined in a representative EPIC sample from the 23 participating EPIC centers. A total of 1,945 individuals were followed for a median of 4.9 years to monitor weight change. The association between elaidic acid level and percent change of weight was investigated using a multinomial logistic regression model, adjusted by length of follow-up, age, energy, alcohol, smoking status, physical activity, and region. RESULTS In women, doubling elaidic acid was associated with a decreased risk of weight loss (odds ratio (OR) = 0.69, 95% confidence interval (CI) = 0.55-0.88, p = 0.002) and a trend was observed with an increased risk of weight gain during the 5-year follow-up (OR = 1.23, 95% CI = 0.97-1.56, p = 0.082) (p-trend<.0001). In men, a trend was observed for doubling elaidic acid level and risk of weight loss (OR = 0.82, 95% CI = 0.66-1.01, p = 0.062) while no significant association was found with risk of weight gain during the 5-year follow-up (OR = 1.08, 95% CI = 0.88-1.33, p = 0.454). No association was found for saturated and cis-monounsaturated fatty acids. CONCLUSIONS These data suggest that a high intake of industrial trans fatty acids may decrease the risk of weight loss, particularly in women. Prevention of obesity should consider limiting the consumption of highly processed foods, the main source of industrially-produced trans fatty acids.

Efeitos da gestão baseada em EVA® nas decisões intertemporais: um estudo com gerentes de vendas

Neste estudo, investigam-se a utilização do lucro residual para os propósitos de incentivo e a sua influência no comportamento dos gerentes, especificamente em decisões intertemporais orientadas para o longo prazo (OTLP). Por meio de um questionário respondido por 97 gerentes de vendas, atuantes em duas empresas que utilizam o EVA® para a avaliação de desempenho gerencial e organizacional, avaliou-se a importância relativa de três categorias de indicadores de avaliação de desempenho (indicador EVA®, indicadores contábil-financeiros e indicadores não financeiros) para a OTLP. Os resultados dos testes empíricos não confirmaram a hipótese de que a avaliação de desempenho baseada no EVA®, usada para os propósitos de incentivo, afeta positivamente as decisões intertemporais. Entretanto, quando analisadas de forma conjunta, as três categorias de indicadores de desempenho explicam a OTLP com significância estatística. Outro resultado relevante mostra que, quanto menor a percepção dos gerentes sobre sua avaliação de desempenho por indicadores contábil-financeiros, maior sua OTLP, o que está em consonância com a literatura.

Aspectes fonològics del català de la comarca de la Selva

En aquest treball es presenten alguns dels aspectes més destacats de la fonologia del català parlat a la comarca de la Selva. A partir de 34 entrevistes realitzades a informants de dues generacions diferents de 17 municipis selvatans, el treball descriu els trets observats i planteja també una anàlisi de la variació observada entre els diferents municipis i entre les dues franges d’edat enquestades