Genome-wide association study of germline variants and breast cancer-specific mortality.

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.ConclusionsWe uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

La protection des cours d'eau domaniaux au moyen de la contravention de grande voirie

Lecarpentier Eric. La protection des cours d'eau domaniaux au moyen de la contravention de grande voirie. In: Revue Juridique de l'Environnement, numéro spécial, 2004. Le juge administratif et l'environnement. pp. 169-175

Formation postdoctorale en médecine d’urgence : analyse des résultats d’une enquête nationale auprès des apprenants

Contexte : L’évaluation des compétences professionnelles des futurs médecins appelés à exercer la médecine d’urgence en France est une exigence et un enjeu pédagogique. But : L’objectif de la recherche est de recueillir l’opinion des médecins sur leurs performances à l’issue de la capacité de médecine d’urgence : enseignement national d’une durée de deux ans. Méthode : L’avis des médecins titulaires du diplôme est recueilli à partir d’une enquête nationale de satisfaction, portant sur cinq années d’enseignement entre 1994 et 1999. Résultats : 520 médecins ont répondu au questionnaire. Les résultats mettent en évidence la nécessité et l’intérêt d’une formation postdoctorale en médecine d’urgence, les faiblesses de l’apprentissage et les contraintes organisationnelles. Conclusion : Les résultats plaident pour la création d’un nouveau curriculum en formation initiale et la création d’une spécialité de médecine d’urgence

Former le personnel hospitalier à agir en cas d’attentat par agent chimique : un enjeu pédagogique

Contexte : Les événements du 11 septembre 2001 à New York ont mis en exergue la possibilité d'attentats non conventionnels. La prise de conscience de la vulnérabilité et du manque de préparation des structures sanitaires a réactivé une dynamique de formation face aux risques émergents. But : L'objectif de l'article est de rapporter et d'analyser l'élaboration d'un dispositif de formation des personnels des établissements de santé en France. L'objectif de la formation est l'action des professionnels de santé face à une attaque par agents chimiques. Matériel et Méthode : Les objectifs pédagogiques ont été sélectionnés par des experts civils et militaires. Les stratégies d'enseignement et d'apprentissage ont été testées au cours de formations pilotes. Résultats : Le manque de motivation du public face à un risque peu probable, ses peurs et représentations, les contraintes de temps ont été évalués et pris en compte pour le choix des méthodes pédagogiques dominantes, techniques et outils qui servent de référentiels. Conclusion : La formation est institutionnalisée par le ministère. Un module type est proposé. Un maintien des compétences est nécessaire pour garder une cohérence entre des savoirs évolutifs et des pratiques rares

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis

International audienceOBJECTIVE:To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction.METHODS:This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks.RESULTS:Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery.CONCLUSION:Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials

Factors affecting medical file documentation during telephone triage at an emergency call centre: a cross-sectional study of out-of-hours home visits by general practitioners in France

Background: In France, general practitioners (GPs) perform out-of-hours home visits (OOH-HVs) after physician-led telephone triage at the emergency call centre. The quality of a systematic physician-led triage has not been determined in France and may affect the efficiency of the OOH-HV process. The objectives of this study were first, to evaluate the quality of reporting in the electronic patient's file after such triage and second, to analyse the factors associated with altered reporting. Methods: Cross-sectional study in a French urban emergency call centre (district of Paris area) from January to December 2015. For a random selection of 30 days, data were collected from electronic medical files that ended with an OOH-HV decision. Missing key quality criteria (medical interrogation, diagnostic hypothesis or ruled-out severity criteria) were analysed by univariate then multivariate logistic regression, adjusted on patient, temporal and organizational data. Results: Among 10,284 OOH-HVs performed in 2015, 748 medical files were selected. Reasons for the encounter were digestive tract symptoms (22%), fever (19%), ear nose and throat symptoms, and cardiovascular and respiratory problems (6% each). Medical interrogation was not reported in 2% of files (n = 16/748) and a diagnostic hypothesis in 58% (n = 432/748); ruled-out severity criteria were not reported in 60% (n = 449/748). On multivariate analysis, altered reporting was related to the work overload of triage assistants (number of incoming calls, call duration, telephone occupation rate; p < 0.03). Conclusion: In the electronic files of patients requiring an OOH-HV by a GP in a French urban area, quality in medical reporting appeared to depend on organizational factors only, especially the triage assistants-related work factors. Corrective measures are needed to ensure good quality of triage and care