Gestion des appels d'urgence routiers : contexte et perspectives d'évolution

Face à la diversification des moyens d'appels à disposition des usagers de la route en détresse, se pose la question de l'évolution du RAU (réseau d'appels d'urgence), équipement routier dédié aux urgences. Pour l'évaluer ce document présente :Le diagnostic de fonctionnement du RAU et des appels d'urgence au travers des aspects techniques(RAU, téléphonie mobile. . .), de l'organisation des centres d'appels d'urgence, de l'acheminements des appels, d'enquêtes auprès des acteurs et des usagers.Le fonctionnement dans quatre pays européens, synthèse d'une étude faite en Allemagne,Grande-Bretagne, Italie, Hollande.Une corrélation accidents, appels d'urgence : croisement géographique de l'implantation des PAU sur RN avec des données accidents.Des perspectives d'évolutions sur le plan technique, sur l'organisation et l'acheminement des appels.Une synthèse de propositions et de suites à donner

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Gestion des appels d'urgence routiers : contexte et perspectives d'évolution

Face à la diversification des moyens d'appels à disposition des usagers de la route en détresse, se pose la question de l'évolution du RAU (réseau d'appels d'urgence), équipement routier dédié aux urgences. Pour l'évaluer ce document présente :Le diagnostic de fonctionnement du RAU et des appels d'urgence au travers des aspects techniques(RAU, téléphonie mobile. . .), de l'organisation des centres d'appels d'urgence, de l'acheminements des appels, d'enquêtes auprès des acteurs et des usagers.Le fonctionnement dans quatre pays européens, synthèse d'une étude faite en Allemagne,Grande-Bretagne, Italie, Hollande.Une corrélation accidents, appels d'urgence : croisement géographique de l'implantation des PAU sur RN avec des données accidents.Des perspectives d'évolutions sur le plan technique, sur l'organisation et l'acheminement des appels.Une synthèse de propositions et de suites à donner

Gestion des appels d'urgence routiers : contexte et perspectives d'évolution

Face à la diversification des moyens d'appels à disposition des usagers de la route en détresse, se pose la question de l'évolution du RAU (réseau d'appels d'urgence), équipement routier dédié aux urgences. Pour l'évaluer ce document présente :Le diagnostic de fonctionnement du RAU et des appels d'urgence au travers des aspects techniques(RAU, téléphonie mobile. . .), de l'organisation des centres d'appels d'urgence, de l'acheminements des appels, d'enquêtes auprès des acteurs et des usagers.Le fonctionnement dans quatre pays européens, synthèse d'une étude faite en Allemagne,Grande-Bretagne, Italie, Hollande.Une corrélation accidents, appels d'urgence : croisement géographique de l'implantation des PAU sur RN avec des données accidents.Des perspectives d'évolutions sur le plan technique, sur l'organisation et l'acheminement des appels.Une synthèse de propositions et de suites à donner

Gestion des appels d'urgence routiers : contexte et perspectives d'évolution

Face à la diversification des moyens d'appels à disposition des usagers de la route en détresse, se pose la question de l'évolution du RAU (réseau d'appels d'urgence), équipement routier dédié aux urgences. Pour l'évaluer ce document présente : Le diagnostic de fonctionnement du RAU et des appels d'urgence au travers des aspects techniques (RAU, téléphonie mobile. . .), de l'organisation des centres d'appels d'urgence, de l'acheminements des appels, d'enquêtes auprès des acteurs et des usagers. Le fonctionnement dans quatre pays européens, synthèse d'une étude faite en Allemagne, Grande-Bretagne, Italie, Hollande. Une corrélation accidents, appels d'urgence : croisement géographique de l'implantation des PAU sur RN avec des données accidents. Des perspectives d'évolutions sur le plan technique, sur l'organisation et l'acheminement des appels. Une synthèse de propositions et de suites à donner.56 pages, figures, tableaux, 13 références bibliographique

Gestion des appels d'urgence routiers Contexte et perspectives d'evolution

Available from INIST (FR), Document Supply Service, under shelf-number : RL 392 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc