Effect of ventilator-associated tracheobronchitis on outcome in patients without chronic respiratory failure: a case–control study

INTRODUCTION: Our objective was to determine the effect of ventilator-associated tracheobronchitis (VAT) on outcome in patients without chronic respiratory failure. METHODS: This was a retrospective observational matched study, conducted in a 30-bed intensive care unit (ICU). All immunocompetent, nontrauma, ventilated patients without chronic respiratory failure admitted over a 6.5-year period were included. Data were collected prospectively. Patients with nosocomial pneumonia, either before or after VAT, were excluded. Only first episodes of VAT occurring more than 48 hours after initiation of mechanical ventilation were studied. Six criteria were used to match cases with controls, including duration of mechanical ventilation before VAT. Cases were compared with controls using McNemar's test and Wilcoxon signed-rank test for qualitative and quantitative variables, respectively. Variables associated with a duration of mechanical ventilation longer than median were identified using univariate and multivariate analyses. RESULTS: Using the six criteria, it was possible to match 55 (87%) of the VAT patients (cases) with non-VAT patients (controls). Pseudomonas aeruginosa was the most frequently isolated bacteria (34%). Although mortality rates were similar between cases and controls (29% versus 36%; P = 0.29), the median duration of mechanical ventilation (17 days [range 3–95 days] versus 8 [3–61 days]; P < 0.001) and ICU stay (24 days [range 5–95 days] versus 12 [4–74] days; P < 0.001) were longer in cases than in controls. Renal failure (odds ratio [OR] = 4.9, 95% confidence interval [CI] = 1.6–14.6; P = 0.004), tracheostomy (OR = 4, 95% CI = 1.1–14.5; P = 0.032), and VAT (OR = 3.5, 95% CI = 1.5–8.3; P = 0.004) were independently associated with duration of mechanical ventilation longer than median. CONCLUSION: VAT is associated with longer durations of mechanical ventilation and ICU stay in patients not suffering from chronic respiratory failure

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

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

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

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

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

Insuffisances rénales aiguës traitées par hémodiafiltration en réanimation (épidémiologie et facteurs pronostics : à propos de 197 patients)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France

International audienceHereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3-1103+8del activated a cryptic splice site 22 bp upstream, and c. 1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112-1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhone-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot