Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Real-time exhaled breath analysis in patients with cystic fibrosis and controls

ISSN:1752-7155ISSN:1752-716

Real-time exhaled breath analysis in patients with cystic fibrosis and controls

We aimed at defining profiles of volatile organic compounds in exhaled breath from patients with cystic fibrosis (CF) using a novel real-time mass spectrometry technique. In this prospective matched case-control study, 30 patients with CF, and 30 healthy control subjects were matched one-to-one according to age, gender, and smoking state. We performed exhaled breath analysis by untargeted secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS). Patients with CF (mean age 26.0 ± 13.0 years) and controls (mean age 27.9 ± 14.0 years) were analyzed using SESI-HRMS. 49 exhaled breath features were found to be altered (p-value < 0.05/q-value < 0.1) in CF patients, in comparison to healthy controls. The two most discriminating features showed a prediction AUROC of 77.1% (95% CI 62.2%-87.8%) with a specificity of 80.0% and a sensitivity of 63.3%. Levels of oxidative stress metabolites such as fatty acids were found to differ significantly between patients with CF and healthy controls. Furthermore, in patients with CF, 11 features correlated with the mucus concentration of Stenotrophomonas maltophilia bacteria. Exhaled breath analysis with SESI-HRMS allows the identification of CF specific compounds in real-time and may trace bacterial strains in affected patients with CF

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I 2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Mapping of the 17q21 locus.

<p><i>Top 3 panels:</i> P-values of association (−log₁₀ scale) with ovarian cancer risk for genotyped and imputed SNPs (1000 Genomes Project CEU), by chromosome position (b.37) at the 17q21 region, for <i>BRCA1</i>, <i>BRCA2</i> mutation carriers and combined. Results based on the kinship-adjusted score test statistic (1 d.f.). <i>Fourth panel:</i> Genes in the region spanning (43.4–44.9 Mb, b.37) and the location of the most significant genotyped SNPs (in red font) and imputed SNPs (in black font). <i>Bottom panel:</i> Pairwise r² values for genotyped SNPs on iCOG array in the 17q21 region covering positions (43.4–44.9 Mb, b.37).</p