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Mutations in the BRCA1 and BRCA2 genes increase the risk for various cancers including breast, ovarian, prostate, pancreas and melanoma. Identifying BRCA1/2 mutation carriers enables risk assessment, surveillance, early detection and risk reduction. In certain Israeli sub-populations recurring and founder mutations have been identified and for these, testing for founder mutations is simple, efficient and cost-effective. Founder mutations in the Jewish Ethiopian population have not been described. We report here the identification of a recurring BRCA2 mutation in the Ethiopian Jewish population; c.5159C>A; p.Ser1720Ter, which has only been described once before in this population. In addition, in another family of the same origin we found the BRCA2 c.7579delG; p.Val2527Ter mutation that has been previously described in two different Jewish Ethiopian families. In Israel genetic testing is performed in a sequential stepwise manner, first testing a panel of predominant mutations and if negative further testing by gene sequencing is offered. Recently it has been decided to expand the founder mutation panel to include mutations which have been found in two or more separate families. This new panel will include the BRCA2 c.7579delG; p.Val2527Ter mutation, and we recommend that the BRCA2 c.5159C>A; p.Ser1720Ter mutation should also be added to the new predominant mutation panel.

Purpose While the spectrum of germline mutations in BRCA1/2 genes in the Israeli Jewish population has been extensively studied, there is a paucity of data pertaining to Israeli Arab high-risk cases. Methods Consecutive Israeli Arab breast and/or ovarian cancer patients were recruited using an ethically approved protocol from January 2012 to February 2019. All ovarian cancer cases were referred for BRCA genotyping. Breast cancer patients were offered BRCA sequencing and deletion/duplication analysis after genetic counseling, if the calculated risk for carrying a BRCA mutation by risk prediction algorithms was ≥10%. Results Overall, 188 patients participated; 150 breast cancer cases (median age at diagnosis: 40 years, range 22–67) and 38 had ovarian cancer (median age at diagnosis: 52.5 years, range 26–79). Of genotyped cases, 18 (10%) carried one of 12 pathogenic or likely-pathogenic variants, 12 in BRCA1, 6 in BRCA2 . Only one was a rearrangement. Three variants recurred in more than one case; one was detected in five seemingly unrelated families. The detection rate for all breast cancer cases was 4%, 5% in bilateral breast cancer cases and 3% if breast cancer was diagnosed < 40 years. Of patients with ovarian cancer, 12/38 (32%) were carriers; the detection rate reached 75% (3/4) among patients diagnosed with both breast and ovarian cancer. Conclusions The overall yield of comprehensive BRCA1/2 testing in high-risk Israeli Arab individuals is low in breast cancer patients, and much higher in ovarian cancer patients. These results may guide optimal cancer susceptibility testing strategy in the Arab–Israeli population.

Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V mutation, a mutation previously reported but not further characterised. We have introduced this mutation into an arylsulphatase A expression vector by site directed mutagenesis. Transient expression of this mutant plasmid in COS cells yields very low levels of arylsulphatase A activity consistent with the patient's phenotype. The arylsulphatase A pseudodeficiency also segregates in this family causing difficulty in interpreting enzyme levels in the absence of DNA data. Two other patients from the same province, also carrying the A212V allele, have juvenile and adult onset MLD and are heterozygous for P426L (\"A\" allele) and I179S alleles respectively, known late onset alleles.

Many patients have iliofemoral vessel anatomy unsuitable for conventional transfemoral (TF) transcatheter aortic valve implantation (TAVI). Safe and practical alternatives to the TF approach are, therefore, needed. This study compared outcomes of alternative nonfemoral routes, transapical (TA), direct aortic (DA), and subclavian (SC), with standard femoral access. In this retrospective study, data from 3,962 patients in the UK TAVI registry were analyzed. All patients who received TAVI through a femoral, subclavian, TA, or DA approach were eligible for inclusion. The primary outcome measure was survival up to 2 years. Median Logistic EuroSCORE was similar for SC, DA, and TA but significantly lower in the TF cohort (22.1% vs 20.3% vs 21.2% vs 17.0%, respectively, p <0.0001). Estimated 1-year survival rate was similar for TF (84.6 ± 0.7%) and SC (80.5 ± 3%, p = 0.27) but significantly worse for TA (74.7 ± 1.6%, p <0.001) and DA (75.2 ± 3.3%, p <0.001). A Cox proportional hazard model was used to analyze survival up to 2 years. Survival in the SC group was not significantly different from the TF group (hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.88 to 1.70, p = 0.24). In contrast, survival in the TA (HR 1.74, 95% CI 1.43 to 2.11; p <0.001) and DA (HR 1.55, 95% CI 1.13 to 2.14; p <0.01) cohorts was significantly reduced compared with TF. In conclusion, TA and DA TAVI were associated with similar survival, both significantly worse than with the TF route. In contrast, subclavian access was not significantly different from TF and may represent the safest nonfemoral access route for TAVI.

Co-morbidities have typically been considered as prevalent cardiovascular risk factors and cardiovascular diseases rather than systematic measures of general co-morbidity burden in patients who underwent percutaneous coronary intervention (PCI). Charlson co-morbidity index (CCI) is a measure of co-morbidity burden providing a means of quantifying the prognostic impact of 22 co-morbid conditions on the basis of their number and prognostic impact. The study evaluated the impact of the CCI on cardiac mortality and major adverse cardiovascular events (MACE) after PCI through analysis of the Nobori-2 study. The prognostic impact of CCI was studied in 3,067 patients who underwent PCI in 4,479 lesions across 125 centers worldwide on 30-day and 1- and 5-year cardiac mortality and MACE. Data were adjusted for potential confounders using stepwise logistic regression; 2,280 of 3,067 patients (74.4%) had ≥1 co-morbid conditions. CCI (per unit increase) was independently associated with an increase in both cardiac death (odds ratio [OR] 1.47 95% confidence interval [CI] 1.20 to 1.80, p = 0.0002) and MACE (OR 1.29 95% CI 1.14 to 1.47, p ≤0.0011) at 30 days, with similar observations recorded at 1 and 5 years. CCI score ≥2 was independently associated with increased 30-day cardiac death (OR 4.25, 95% CI 1.24 to 14.56, p = 0.02) at 1 month, and this increased risk was also observed at 1 and 5 years. In conclusion, co-morbid burden, as measured using CCI, is an independent predictor of adverse outcomes in the short, medium, and long term. Co-morbidity should be considered in the decision-making process when counseling patients regarding the periprocedural risks associated with PCI, in conjunction with traditional risk factors.

Gender is a strong predictor of periprocedural major bleeding complications after percutaneous coronary intervention (PCI). The access site represents an important site of such bleeding complications, which has driven adoption of the transradial access (TRA) use during PCI, although female gender is an independent predictor of transradial PCI failure. This study sought to define gender differences in access site practice and study associations between access site choice and clinical outcomes for PCI over a 6-year period, through the analysis of the British Cardiovascular Intervention Society observational database. In-hospital major adverse cardiovascular events (a composite of in-hospital mortality and in-hospital myocardial reinfarction and target vessel revascularization), in-hospital bleeding complications, and 30-day mortality were studied based on gender and access site choice (transfemoral access, TRA) in 412,122 patients who underwent PCI between 2007 and 2012 in the United Kingdom. Use of TRA increased in both genders over time, although this lagged behind in women (21% in 2007 to 58% in 2012) compared with men (24% in 2007 to 64% in 2012). In both men and women, TRA was independently associated with a lower in-hospital major adverse cardiovascular event (odds ratio [OR] 0.82, 95% CI 0.76-0.90; OR 0.75, 95% CI 0.66-0.84), in-hospital major bleeding (OR 0.54, 95% CI 0.44-0.66; OR 0.26, 95% CI 0.20-0.33), and 30-day mortality (OR 0.80, 95% CI 0.73-0.89; OR 0.82, 95% CI 0.71-0.94), respectively. Where possible, TRA should be considered as the preferred access site choice for PCI, particularly in women in whom the greatest reductions bleeding end points were observed across all indications.

The performance of emerging transcatheter aortic valve implantation (TAVI) clinical prediction models (CPMs) in national TAVI cohorts distinct from those where they have been derived is unknown. This study aimed to investigate the performance of the German Aortic Valve, FRANCE-2, OBSERVANT and American College of Cardiology (ACC) TAVI CPMs compared with the performance of historic cardiac CPMs such as the EuroSCORE and STS-PROM, in a large national TAVI registry. The calibration and discrimination of each CPM were analyzed in 6676 patients from the UK TAVI registry, as a whole cohort and across several subgroups. Strata included gender, diabetes status, access route, and valve type. Furthermore, the amount of agreement in risk classification between each of the considered CPMs was analyzed at an individual patient level. The observed 30-day mortality rate was 5.4%. In the whole cohort, the majority of CPMs over-estimated the risk of 30-day mortality, although the mean ACC score (5.2%) approximately matched the observed mortality rate. The areas under ROC curve were between 0.57 for OBSERVANT and 0.64 for ACC. Risk classification agreement was low across all models, with Fleiss's kappa values between 0.17 and 0.50. Although the FRANCE-2 and ACC models outperformed all other CPMs, the performance of current TAVI-CPMs was low when applied to an independent cohort of TAVI patients. Hence, TAVI specific CPMs need to be derived outside populations previously used for model derivation, either by adapting existing CPMs or developing new risk scores in large national registries.

Objective To determine the nature of the association between renal dysfunction and outcomes following transcatheter aortic valve implantation (TAVI) in all cases performed in the UK between 2007 and 2012. Methods The UK TAVI registry was established to report outcomes on all TAVI procedures performed within the UK. Data were collected prospectively on 3980 patients from 1 January 2007 until 31 December 2012. Results In total, 205 patients (5.5%) died during their admission. Moderate to advanced chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2) was significantly associated with increased mortality, even after adjustment for risk factors (OR 1.45, 95% CI 1.03 to 2.05; p=0.04). For every 10 mL/min/1.73 m2 decrease in eGFR, in-hospital mortality increased by 8.2% (95% CI 1.1% to 14.7%; p=0.03). In total 1119 patients (30.2%) died during the follow-up period (median 543 days). Moderate to advanced CKD (eGFR <45 mL/min/1.73 m2) was significantly associated with increased mortality, even after adjustment for risk factors (OR 1.36, 95% CI 1.17 to 1.58; p<0.001). For every 10 mL/min/1.73 m2 decrease in eGFR, cumulative mortality increased by 4.4% (95% CI 1.2% to 7.5%; p=0.007). Preoperative kidney function and the need for preoperative dialysis treatment discriminated between patients who died and survived. However, predictive power was poor with none of the c-statistics being >0.6. Conclusions Pre-procedural renal dysfunction is associated, in a graded fashion independently of dialysis status, with worse outcomes, including mortality in patients undergoing TAVI.

Mark Samuels and colleagues report the identification of mutations in mitochondrial carrier family member SLC25A38 in nonsyndromic autosomal recessive congenital sideroblastic anemia. The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts—bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, we define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes.

ObjectiveTo define the incidence and risk factors for infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI).MethodsAll patients who underwent first SAVR or TAVI in England between 2007 and 2016 were identified from the NICOR databases. Hospital admissions with a primary diagnosis of IE were identified by linkage with the NHS Hospital Episode Statistics database. Approval was obtained from the NHS Research Ethics Committee.Results2057 of 91 962 patients undergoing SAVR developed IE over a median follow-up of 53.9 months—an overall incidence of 4.81 [95% CI 4.61 to 5.03] per 1000 person-years. Correspondingly, 140 of 14 195 patients undergoing TAVI developed IE over a median follow-up of 24.5 months—an overall incidence of 3.57 [95% CI 3.00 to 4.21] per 1000 person-years. The cumulative incidence of IE at 60 months was higher after SAVR than after TAVI (2.4% [95% CI 2.3 to 2.5] vs 1.5% [95% CI 1.3 to 1.8], HR 1.60, p<0.001). Across the entire cohort, SAVR remained an independent predictor of IE after multivariable adjustment. Risk factors for IE included younger age, male sex, atrial fibrillation, and dialysis.ConclusionsIE is a rare complication of SAVR and TAVI. In our population, the incidence of IE was higher after SAVR than after TAVI.