BRCA tumour testing is a crucial tool for personalised therapy of patients with ovarian cancer. Since different next-generation sequencing (NGS) platforms and BRCA panels are available, the NGS Italian Network proposed to assess the robustness of different technologies.

Six centres, using four different technologies, provided raw data of 284 cases, including 75 cases with pathogenic/likely pathogenic variants, for a revision blindly performed by an external bioinformatic platform.

The third-party revision assessed that all the 284 raw data reached good quality parameters. The variant calling analysis confirmed all the 75 pathogenic/likely pathogenic variants, including challenging variants, achieving a concordance rate of 100% regardless of the panel, instrument and bioinformatic pipeline adopted. No additional variants were identified in the reanalysis of a subset of 41 cases.

BRCA tumour testing performed with different technologies in different centres, may achieve the realibility and reproducibility required for clinical diagnostic procedures.

BRCA tumour testing performed with different technologies in different centres, may achieve the realibility and reproducibility required for clinical diagnostic procedures.Ewing sarcoma is an aggressive pediatric tumor of the bone and soft tissue. The current standard of care is radiation and chemotherapy, and patients generally lack targeted therapies. One of the defining molecular features of this tumor type is the presence of significantly elevated levels of replication stress as compared with both normal cells and many other types of cancers, but the source of this stress is poorly understood. Tumors that harbor elevated levels of replication stress rely on the replication stress and DNA damage response pathways to retain viability. Understanding the source of the replication stress in Ewing sarcoma may reveal novel therapeutic targets. Ewing sarcomagenesis is complex, and in this review, we discuss the current state of our knowledge regarding elevated replication stress and the DNA damage response in Ewing sarcoma, one contributor to the disease process. SBI-477 mouse will also describe how these pathways are being successfully targeted therapeutically in other tumor types, and discuss possible novel, evidence-based therapeutic interventions in Ewing sarcoma. We hope that this consolidation will spark investigations that uncover new therapeutic targets and lead to the development of better treatment options for patients with Ewing sarcoma. IMPLICATIONS This review uncovers new therapeutic targets in Ewing sarcoma and highlights replication stress as an exploitable vulnerability across multiple cancers.

Congenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans (

,

, and

).

Genome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene.

Two patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in

(NM_001348097.1c.676C>T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in

. The second patient was homozygous for a frameshift variant (NM_001348097.1c.1294delA, p.[Thr432Profs*13]). The

gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease.

These findings strongly support the causal role of

-inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.

These findings strongly support the causal role of GFRA1-inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.This article presents a survival analysis of long-term risk of firearm-related and other violent crime in a large sample of adults with serious mental illness in Florida, comparing those who received a gun-disqualifying civil commitment after a short-term hold, those who were evaluated for commitment but were released or hospitalized voluntarily, and a third group with no holds or commitments. #link# Among 77,048 adults with a diagnosis of schizophrenia-spectrum disorder, bipolar disorder, or major depression, 42.7 percent were detained for psychiatric examination under Florida’s Baker Act; of that detained group, 8.4 percent were involuntarily committed while the remainder were released within 72 hours or agreed to voluntary admission. Over a follow-up period averaging six to seven years, 7.5 percent of the sample were arrested for a violent offense not involving a gun, and 0.9 percent were arrested for a violent crime involving a gun. A short-term hold with or without commitment was associated with a significantly higher risk of future arrest for violent crime, although the study population had other violence risk factors unrelated to mental illness. Risk of gun-involved crime, specifically, was significantly higher in individuals following a short-term hold only, but not in those who were involuntarily committed and became ineligible to purchase or possess guns. Policy implications are discussed.

In 2014, the National Institute for Health and Care Excellence (NICE) changed the recommended threshold for initiating statins from a 10-year risk of cardiovascular disease (CVD) of 20% to 10% (Clinical Guideline 181), making 4.5 million extra people eligible for treatment.

To evaluate the impact of this guideline change on statin prescribing behaviour.

A descriptive study using data from Clinical Practice Research Datalink (CPRD), a primary care database in England.

People aged 25-84 years being initiated on statins for the primary prevention of CVD were identified. CVD risk predictions were calculated for every person using data in their medical record (calculated risks), and were extracted directly from their medical record if a QRISK score was recorded (coded risks). The 10-year CVD risks of people initiated on statins in each calendar year were compared.

The average ‘calculated risk’ of all people being initiated on statins was 20.65% in the year before the guideline change, and 20.27% after. When considering only the ‘coded risks’, the average risk was 21.