Birmingham Women's Hospital is a women's hospital which is located directly opposite The Queen Elizabeth Hospital in Birmingham, England. It is managed by Birmingham Women's and Children's NHS Foundation Trust.
BACKGROUND:Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination. The objective of this study was to investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who had received a vaginal cervical cerclage. METHODS AND FINDINGS:This is a secondary post-hoc analysis of women recruited to the C-STICH randomised controlled trial, which recruited in 75 obstetric units in the UK between 2015 and 2021. In the C-STICH trial, women with a singleton pregnancy, receiving a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were randomised to cerclage with braided or monofilament suture, with a primary outcome of pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life. In this secondary analysis, the primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes, and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for prespecified prognostic variables. From the 2,048 women recruited to C-STICH, 1943 (95%) women had a vaginal cerclage placed and available progesterone data. Of these, 834 (43%) women received progesterone and 1,109 (57%) did not receive progesterone. In women with primary outcome data available, in our predefined analysis pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1,103 women who did not receive progesterone (adjusted* risk ratio 0.70 (95% confidence interval (CI) [0.50, 0.99]); adjusted risk difference -0.02 (95% CI [-0.04, -0.001], *adjusted for indication, obstetric history, surgical technique, and maternal age). Further exploratory analysis excluding women who had termination of pregnancy for foetal anomaly demonstrated a nonsignificant reduction in the risk of pregnancy loss. Key limitations of this study include a nonrandomised trial design and unknown confounding relating to variation in progesterone use. CONCLUSION:In women with a vaginal cervical cerclage and concomitant progesterone there appears to be an association with a reduced risk of pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high-risk cohort.
BACKGROUND AND OBJECTIVE:BRCA1 and BRCA2 pathogenic germline variants (PGVs) are associated with higher risk of prostate cancer (PC). The IMPACT study evaluated the utility of targeted prostate-specific antigen (PSA) screening in BRCA1/BRCA2 PGV carriers. Here we report outcomes after five rounds of PSA screening in IMPACT. METHODS:Between 2005 and 2015, 3063 participants aged 40-69 yr (median 54 yr) were recruited from 65 centres in 20 countries in two cohorts: (1) BRCA1/BRCA2 PGV carriers (915 BRCA1, 901 BRCA2); and (2) age-matched noncarriers for a familial PGV (727 BRCA1 and 520 BRCA2 noncarriers). Annual PSA screening was performed, with PSA >3.0 ng/ml used as the indication for prostate biopsy. Our aim was to identify differences by PGV status in (1) the incidence of PC and of clinically significant PC (csPC; grade group ≥2) and (2) tumour stage and characteristics after five screening rounds. KEY FINDINGS AND LIMITATIONS:There was no statistically significant difference in PC incidence between BRCA1/BRCA2 PGV carriers and noncarriers. csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017). There were no T4 or metastatic PC cases. Pathology after radical prostatectomy revealed tumour upgrading for 7/23 (26%) BRCA1 PGV carriers and 10/34 (26%) BRCA2 PGV carriers, with no tumour upgrading for men without PGVs. Study limitations include the biopsy compliance rate and changes in PC diagnostic pathways since 2005. CONCLUSIONS AND CLINICAL IMPLICATIONS:Annual PSA screening in BRCA2 PGV carriers confirmed a higher incidence of csPC and detection of clinically relevant tumours in comparison to noncarriers. For the first time, we confirm that PSA screening in BRCA1 PGV carriers results in early detection of NCCN IR-U/HR PC. Systematic PSA screening is recommended for BRCA2 PGV carriers and should be considered for BRCA1 PGV carriers.
Background Establishing best practice recommendations helps to increase consistency, equity and innovation in clinical genomics services. Bioinformatics approaches are a core component of clinical genomics services that use high-throughput genomic sequencing applied in the diagnosis of rare disorders and cancer. While a broad range of international recommendations exist for genomic diagnostic testing and genetic variant classification, the current UK-specific best practice recommendations for bioinformatics approaches applied in this context are outdated. Methods We assembled a team of bioinformaticians and scientists with diverse expertise in rare disease and cancer genomics applied in clinical diagnostics within the UK National Health Service. Through structured discussion, polls and surveys, we developed an updated set of best practice recommendations for bioinformatics approaches applied to high-throughput genomic sequencing in clinical genomic testing. Results We provide best practice recommendations across the spectrum of activities within a clinical genomics bioinformatics pipeline, including quality control, primary, secondary and tertiary analysis approaches and shared knowledge bases. We also comment on issues related to software development and maintenance. The recommendations can be applied to multiple sequencing technologies and encompass both targeted and whole genome sequencing approaches applied to germline and tumour DNA samples. Conclusion The best practice recommendations outlined in this study provide a national framework for adoption and innovation of bioinformatics approaches across diverse clinical genomic testing strategies in the UK National Health Service.
Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.
