British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for genetic testing in epithelial ovarian cancer in the United Kingdom.

Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.

Confirmatory information seeking is robust in psychologists' diagnostic reasoning.

OBJECTIVE: Across two experiments, we examined three cognitive biases (order effects, context effects, confirmatory bias) in licensed psychologists' diagnostic reasoning. HYPOTHESES: Our main prediction was that psychologist-participants would seek confirming versus disconfirming information after forming an initial diagnostic hypothesis, even given multiple opportunities to seek new information in the same case. We also expected that individual differences would affect diagnostic reasoning, such that psychologists with lower (vs. higher) cognitive reflection tendencies and larger (vs. smaller) bias blind spots would be more likely to demonstrate confirmatory bias. METHOD: In Study 1, we recruited 149 licensed psychologists (M = 18 years of experience; 44% women; 71% White) and exposed them to one of four randomly assigned vignettes that varied order effects (one set of symptoms in reversed orders) and context effects (court referral vs. employer referral). They rank ordered a list of four possible initial diagnostic hypotheses and received a piped follow-up choice of which of two pieces of information (confirmatory or disconfirmatory) they wanted to test their initial hypothesis. Study 2 (n = 131; M = 21 years of experience; 53% men; 68% White) replicated and extended Study 1, following the same procedure except offering three sequential choice opportunities. RESULTS: Both studies found robust confirmatory information seeking: 92% sought confirmatory information in Study 1, and confirmation persisted across three opportunities in Study 2 (90%, 84%, 77%), although it lowered with each opportunity (generalized logistic mixed regression model), F(2, 378) = 3.85, p = .02, ηp² = .02. CONCLUSION: These findings expand a growing body of research on bias in expert judgment. Specifically, psychologists may engage in robust confirmation bias in the process of forming diagnoses. Although further research is needed on bias and its impact on accuracy, psychologists may need to take steps to reduce confirmatory reasoning processes, such as documenting evidence for and against each decision element. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Rethinking Health Systems Responsiveness in Low- and Middle-Income Countries: Validation Study.

BACKGROUND: Health systems responsiveness (HSR) is the ability of systems to respond to legitimate non-health expectations of the population. The concept of HSR by the World Health Organization (WHO) includes respect for dignity, individual autonomy, confidentiality, prompt attention to care, availability of basic amenities, choice of provider, access to social support networks, and clarity of communication. The WHO tool is applied globally to assess HSR in low, middle, and high-income countries. OBJECTIVE: We have revised the conceptual framework of HSR following a rigorous systematic review and made it specific for low- and middle-income countries (L&MICs). This study is designed to (1) run the Delphi technique to validate the upgraded conceptual framework of HSR, (2) modify and upgrade the WHO measurement tool for assessing HSR in the context of L&MICs, and (3) determine the validity of the upgraded HSR measurement tool by pilot testing it in Pakistan. METHODS: The Delphi technique will be run by inviting global public health experts to provide suggestions on the domains and subdomains of HSR specific to L&MICs. Cronbach ɑ will be calculated to determine internal consistency among the participants. The upgraded HSR conceptual framework will serve as a beacon to modify the measurement tool by the research team, which will be reviewed by subject experts for refinement. The modified tool will be pilot-tested by administering it to 1128 participants from primary, secondary, and tertiary care hospitals in Rawalpindi district, Pakistan. Additionally, an "observation checklist" of HSR domains and subdomains will be completed to objectively measure the state of HSR across health care facilities. HSR assessment will be further strengthened by incorporating the perspective of hospital managers, service providers, and policy makers (ie, the supply side) as well as community leaders and representatives (ie, the demand side) through qualitative interviews. RESULTS: The study was started in January 2024 and will continue until February 2025. A multidimensional approach will yield significant quantifiable information on HSR from the demand and supply sides of L&MICs. CONCLUSIONS: This study will provide a conceptual understanding of HSR and a corresponding measurement tool specific to L&MICs. It will contribute to global public health literature and provide a snapshot of HSR in Rawalpindi district, Pakistan, with concrete action points for policy makers. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/59836.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSION: Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Associations Between Oversedation and Agitation in Postanesthesia Recovery Room and Subsequent Severe Behavioral Emergencies.

OBJECTIVES: Hospital-based behavioral emergency response teams (BERT) respond to acute behavioral disturbances among hospitalized patients. We aimed to examine associations between altered mental status in postanesthesia care unit (PACU) and behavioral disturbances on surgical wards requiring BERT activation. METHODS: Electronic medical records of patients who underwent general anesthesia and were admitted to the PACU between May 2018-December 2020 were reviewed for episodes of BERT activations on surgical wards. Characteristics of BERT patients were compared with the rest of surgical population during the same period to examine risk factors for BERT. RESULTS: Of 56,275 adult surgical patients, 133 patients had 178 BERT activations (incidence 2.4, 95% confidence interval [CI] 2.0-2.8 per 1000 admissions), with 21 being for physical assault. The risk for BERT activation was increased with each decade over age of 50 as well as younger age (30 versus 50 y), male sex (odds ratio [OR] = 2.48, 95% CI 1.69, 3.62), longer procedures (OR = 1.08 per 30 minutes, 95% CI 1.05, 1.11), and alterations in mental status in PACU, with both moderate/deep sedation (OR = 1.63, 95% CI 1.04, 2.57) and agitation/combative state (OR = 8.47, 95% CI 5.13, 14.01), P < 0.001 for all comparisons. CONCLUSIONS: Early postoperative agitation and oversedation are associated with BERT activation on surgical wards. Altered mental status in PACU should be conveyed to accepting hospital units so healthcare staff can be vigilant for the potential development of behavioral disturbances.

Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation.

A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.

Outcome evaluation of prophylactic internal iliac balloon occlusion in the management of patients with placenta accreta spectrum.

PURPOSE: To evaluate outcomes and complications of prophylactic internal iliac balloon occlusion (PIIBO) in the management of patients with placenta accreta spectrum (PAS) at a large regional referral centre. MATERIALS AND METHODS: A retrospective review of all PIIBO for PAS performed over a 12-year period (2010-2022). Information for analysis was gathered from the local RIS/PACS and clinical documentation. Collected data included patient demographics, indication for procedure, sheath insertion and removal time, total duration of balloon inflation and complications that occurred. RESULTS: 106 patients underwent temporary internal iliac artery balloon occlusion within the 12-year period. All procedures utilised bilateral common femoral artery punctures, 6Fr sheath and 5Fr Le Maitre occlusion balloons. Catheters were successfully positioned and balloons inflated in obstetric theatre following caesarean delivery in 100% of the cases. The uterus was conserved in every case. There was no maternal mortality or foetal morbidity. Twenty patients (18.9%) had some form of complication that required further intervention. Of these, 7(6.6%) had post-operative PPH, which was treated with uterine artery embolisation; and 13 (12.3%) had arterial thrombus which required aspiration thrombectomy. All procedures were technically successful with no long-term sequelae. CONCLUSION: PIIBO plays an important part in reducing morbidity and mortality in patients with PAS. Clear pathways and multidisciplinary team working is critical in the management of these patients to ensure that any complications are dealt with promptly to avoid long-term sequelae.

A Proposed Systematic Approach to Safe Inter Hospital Patient Transfer in Interventional Radiology: From Referral to Repatriation.

WHAT THIS PAPER ADDS: There is no reference in the literature regarding the transfer of patients between hospitals for interventional radiology procedures. This paper outlines an approach to assist with the safe assessment, reassessment and repatriation of patients requiring urgent procedures in a different hospital.

Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: Lower rates for 5 years post chemotherapy.

PURPOSE: The identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis. METHODS: We reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1 = 541). Cumulative annual breast cancer incidence was assessed at 2, 5, 10, and >10 years after ovarian cancer diagnosis date. RESULTS: Breast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1 = 425). Incidence was lower at 2 years (1.18%) and 2 to 5 years (1.13%) but rose thereafter for BRCA1 with incidence post 10 years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple-negative breast cancer and more lower-grade hormone-receptor-positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis, <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer after ovarian cancer diagnosis were due to breast cancer. CONCLUSION: Women can be reassured that incidence of breast cancer after ovarian cancer diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Comparing survival rates and mortality in operative versus nonoperative treatment for femoral neck fractures among Alzheimer's disease patients: A retrospective cohort study.

Introduction: Addressing femoral neck fractures resulting from ground-level falls in older adults with Alzheimer's disease (AD) involves a personalized treatment plan. There is considerable ongoing debate concerning the relative advantages and disadvantages of surgical treatment (internal fixation or arthroplasty) vs nonoperative treatment for femoral neck fractures in older persons with AD. Methods: This retrospective cohort study compared the mortality, hazard ratio, and survival rate between operative and nonoperative treatments, controlling for patients' demographic information and baseline health status. The study population consisted of Optum beneficiaries diagnosed with AD who experienced an initial femoral neck fracture claim between January 1, 2012, and December 31, 2017. Kaplan-Meier survival curves were applied to compare the treatment groups' post-fracture survival rates and mortality. Cox regression was used to examine the survival period by controlling the covariates. Results: Out of the 4157 patients with AD with femoral neck fractures, 59.8% were women (n = 2487). The median age was 81 years. The 1-year survival rate for nonoperative treatment (70.19%) was lower than that for internal fixation (75.27%) and arthroplasty treatment (82.32%). Compared with the nonoperative group, arthroplasty surgical treatment had significant lower hazard risk of death (arthroplasty hazard ratio: 0.850, 95% CI: 0.728-0.991, P < 0.05). Discussion: The findings suggest that the operative treatment group experiences higher survival rates and lower mortality rates than the nonoperative group. This paper provides insights into treatment outcomes of older adults with AD receiving medical care for femoral neck fractures.

Implementing a Treatment for People with Serious Mental Illness in Jail: A Mixed-Methods Study of Stakeholder Perspectives on Feasibility and Acceptability.

People with mental illness are over-represented in the U.S. criminal legal system. Jail presents an optimal opportunity to provide needed mental health care as the entry point to corrections. However, there is a lack of programming available in jails, which may be partly due to limited understanding of how to successfully implement interventions in this complex setting. We implemented a nine-session psychotherapeutic intervention for people with serious mental illness in a county jail. As part of a larger implementation-effectiveness hybrid study, we gathered mixed-methods data from stakeholders (treatment recipients and jail administrators) on the feasibility and acceptability of the intervention's implementation. In focus group discussions and qualitative interviews, treatment recipients (n = 29) provided qualitative and quantitative data on their perceptions of the implementation's feasibility and acceptability. Jail administrators (n = 6) completed two quantitative self-report measures on their perceptions of the treatment's feasibility and acceptability. Qualitative analyses were conducted by two coders using inductive thematic template analysis; seven global themes relating to treatment recipients' perceptions of the assets and hindrances to feasibility and acceptability were developed and are presented with supporting quotations. Quantitatively, all treatment recipients endorsed the intervention's feasibility (100%), and nearly all (97%) endorsed its acceptability. On both self-report measures, jail administrators' mean scores fell above a-priori thresholds indicating feasibility and acceptability. We found qualitative and quantitative support for the use of this intervention in jail from both sets of stakeholders. These results have implications for clinical service and policy in jail, where service providers struggle to meet the considerable demand for mental health services.

DNA methylation differences between the female and male X chromosomes in human brain.

The mechanisms of X chromosome inactivation suggest fundamental epigenetic differences between the female and male X chromosomes. However, DNA methylation studies often exclude the X chromosomes. In addition, many previous studies relied on techniques that examine non-randomly selected subsets of positions such as array-based methods, rather than assessing the whole X chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Here we addressed this gap of knowledge by studying X chromosome DNA methylation using 89 whole genome bisulfite sequencing (WGBS) maps from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that DNA methylation of the female X chromosomes is globally reduced (hypomethylated) across the entire chromosome compared to the male X chromosomes and autosomes. On the other hand, the majority of X-linked promoters were more highly methylated (hypermethylated) in females compared to males, consistent with the role of DNA methylation in X chromosome inactivation and dosage compensation. Remarkably, hypermethylation of female X promoters was limited to a group of previously lowly methylated promoters. The other group of highly methylated promoters were both hyper- and hypo-methylated in females with no obvious association with gene expression. Therefore, X chromosome inactivation by DNA methylation was exclusive to a subset of promoters with distinctive epigenetic feature. Apart from this group of promoters, differentially methylated regions in the female and male X chromosomes were dominated by female hypomethylation. Our study furthers the understanding of X-chromosome dosage regulation by DNA methylation on the chromosomal level as well as on individual gene level.